Gasotransmitters in the tumor microenvironment: Impacts on cancer chemotherapy (Review)

Salihi,Abbas; Al‑Naqshabandi,Mohammed A.; Khudhur,Zhikal Omar; Housein,Zjwan; Hama,Harmand A.; Abdullah,Ramyar M.; Hussen,Bashdar Mahmud; Alkasalias,Twana

doi:10.3892/mmr.2022.12749

Gasotransmitters in the tumor microenvironment: Impacts on cancer chemotherapy (Review)

Authors:
- Abbas Salihi
- Mohammed A. Al‑Naqshabandi
- Zhikal Omar Khudhur
- Zjwan Housein
- Harmand A. Hama
- Ramyar M. Abdullah
- Bashdar Mahmud Hussen
- Twana Alkasalias
View Affiliations

Affiliations: Department of Biology, College of Science, Salahaddin University‑Erbil, Erbil, Kurdistan Region 44001, Iraq, Department of Clinical Biochemistry, College of Health Sciences, Hawler Medical University, Erbil, Kurdistan Region 44001, Iraq, Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Kurdistan Region 44001, Iraq, Department of Medical Laboratory Technology, Technical Health and Medical College, Erbil Polytechnique University, Erbil, Kurdistan Region 44002, Iraq, Department of Biology, Faculty of Education, Tishk International University, Erbil, Kurdistan Region 44002, Iraq, College of Medicine, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq, Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq, General Directorate of Scientific Research Center, Salahaddin University‑Erbil, Erbil, Kurdistan Region 44002, Iraq
Published online on: May 25, 2022 https://doi.org/10.3892/mmr.2022.12749
Article Number: 233
Copyright: © Salihi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Nitric oxide, carbon monoxide and hydrogen sulfide are three endogenous gasotransmitters that serve a role in regulating normal and pathological cellular activities. They can stimulate or inhibit cancer cell proliferation and invasion, as well as interfere with cancer cell responses to drug treatments. Understanding the molecular pathways governing the interactions between these gases and the tumor microenvironment can be utilized for the identification of a novel technique to disrupt cancer cell interactions and may contribute to the conception of effective and safe cancer therapy strategies. The present review discusses the effects of these gases in modulating the action of chemotherapies, as well as prospective pharmacological and therapeutic interfering approaches. A deeper knowledge of the mechanisms that underpin the cellular and pharmacological effects, as well as interactions, of each of the three gases could pave the way for therapeutic treatments and translational research.

Introduction

Cancer is one of the most dreaded diseases and is a major threat to human life. Among different clinical disorders, cancer is the second most common cause of death after cardiovascular diseases (1). Different approaches and strategies, such as chemotherapy, radiotherapy, surgery, immunotherapy and small molecule-targeted therapy, have been studied and applied to target and treat cancer (2,3).

Chemotherapeutic drugs work by targeting fast-growing and proliferating cells, leading to cell death and shrinking of the tumors. The conventional cancer chemotherapy, ‘the standard treatment’, is not always successful, even after 50–100 years of research and clinical experience, although cases of lymphocytic leukemia and Hodgkin's lymphoma have been treated successfully in this manner (1). Conventional chemotherapy indiscriminately delivers the toxic anticancer agent to tumors and normal tissues simultaneously (4). Therefore, cancer-selective drug delivery approaches are required to avoid undesirable systemic side effects. One way of tackling these problems is to deliver anticancer drugs selectively to the tumor site (5). One of the different approaches is using gasotransmitters to selectively provide anticancer drugs to the tumor site (6).

The three small, diffusible gaseous mediators nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) serve multiple roles in normal physiology and the pathogenesis of numerous diseases. Several studies have emphasized the roles of NO, CO and H2S in cancer (7–10); however, there are numerous puzzles and controversies. Some studies have demonstrated that these mediators are pro-tumorigenic, while others have reported that they have an antitumorigenic effect (11–13). It is now recognized that these three gases exhibit bell-shaped (also termed ‘biphasic’, ‘bimodal’ or ‘Janus-faced’) pharmacological characteristics in cancer (6). An improved understanding of the complicated pharmacological nature of these mediators has far-reaching consequences. It also tackles some of the difficulties of the field, enabling the development of novel therapeutic techniques based on pharmacologically suppressing mediator production (6). The present review discusses the important roles of NO, CO and H2S in tumor pathophysiology, addressing how different levels of these gases can affect tumor growth, angiogenesis and survival. Furthermore, it highlights the potential therapeutic value of the gasotransmitters in cancer chemotherapy.

Chemotherapy

History of chemotherapy

The use of chemicals to treat a disease is called chemotherapy. This therapeutic model was conceptually born in the early 20th century when the German physician Paul Ehrlich adopted chemicals to treat infectious diseases (14,15). Ehrlich stepped into the field of oncology with great ambition, trying to explore de novo pharmacological bullets to shoot cancer cells (16). The net findings of all his experiments were disappointing since none of the proposed drugs worked on cancer cells (17).

Cancer chemotherapy remained indistinct for >30 years, and scientists continued to follow Ehlrich's fishing strategy after his death. Certain researchers studied the effect of mustard gas or its derivatives on bone marrow eradication; an idea that was obtained from using the gases during the First World War (18,19). Others, such as Sidney Farber, used anti-folates, such as aminopterin and 6-mercaptopurine, to treat childhood cancers (20). In 1950, 6-mercaptopurine was selected for a clinical trial investigating the treatment of acute lymphatic leukemia in children. Despite the promising initial results leading to cancer remission, all investigated chemicals had significant adverse effects indicated by quick relapse a few weeks after treatment (21). The chemotherapeutic drug screening mission was continued. By 1964, ~215,000 chemicals, plant derivatives and fermentation products were studied, and several million mice were included in these studies (22). The challenges encountered in the discovery and delivery of the proper anticancer chemotherapeutics were developing a convenient model to reduce the vast repertoire of chemicals into a considerable list that could have efficiency against cancer, obtaining suitable funds to support the suggested studies and treatment modalities, and admission to clinical facilities to examine the impact of the selected substances. Therefore, different organizations, funding agencies and research centers were established to support scientists and oncologists economically, in order to defeat cancer.

After all these chemotherapeutic screening failures, scientists turned the view back, asking what makes cancer cells switch their response to treatment from sensitive to resistant. Scientists examined if it would be better to employ dual chemotherapy rather than the conventional monotherapy approach used, and this idea of using multiple chemical combinations immediately appeared promising. Freireich et al (23) were the first scientists who combined a four-drug regime (vincristine, amethopterin, mercaptopurine and prednisone) to treat leukemia in children. Despite full cancer remission for several months, they observed severe brain metastasis and death, and thus, stopped this chemotherapeutic regimen. The outcome of tetra-combinatorial therapeutic approaches, including mechlorethamine, oncovin, procarbazine and prednisone (MOPP), and mechlorethamine, oncovin, methotrexate and prednisone, in treating Hodgkin's diseases was surprising, as the complete remission rate increased to 80% in the USA (24). Furthermore, ~60% of patients with Hodgkin's treated with MOPP never relapsed (25). MOPP, ‘the miracle’, made the concept of cancer curability possible. Indications from combination chemotherapies in treating certain types of advanced hematological malignancies motivated scientists to consider a similar therapeutic regime for solid tumors; however, the primary method for treating solid tumors was surgery (26). By the early 1970s, the adjuvant chemotherapy approach was introduced, where chemotherapy was used after surgery to target microscopic tumors and reduce cancer recurrence (26). Bonadonna et al (27) introduced the first combinational chemotherapeutic-postoperative approach, called cyclophosphamide, methotrexate, fluorouracil-adjuvant therapy, to treat early-stage breast cancer in women. The concept of combinational adjuvant chemotherapy was popular in the USA. Fisher et al (28) examined L-phenylalanine mustard to target breast cancer and other solid tumors, such as colorectal cancer. Depending on the type and size of the tumor, an additional approach, called neoadjuvant chemotherapy, is currently used. In this approach, chemotherapy is applied before the surgery or the primary therapy (29).

Most, if not all, solid tumors acquire drug resistance after a few cycles of chemotherapy, and thus, an efficient chemotherapeutic approach has not been developed yet. This is mainly due to dynamic phenotypic and genotypic changes in cancer cells and their surrounding microenvironment. Despite the common non-curative effect of chemotherapy, the disease progression-free survival curves have been markedly improved (30). Any effective therapeutic approach requires systematic knowledge regarding the drug's mechanism of action, primary pharmacologic metabolites, the differences in pharmacokinetics and pharmacodynamics, and the behavior of cancer cells and their crosstalk with the tumor microenvironment (TME) (31). This knowledge has markedly progressed during the last 20–30 years upon the emergence of novel technical avenues in genomic and proteomic analysis. As a result, novel treatment modalities, such as immunotherapy and targeted therapy, have been introduced and suggested to be applied either separately or in combination with chemotherapy.

Mechanism of action and classification of chemotherapy

Chemotherapeutic drugs are clustered into subgroups according to their structure and overall mechanisms of action. Each subgroup is subdivided into several cytostatic drugs, which are used to treat different types of cancer (32). Table SI lists the most prominent types of drugs, their mechanism of action, the targeted cancer types and the number of clinical trials for each drug.

Microenvironment and chemotherapy

In non-hematological malignancy, a tumor is a disorganized, miscommunicated aberrant tissue, where tumor cells are surrounded by stroma and they all interact unsystematically within one unit. The stroma consists of cellular and non-cellular compartments, and altogether they are referred to as the TME. The TME is made up of different types of cells, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), different sub-types of anti- and pro-inflammatory immune cells, adipocytes and tumor-associated vasculature (endothelial cells and pericytes), and extracellular matrix (ECM) (33). These compartments interact with each other and with tumor cells, initiating various biochemical and cellular signals, which drive cancer cell proliferation, invasion and the response to treatment (34). Chemotherapy eliminates and reduces tumor growth primarily, whereas a small population of cancer cells shift their survival machinery and do not respond to the treatment, as they become more aggressive cells, which serve as the source of relapse. The TME has the potential to drive the anti-chemotherapeutic effect of cancer cells by interfering with different survival mechanisms and cellular signaling pathways (35). This is evident in different types of cancer, such as breast and ovarian cancer, in which enriched TME signatures associated with a treatment-resistant phenotype are observed (34). Among the different signatures, the hypoxic nature of the TME decreases the proliferation rate and induces survival of cancer cells, thus reducing their response to chemotherapy (36–38). The hypoxic TME triggers angiogenic switch by inducing aberrant blood vessel formation in cancer, and due to the leaky properties of cancer-associated vasculature, the drugs that circulate in the blood will not be delivered efficiently to the core of the tumor (39,40). Additionally, the pharmacokinetic action of certain chemotherapeutic drugs depends on the availability of free radicals. Therefore, the cytotoxic activity of those drugs is reduced in the absence or presence of low oxygen (O2) levels (40,41).

The architecture of the TME, characterized by its phenotypic plasticity and heterogenic properties, is essential to allow or prevent drug delivery to the tumor (42). The reorganization of the ECM due to the interaction of cancer cells with CAFs and TAMs leads to drug sequestration, preventing them from reaching the cancer cells (34,43,44).

Gasotransmitters

In the last decades, three gaseous molecules have been identified as gasotransmitters: NO, CO and H2S. These particular gases are similar to each other in their production and function, but exert their functions in unique ways in the human body (45). NO is produced endogenously in endothelial cells from L-Arg by a family of enzymes, called NO synthases (NOS), in the vasculature, which modulates vascular tone by activating soluble guanylyl cyclase (sGC) enzyme and producing cyclic GMP (46). Endogenous CO is produced by the enzyme heme oxygenase (HO), which converts free heme to biliverdin (47). CO has a vasorelaxant and an antiproliferative action on vascular smooth muscles cells (VSMCs), making it an important determinant of vascular tone in several pathophysiological conditions (48). H2S is produced endogenously in mammalian tissues from L-cysteine by cystathionine-β-synthase (CBS), cystathionine γ-lyase and another mitochondrial enzyme, 3-mercaptopyruvate sulfurtransferase (49). It regulates vascular diameter, and protects the endothelium from oxidative stress, ischemia reperfusion injury and chronic inflammation by activating several K+ channels in VSMCs (50,51). According to Wang et al (52), other molecules, such as sulfur dioxide, methane, hydrogen gas, ammonia and carbon dioxide, are also considered to be potential gasotransmitter candidates, despite the fact that they have not been adequately explored or do not completely fit the diagnostic criteria for endogenous gasotransmitters.

History of gasotransmitters

NO was discovered in 1772 by Joseph Priestley as a clear, colorless gas with a half-life of 6–10 sec (53). In 1979, Gruetter et al (54) found that adding NO in a mixture with nitrogen or argon gases into an organ bath vessel containing isolated pre-contracted strips of a bovine coronary artery induces vascular smooth muscle relaxation. In 1980, Furchgott and Zawadzki (55) revealed that endothelial cells produce endothelium-derived relaxing factor (EDRF) in response to stimulation by acetylcholine in vessels with intact endothelium. After 7 years and in two unrelated studies, both Ignarro et al (56,57) and Palmer et al (56,57) demonstrated that EDRF is NO. Moncada et al (58) demonstrated that NO is synthesized from the amino acid L-arginine. Earlier, Murad et al (59) reported that nitro vasodilators, such as nitroglycerin (GTN) and sodium nitroprusside, induce vascular tissue relaxation, stimulate sGC expression and increase cGMP levels in tissues. All these studies contributed to the establishment of a signaling molecule in the cardiovascular system. In 1992, the cover of Science magazine proclaimed NO as the molecule of the year (60). Furthermore, 6 years later, Pfizer, Inc. introduced Viagra, a drug that inhibits phosphodiesterase-5 via the NO-cGMP signaling cascade, which revolutionized the management of erectile dysfunction (61). In the same year, the importance of the NO discovery was acknowledged by awarding the Nobel Prize in Physiology and Medicine to Furchgott, Ignarro and Murad (62).

Few discoveries have had the type of impact on biology that NO has had since it was discovered (63). The first scientific article described NO in 1816 (64), while in 1994, Thomsen, et al (48,65) were the first to report a link between NO and cancer action. In 1993, there were >1,000 new publications on the biology of NO. At the end of the 20th century, the rate of NO publications approached a plateau at ~6,000 papers per year, spanning almost every area of biomedicine (63). The number of published articles in PubMed (pubmed.ncbi.nlm.nih.gov/) reached 58,848 by the end of 2020.

In the late 1200s, a poisonous gas produced by the incomplete combustion of wood similar to CO was described by the Spanish alchemist Arnold of Villanova (66). Between 1772 and 1799, an English chemist, Joseph Priestley, recognized and characterized CO (53). The first scientific article described CO in 1899 (67), and subsequently, the ‘first paper linking CO to cancer was published in 1927 (68). Between 1920 and 1960, Roughton performed several kinetic studies on CO and hemoglobin (69–71). In 1944, he revealed that CO bound to hemoglobin changed the oxyhemoglobin dissociation curve, and demonstrated that CO was produced in the body during the metabolism of the hemoglobin molecule (72). Subsequently, Tenhunen et al (73) described and characterized HO as the enzyme responsible for breaking down heme in the body, demonstrating that heme catalysis resulted in the subsequent release of CO and free iron as by-products.

H2S was first discovered in 1777 by Carl Wilhelm Scheele (74), and the first paper related to H2S was published in 1917 (75). The importance of H2S in cell physiology was highlighted in the mid-1990s, and the first link between H2S and cancer was reported in 2005. H2S at physiological concentrations can reduce the apoptotic effects of chemopreventative drugs and play an important role in the response of colonic epithelial cells of the human adenocarcinoma cell line HCT116 to both beneficial and toxic chemicals (76). It is clear that H2S, similar to other endogenous gases, has now been identified as a gasotransmitter (77). It was initially regarded as highly poisonous in the environment; however, this perception has changed as a growing number of studies have illustrated H2S as a cytoprotective and cardioprotective agent (78,79). Fig. 1 depicts a timeline of important scientific developments in the history of gasotransmitter research and therapeutic usage.

Figure 1.

Timeline of key scientific advances during the history of gasotransmitters research and its therapeutic use. CO, carbon monoxide; EDRF, endothelium-derived relaxing factor; H2S, hydrogen sulfide; NO, nitric oxide.

Role of NO in cancer

NO is a small biomolecule that exerts different effects on tumor growth and invasion. It is a pleiotropic regulator and serves essential roles in various intercellular or intracellular processes, including vasodilatation, neurotransmission and macrophage-mediated immunity (7). Vascular endothelial cells can synthesize NO from L-arginine, and this biosynthetic pathway has been thoroughly documented in numerous other cell types, including nervous and immune cells (80,81). It can display a cytotoxic property at higher concentrations as generated by activated macrophages and endothelial cells (7). A total of three different isoforms of the NOS family synthases have been identified: Endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). The gene symbol nomenclatures are NOS1 for nNOS, NOS2 for iNOS and NOS3 for eNOS (7). However, the role of NO in cancer biology, particularly in breast cancer, only started to be elucidated in 1994 (82). It has been detected that NOS expression is increased in various types of cancer, such as breast, cervical, brain, laryngeal, and head and neck cancer (83) (Table I). NO exhibits a pro- or antitumorigenic effect (84). NO appears to enhance tumor growth and cell proliferation at measurable concentrations in different clinical samples from different cancer types (85).

Table I.

Studies on the involvement of NO, H2S and CO synthesis enzymes in the modulation of cancer.

Table I.

Studies on the involvement of NO, H2S and CO synthesis enzymes in the modulation of cancer.

First author/s, year	Gasotransmitters	Enzyme	Type of cancer	(Refs.)
Aaltoma, 2001, Aaltomaa, 2000, Bhowmick and Girotti, 2014, Coulter, 2010, Cronauer, 2007, Erlandsson, 2018, McCarthy, 2007, Fahey and Girotti, 2015, D'Este, 2020, Ryk, 2015, Uotila, 2001	NO	iNOS	Prostate	(170–180)
Abdelmagid, 2011, Abdelmagid and Too, 2008, Ambs and Glynn, 2011, Alalami and Martin, 1998, Basudhar, 2017, Bentrari, 2005, Bing, 2001, Deepa, 2013, Duenas-Gonzalez, 1997, Evig, 2004, Flaherty, 2019, Garrido, 2017, Hsu, 2000, Kanugula, 2014, Kotamraju, 2007, López-Sánchez, 2020, Loibl, 2005a, Lahiri and Martin, 2004, Oktem, 2004, Martin, 1999, Nafea, 2020, Oktem, 2006, Zeybek, 2011, Walsh, 2016, Wink, 2015, Tschugguel, 1999			Breast	(181–206)
Abadi and Kusters, 2013, Chen, 2006, Doi, 1999, Goto, 1999, Goto, 2006, Hirst and Robson, 2010, Hirahashi, 2014, Huang, 2012, Ikeguchi, 2002, Jun, 1999, Jung, 2002; Rafiei, 2012, Rajnakova, 2001, Zhang, 2011, Sawa, 2008, Shen, 2004, Son, 2001, Song, 2004			Gastric	(207–224)
Ambs, 1998b, Bing, 2001, Bocca, 2010, Dabrowska, 2018, Deepa, 2013, Narayanan, 2004, Narayanan, 2003, Kwak, 2000, Kapral, 2015, Puglisi, 2015, Williams, 2003, Tong, 2007; Sasahara, 2002, Shen, 2015, Spiegel, 2005			Colon	(187,188,225–237)
Eijan, 2002, Hosseini, 2006, Klotz, 1999, Koskela, 2012, Langle, 2020, Lin, 2003, Ryk, 2010, Ryk, 2011b, Wolf, 2000, Sandes, 2005, Sandes, 2012			Bladder	(238–248)
Jung, 2002, Ambs and Harris, 1999, Chung, 2003, Cianchi, 2004, Cianchi, 2003, Fransen, 2005, Gallo, 1999, Ropponen, 2000, Zafirellis, 2010, Wang, 2004			Colorectal	(217,249–257)
Delarue, 2001, Hu, 1998, Li, 2014, Liu, 1998, Liu, 2010, Zhang, 2014a, Ye, 2013, Sim, 2012			Lung	(258–265)
Franco, 2004, Kong, 2001, Kong, 2002, Wang, 2016a, Vickers, 1999, Takahashi, 2008			Pancreatic	(266–271)
Chen, 2005, Dong, 2014, Jiang, 2015, Lee, 2007, Ryu, 2015, Sowjanya, 2016			Cervical	(272–277)
Li, 2017b, Malone, 2006, Martins Filho, 2014, Raspollini, 2004, Zhao, 2016, Xu, 1998, Trinh, 2015, Sanhueza, 2016b			Ovarian	(278–285)
Jayasurya, 2003			Nasopharyngeal	(286)
Lukes, 2008			Tonsillar	(287)
Soler, 2000			Thyroid	(288)
Rafa, 2017			Colitis	(289)
Amasyali, 2012, Klotz, 1999, Lin, 2003, Polat, 2015, Ryk, 2011a		eNOS	Bladder	(240,243,290–292)
Abedinzadeh, 2020, Brankovic, 2013, Diler and Oden, 2016, Fu, 2015, Medeiros, 2003, Medeiros, 2002a, Medeiros, 2002b, Nikolic, 2015, Marangoni, 2006, Martin, 1999, Polytarchou, 2009, Re, 2011, Re, 2018, Ziaei, 2013, Zhao, 2014, Yu, 2013, Wu, 2014, Safarinejad, 2013, Sanli, 2011			Prostate	(200,293–310)
Bayraktutan, 2020, Cheon, 2000, Fujita, 2010, Kocer, 2020, Peddireddy, 2018			Lung	(311–315)
Chen, 2018, Crucitta, 2019, Basaran, 2011, Hao, 2010, Hefler, 2006, Kafousi, 2012, Lahiri and Martin, 2004, Loibl, 2006, Loibl, 2005b, Lu, 2006, Mortensen, 1999a, Mortensen, 1999b, Oktem, 2006, Martin, 2000b, Ramirez-Patino, 2013, Zintzaras, 2010, Zhang, 2016a, Zeybek, 2011			Breast	(198,202,203,316–330)
Carkic, 2020, Karthik, 2014			Oral	(331,332)
Chen, 2014, Mortensen, 2004, Penarando, 2018, Yeh, 2009			Colorectal	(333–336)
Dabrowska, 2018			Colon	(227)
Hefler, 2002			Ovarian	(337)
Doi, 1999, Krishnaveni, 2015, Wang, 2005, Tecder Unal, 2010			Gastric	(209,338–340)
de Fatima, 2008			Renal	(341)
Lukes, 2008			Tonsillar	(287)
Hung, 2019, Waheed, 2019			Uterine and cervical	(342,343)
Riener, 2004			Vulvar	(344)
Wang, 2016b			Pancreatic	(345)
Yanar, 2016			Larynx	(346)
Chen, 2013		nNOS	Neural stem cell	(347)
de Fatima, 2008			Renal	(341)
Karihtala, 2007			Breast	(348)
Lewko, 2001			Lung	(349)
Ahmed, 2012, Al Dhaheri, 2013, Avtandilyan, 2018, Bani, 1995, Avtandilyan, 2019, Alagol, 1999, Bhattacharjee, 2012, Cendan, 1996a, Cendan, 1996b, Chakraborty, 2004, Coskun, 2003, Coskun, 2008, Dave, 2014, De Vitto, 2013, Deliconstantinos, 1995, Demircan, 2020, Duan, 2014, El Hasasna, 2016, Engelen, 2018, Erbas, 2007, Gaballah, 2001, Gajalakshmi, 2013, Ganguly Bhattacharjee, 2012, Ganguly Bhattacharjee, 2014, Gaspari, 2020, Guha, 2002, Gunel, 2003, Kampa, 2001, Khalkhali-Ellis and Hendrix, 2003, Konukoglu, 2007, Kumar and Kashyap, 2015, Lahiri and Martin, 2009, Lee, 2014a, Hewala, 2010, Finkelman, 2017, Jadeski, 2002, McCurdy, 2011, Metwally, 2011, Mishra, 2020, Nakamura, 2006, Negroni, 2010, Martin, 2000a, Pervin, 2001b, Pervin, 2007, Martin, 2003, Nath, 2015, Pance, 2006, Parihar, 2008, Pervin, 2001a, Pervin, 2008, Pervin, 2003, Punathil, 2008, Radisavljevic, 2004, Rashad, 2014, Ray, 2001, Reveneau, 1999, Ridnour, 2012, Zhu, 2015, Zheng, 2020, Zeillinger, 1996, Wang, 2010, Thamrongwittawatpong, 2001, Toomey, 2001, Salaroglio, 2018, Sen, 2013a, Sen, 2013b, Shoulars, 2008, Simeone, 2003, Simeone, 2002, Simeone, 2008, Singh and Katiyar, 2011, Smeda, 2018, Song, 2002, Switzer, 2012, Switzer, 2011		Non- specific	Breast	(350–424)
Ai, 2015, Babykutty, 2012, Bessa, 2002, Cendan, 1996a, Chattopadhyay, 2012b, Edes, 2010, Ishikawa, 2003, Jarry, 2004, Jenkins, 1994, Jeon, 2005, Kim, 2020, Kopecka, 2011, Liu, 2003, Liu, 2008, Mojic, 2012, Millet, 2002, Oláh, 2018, Prevotat, 2006, Rao, 2004, Rao, 2006, Riganti, 2005, Wang and MacNaughton, 2005, Xie, 2020, Wenzel, 2003, Williams, 2001, Voss, 2019, Tesei, 2007, Thomsen, 1995, Stettner, 2018			Colon	(357,425–452)
Ambs, 1998, Cembrzynska-Nowak, 1998, Cembrzyńska-Nowak, 2000, Chen, 2019b, Deliu, 2017, Fu, 2019, Fujimoto, 1997, Gao, 2019a, Hwang, 2017, Kaynar, 2005, Koizumi, 2001, Munaweera, 2015, Maciag, 2011, Maiuthed, 2020, Lee, 2006; Liaw, 2010, Liu, 2018, Luanpitpong and Chanvorachote, 2015, Muto, 2017, Masri, 2010, Masri, 2005, Matsunaga, 2014, McCurdy, 2011, Powan and Chanvorachote, 2014, Punathil and Katiyar, 2009, Zhou, 2000, Zhou, 2020, Zhang, 2014, Yongsanguanchai, 2015, Wongvaranon, 2013, Saisongkorh, 2016, Saleem, 2011, Sanuphan, 2013, Sanuphan, 2015, Su, 2010, Suzuki, 2019, Szejniuk, 2019			Lung	(386,453–488)
Arif, 2010, Beevi, 2004, Korde Choudhari, 2012, Patel, 2009			Oral	(489–492)
Brankovic, 2017, El-Mezayen, 2012, Gao, 2019b, Gao, 2019c, Jiang, 2013, Krzystek-Korpacka, 2020, Liu, 2004, McIlhatton, 2007, Moochhala, 1996, Muscat, 2005, Mandal, 2018, Yagihashi, 2000, Yu, 2005, Wei, 2008, Siedlar, 1999			Colorectal	(493–507)
Arora, 2018, Atala, 2019, Dillioglugil, 2012, Della Pietra, 2015, Huh, 2006, Laschak, 2012, Lee, 2009;			Prostate	(94,152,176,508–519)
McCarthy, 2007, Rezakhani, 2017, Royle, 2004, Wang, 2007, Tan, 2017, Thomas, 2012, Siemens, 2009, Soni, 2020
Caneba, 2014, El-Sehemy, 2013, El-Sehemy, 2016, Kielbik, 2013, Leung, 2008, Thomsen, 1998, Salimian Rizi, 2015, Stevens, 2010			Ovarian	(520–527)
Camp, 2006, Chen, 2020; Fujita, 2014, Fujita, 2019, Zhou, 2009, Wang, 2003, Wang and Xie, 2010, Thomas, 2002, Stewart, 2011, Sugita, 2010			Pancreatic	(528–537)
Caygill, 2011, Sun, 2013			Esophageal	(538,539)
Gecit, 2012, Gecit, 2017, Jansson, 1998, Kilic, 2006, Khalifa, 1999, Morcos, 1999, Wang, 2001, Thiel, 2014, Saygili, 2006			Bladder	(540–548)
Bakan, 2002, Dincer, 2006, Holian, 2002, Eroglu, 1999, Koh, 1999, Oshima, 2001, Rajnakova, 1997, Yao, 2015, Sang, 2011, Sang, 2010			Gastric	(549–558)
Li, 2017b, Muntane, 2013; Sayed-Ahmad and Mohamad, 2005			Liver	(559–561)
Li, 2017a, Park, 2003, Wei, 2011, Sudhesh, 2013, Sundaram, 2020			Cervical	(562–566)
Menendez, 2007, Yang, 2016			Bone	(567,568)
Giusti, 2003, Ragot, 2015			Thyroid	(569,570)
Gallo, 1998, Kawakami, 2004, Wu, 2020, Utispan and Koontongkaew, 2020			Head and neck	(571–574)
Taysi, 2003			Larynx	(575)
Thomsen, 1994, Sanhueza, 2016			Gynecological	(65,576)
Chattopadhyay, 2012a, Dong, 2019, Li, 2020, Lv, 2014	H₂S	CSE, CBS and 3-MST	Breast	(577–580)
Choi, 2012, Kawahara, 2020b, Sekiguchi, 2016, Wang, 2019, Ye, 2020, Zhang, 2015			Gastric	(126,581–585)
Chattopadhyay, 2012b, Chen, 2019a, Cai, 2010, Hale, 2018, Hong, 2014, Kodela, 2015, Rose, 2005, Oláh, 2018, Szabo, 2013, Chen, 2017			Colon	(76,113,428,440,586–591)
Chen, 2017, Elsheikh, 2014, Faris, 2020, Malagrinò, 2019, Sakuma, 2019			Colorectal	(591–595)
Liu, 2017			Bladder	(596)
Pei, 2011, Liu, 2016			Prostate	(96,597)
Wang, 2020			Lung	(110)
Zhang, 2016			Oral	(598)
Zhuang, 2018			Bone	(599)
Xu, 2018			Thyroid	(600)
Huang, 2020, Kawahara, 2017, Kim, 2018, Kourti, 2019, Lee, 2014	CO	HO	Breast	(601–605)
Kawahara, 2020a, Kawahara, 201			Ovarian	(606,607)
Khasag, 2014, Liptay, 2009, Nemeth, 2016, Shao, 2018, Shirabe, 1970, Zarogoulidis, 2012			Lung	(608–613)
Lian, 2016			Gastric	(614)
Lv, 2019, Yin, 2014			Colorectal	(615,616)
Nitta, 2019			Testicular	(617)
Oláh, 2018			Colon	(440)
van Osch, 2019			Bladder	(618)
Vítek, 2014			Pancreatic	(619)

[i] 3-MST, 3-mercaptopyruvate sulfurtransferase; CBS, cystathionine-β-synthase; CO, carbon monoxide; CSE, cystathionine-γ-lyase; eNOS, endothelial NOS; H₂S, hydrogen sulfide; HO, heme oxygenase; iNOS, inducible NOS; nNOS, neuronal NOS; NO, nitric oxide.

In contrast to conventional signaling molecules that act by binding to specific receptor molecules, NO exerts its biological actions via a wide range of chemical reactions (86). The NO concentration and minor differences in the composition of the intracellular and extracellular environment determine the exact reactions attained. Under normal physiological conditions, cells produce small but significant amounts of NO, contributing to the regulation of anti-inflammatory effects and its antioxidant properties (83). However, in tissues with a high NO output, iNOS is activated, and nitration (addition of NO2), nitrosation (addition of NO+) and oxidation will be dominant (87). The interaction of NO with O2 or superoxide (O2−) results in the formation of reactive nitrogen species (RNS). The RNS, dinitrogen trioxide (N2O3) and peroxynitrite (ONOO), can induce two types of chemical stresses: Nitrosative and oxidative (88). N2O3 effectively nitrosates various biological targets to yield potentially carcinogenic nitrosamines and nitrosothiol derivatives, and N-nitrosation may have essential implications in the known association between chronic inflammation and malignant transformation (88). O2− and NO may rapidly interact to produce the potent cytotoxic oxidants ONOO− and its conjugated acid, peroxynitrous acid. In natural solutions, ONOO is a powerful oxidant, oxidizing thiols or thioethers, nitrating tyrosine residues, nitrating and oxidizing guanosine, degrading carbohydrates, initiating lipid peroxidation, and cleaving DNA, which has important implications in cancer (83).

Effect of NO on the TME

The effects of NO in a multistage model of cancer have been reported previously, it can drive angiogenesis, apoptosis, the cell cycle, invasion and the metastatic process (83,85). NO also serves a role in cellular transformation, the onset of neoplastic lesion formation, and the monitoring of invasion and colonization throughout metastasis (89). Therefore, understanding its role in promoting TME elements is crucial as it will reduce the ambiguity, and aid the development of NO-based cancer therapeutics, which will be effective in the prevention and treatment of a range of human cancer types.

The TME is characterized by hypoxia and acidity. Small pH drops (−0.6 U) favor the production of bioactive NO from nitrite, as evidenced by a higher degree of cyclic guanosine 3′,5′-monophosphate-dependent vasorelaxation in arterioles. A small dose of nitrite may make tumors more sensitive to radiation, resulting in a considerable growth delay and improved survival in mice (90). Therefore, low pH has been revealed to be an ideal setting for tumor-selective NO generation in response to nitrite systemic injection (90). The generation of NO by iNOS inhibits C-X-C motif chemokine ligand 10 expression in melanoma cells, resulting in a protumorigenic TME (91). Furthermore, eNOS upregulation in the TME reduced both the frequency and size of tumor implants in a surgical model of pancreatic cancer liver metastasis (92) and the influence of NO on tumor cell protease expression since tumor cell anoikis and invasion are both regulated by myofibroblast-derived matrix. Within tumor cells, eNOS-dependent downregulation of the matrix protease cathepsin B was detected, and cathepsin B silencing reduced tumor cell invasiveness in a manner comparable to eNOS upregulation. Therefore, an NO gradient within the TME influences tumor progression through orchestrated molecular interactions between tumor cells and stroma.

The role of NO in the complex interactions between the TME and the immune response is a good example of how complicated the molecular and cellular mechanisms determining the involvement of NO in cancer biology are. Although the activities of NO in the TME are varied and context-dependent, the evidence suggests that NO is an immunosuppressive mediator (93). By targeting tumors in a cell nonautonomous manner, S-nitroso glutathione (GSNO), a NO donor, reduced the tumor burden in a mouse model of castration-resistant prostate cancer (CRPC). Both the abundance of anti-inflammatory M2 macrophages and protein kinase R-like endoplasmic reticulum kinase expression were decreased by GSNO, indicating that NO influences TAM activity. GSNO also reduced IL-34, indicating that TAM differentiation was suppressed. This demonstrates the importance of NO in CRPC tumor inhibition via the TME (94).

Role of H2S in cancer

H2S is a novel gasotransmitter, which regulates cell proliferation and other cellular functions (95). It has been revealed that H2S serves an essential role as a signal molecule in regulating cell survival (95). It seems paradoxical that, on one hand, H2S acts as a physiological intercellular messenger to stimulate cell proliferation, and on the other hand, it may display cytotoxic activity (96). H2S, at physiologically relevant concentrations, hyperpolarizes the cell membrane, regulates cell proliferation, relaxes blood vessels and modulates neuronal excitability (95). Increased expression of various H2S-producing enzymes in cancer cells of different tissues has been reported, and novel roles of H2S in the pathophysiology of cancer have emerged (9). This is mainly observed in some cancer types, such as breast, lung, gastric, colorectal, bladder, prostate, oral, bone and thyroid cancer, where the malignant cells both express high levels of CBS and produce increased amounts of H2S, which results in enhanced tumor growth and spread by stimulating cellular bioenergetics, activating proliferative, migratory and invasive signaling pathways, and enhancing tumor angiogenesis (97), as indicated in Table I, which highlights the research on the involvement of NO, H2S, and CO production enzymes in cancer regulation. Importantly, in preclinical models of these cancer types, either pharmacological inhibition or genetic silencing of CBS was sufficient to suppress cancer cell bioenergetics in vitro, and to inhibit tumor growth and metastasis in vivo (9,98). This enhances the antitumor efficacy of frontline chemotherapeutic agents, providing a strong rationale for the development of CBS-targeted inhibitors as anticancer therapies (99). However, the observation that inhibition of H2S biosynthesis exerts anticancer effects is contradicted by another study which demonstrated that increasing H2S with exogenous donors also exerts antitumor actions (100). H2S stimulates the cytoprotective PI3K-AKT, p38-MAPK and nuclear factor erythroid 2 (NRF2) signaling pathways when present at low concentrations (101). Sulfhydration partially promotes a number of biological functions of H2S, including ATP-sensitive potassium (KATP) channel opening (101). At physiological concentrations, H2S can also serve a role in stimulating the cellular bioenergetic function by donating electrons to the mitochondrial electron transport chain at complex II, leading to increased mitochondrial levels of cyclic AMP (102). At higher concentrations, H2S inhibits oxidation of cytochrome c, which results in disruption of mitochondrial electron transport, and it can also exert pro-oxidant and DNA-damaging effects (103).

Effect of H2S on the TME

H2S acts as a gaseous signaling molecule and is endogenously generated by three H2S-producing enzymes, namely CBS, cystathionine γ-lyase and 3-mercaptopyruvate sulfur transferase. Imbalances in H2S-producing enzymes as well as H2S levels are associated with malfunctional H2S metabolism, which has been increasingly associated with several human pathological disorders (104). Several cancer cell lines and specimens exhibit upregulation of one or more of the H2S-synthesizing enzymes, and this aberrant expression is suggested to be a tumor enhancer (105). By modulation of the expression of the H2S-producing enzyme, the amount of tumor-derived H2S is altered, thereby modifying the TME and affecting tumor expansion and metastasis (106).

Numerous mechanisms contribute to the pro-tumor effect of H2S, including the induction of angiogenesis, regulation of mitochondrial bioenergetics, acceleration of cell cycle progression and anti-apoptotic functions (107). Furthermore, hypoxia is a common feature of the TME in a number of solid tumors, which affects the level of H2S by preventing H2S catabolism and consequently stimulating cystathionine γ-lyase gene expression (107). Furthermore, under the influence of hypoxia in the microenvironment, the levels of H2S-producing enzymes are upregulated, and the H2S-producing enzymes are transferred toward the mitochondria, which results in increased H2S production (106). Angiogenesis, which is an important process in cancer progression, is stimulated by paracrine signaling between stroma in the TME and epithelial tumor cells (108).

Previous evidence has demonstrated that H2S is an endogenous stimulator of ischemic-induced angiogenesis by promoting the upregulation of hypoxia-inducible factor 1 (HIF-1)-α via activation of different pathways, including the VEGFR2/mTOR and PI3K/AKT signaling pathways (105,109,110). H2S appears to support tumor cell proliferation by increasing vascular endothelial growth factor (a critical growth factor in angiogenesis) expression in kidney and ischemic tissues (111,112). An in vivo study conducted on nude mice revealed that silencing of CBS expression markedly decreased tumor growth. The researchers concluded that the reduction in tumor growth was associated with both the suppression of cancer cell signaling and metabolism, as well as the paracrine mechanism in the tumor environment (113).

In colon cancer, CBS-derived H2S promotes angiogenesis and vasorelaxation, thereby supporting tumor growth (113). In ovarian cancer, CBS knockdown reduces the number of blood vessels, resulting in tumor growth (97). Taken together, these results indicate that CBS serves an essential role in promoting angiogenesis and tumor growth. Therefore, CBS could be a promising molecular target for cancer therapy. Recently, researchers have developed a novel strategy to improve chemotherapy in patients with colorectal cancer by remodeling the TME through reduction of the high levels of H2S in colon tissues using copper iron oxide nanoparticles (114). Another strategy for cancer treatment is destroying the tumor metabolism symbiosis. This method successfully affects cancer cells with minimum impairment to healthy cells by using a zero-waste zwitterion-based H2S-driven nanomotor that generates acidosis in cancer cells within the TME, and consequently, the tumor growth will be suppressed (115).

One of the important characteristics of cancer cells is the acidic microenvironment (reduced intracellular pH) due to accumulation of lactic acid that results from a high rate of glycolysis. H2S donors trigger the activation of cellular transporters, such as glutamine transporter-1 (GLT-1) and ATP-binding cassette transporter A1, which directly regulates the aerobic glycolysis, which is a metabolic indicator of cancer (116). Nevertheless, activation of GLT-1 has both a promoting and an inhibiting effect depending on the cancer cell type, and thus, further studies are required to clarify the consequent responses (8).

It has been demonstrated that most cancer cells exhibit increased uptake of glucose and high lactate production, known as the Warburg effect, due to glycolysis that causes the acidic TME, which enhances tumor progression (117). Previous studies have demonstrated that continuous exposure of cancer cells to a low concentration of H2S results in inhibition of cancer progression. This anticancer effect is mainly due to an increase in metabolic lactic acid production by H2S and diminishes the pH regulatory system, which consequently leads to intense intracellular acidification and eventually drives cancer cell death (107,118).

Within the TME, there are key proteins and enzymes, such as matrix metalloproteinase, adhesive enzymes (E-cadherin) and integrins, which serve an essential role in the migration and metastasis of cancer cells (119,120). Tumor cells that enter the stroma within the TME after detaching from the main tumor move into the blood vessels and ultimately reach the other organs in the body (121). H2S donors have been used in different studies and have been demonstrated to successfully prevent migration and invasion by decreasing proteins and enzymes involved in migration and invasion in different cancer types (8,122,123). For example, it has been reported that treatment of hepatocellular carcinoma cells with 600–1,000 µM sodium hydrosulfide (NaHS), which is an H2S donor, efficiently reduces migration and invasion in a concentration-dependent manner via modulation of the EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways (124). Similarly, NaHS treatment prevents migratory activity in thyroid cancer cells by deactivating the PI3K/AKT/mTOR and MAPK signaling pathways (125). Furthermore, NaHS reduces the MMP-2 protein levels in gastric cancer (126). Additionally, H2S serves a role in a different stage of cancer development and is involved in modulation of the TME, which regulates the rate of cancer progression and the effectiveness of therapy (106).

Role of CO in cancer

CO is best recognized for being a toxic gas produced by the burning of fossil fuels. On the one hand, CO poisoning is associated with high mortality rates, and thus, it attracts a lot of attention (127). On the other hand, CO has been conclusively demonstrated to be a gasotransmitter with physiological activities in mammals (128,129). CO is now accepted as a potential therapeutic agent along with its physiological roles and has entered multiple clinical trials (130,131). CO is produced in all cells by HO-1 and HO-2 (132). Each possesses strong cytoprotective functions for the cell, evidenced by the fact that the absence of either, particularly the stress-response isoform HO-1, is detrimental to the cell and organism (133,134). The inducible HO isoform (HO-1) can be upregulated in response to various stimuli, including heme, oxidative stress, ultraviolet irradiation, heat shock, hypoxia and NO (135). The constitutive HO isoform (HO-2) is expressed in several tissues, including the brain, kidney, liver and spleen (6). Low CO concentrations also activate KATP channels and influence various intracellular kinase pathways, including the PI3K-AKT and p38 MAPK signaling pathways (128). CO exerts adverse biological effects at higher concentrations, which, in vivo, are mainly attributed to the binding of CO to hemoglobin. The resulting carboxyhemoglobin reduces the O2-carrying capacity of the blood and leads to tissue hypoxia. In vitro, CO inhibits mitochondrial electron transport by irreversibly inhibiting cytochrome c oxidase (128).

Cellular and animal pharmacological experiments suggest numerous therapeutic indications where HO-1 or CO administration imparts benefits in treating conditions such as sepsis, bacterial infection, cancer, inflammation, circadian clock regulation, stroke, erectile dysfunction and heart attack (131). Some of the best-characterized physiological effects of CO include anti-inflammatory, antiproliferative, anti-apoptotic and anticoagulative responses. By contrast, at higher concentrations, CO becomes cytotoxic (136). In contrast to NO, the cytoprotective and cytotoxic effects of CO are intimately intertwined. For example, a low level of CO-mediated inhibition of mitochondrial activity, followed by a slight increase in intracellular reactive O2 species production, is important in CO-mediated cytoprotective signaling events (137,138). In a way, the cytoprotective effects of CO resemble the protective effects of pharmacological preconditioning. A short, relatively mild insult triggers a secondary cytoprotective phenotype via activation of the prototypical antioxidant response element NRF2-related factor. Thus, a protective cellular phenotype is maintained in the cell for a long time after CO has already been cleared from the biological system (6).

Gasotransmitter signaling significance

To highlight the significance of gasotransmitter signaling cascades in tumor growth and the chemotherapeutic response, network analysis approaches were utilized to identify the gasotransmitter-tumor signaling signature. Utilizing the PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Web of Science (https://clarivate.com/webofsciencegroup/solutions/web-of-science/) databases, ~127 candidates (genes and proteins) were identified, which were significantly related to the gasotransmitters and tumorigenesis simultaneously. Using the selected list of candidates, the present network analyses were applied using the Enrich R (https://maayanlab.cloud/Enrichr/) and Metascape (https://metascape.org/gp/index.html#/main/step1) databases to identify all possible genes, proteins and pathways that may represent tumor-gasotransmitters interrelated signaling. As shown in Fig. 2A and B, the most relevant enriched pathways in the present analysis were ones related to cancer, which in turn, justifies the relevance and accuracy of the selected candidate list and highlights the significance of gasotransmitter signaling cascades in tumor development and growth. Additionally, different essential cellular signaling pathways were significantly enriched, such as the ‘positive regulation of locomotion’, ‘TNF signaling pathway’, ‘apoptotic signaling pathway’ and ‘HIF-1 signaling pathway’. These pathways serve an essential role in driving the fate of cancer cells and their response to different treatment modalities (139). Therefore, it is reasonably relevant to investigate the crosstalk between gasotransmitters and tumor cells.

Figure 2.

Pathway enrichment analysis. (A) Bar graph of enriched pathways across input gene lists, the top 20 clusters are arranged according to the degree of significance (P-value). (B) Network of the top 20 enriched pathways. The members with the best P-value from each of the 20 clusters were selected with the constraint that there are not >15 members per cluster and not >250 terms in total. Each node represents an enriched member and is colored accordingly. GO, Gene Ontology; HIF-1, hypoxia-inducible factor 1; PID, primary immunodeficiency.

This pathway analysis was further validated using the EviNet database (https://www.evinet.org/). The detected enrichment signature was similar to the one identified using Enrich R and Metascape (data not shown). Furthermore, a deeper enrichment analysis revealing protein-protein interactions was performed considering three direct and physical connections at the minimum (Fig. 3A and B). Accordingly, the candidates were clustered into three densely connected networks upon applying the molecular complex detection algorithm using the Metascape annotation database. Each group or individual candidate within the group may represent a platform for molecular-mechanistic studies to investigate the interaction between the group members and gasotransmitters and their impact on cancer cell proliferation and response to treatment.

Figure 3.

Protein-protein interaction enrichment analysis using the BioGrid, InWeb_IM and OmniPath databases. The network contains the subset of proteins that form physical interactions with at least one other member in the list. The MCODE algorithm was applied for each network containing at least three proteins to identify densely connected network components. (A) Three MCODE clusters and corresponding protein members. Red, proteins enriched in the two best scoring pathways by P-value (‘Cancer Pathways’ and ‘Endocrine Resistance’); blue, two best scoring pathways by P-value (‘Colorectal Cancer’ and ‘Hepatitis B’), and the green cluster represents three pathways: ‘regulation of hematopoiesis’, ‘regulation of myeloid cell differentiation’ and ‘Hepatitis B’. (B) Protein-protein interaction network showing proteins in the three enriched MCODE modules and other candidate proteins, which have one physical contact with each other at the minimum. MCODE, molecular complex detection algorithm.

The present review investigated links between the current candidate list and a drug signature database containing annotations regarding drug induction or inhibition of gene expression. As shown in Table SII, the present candidate list was significantly enriched and associated with different anticancer or cancer-related drugs. The odds ratio ranking method is simply the odds ratio; however, the combined score is the odds ratio multiplied by the negative natural log of the P-value derived from Fisher's exact test and the Enrichr z-score (combined score=log(p)*z). Overall, this suggested that gasotransmitters serve essential roles in drug response signaling by cancer cells. Therefore, well-designed mechanistic studies are required to elucidate such roles and open novel avenues for drug discovery and cancer treatment modalities.

Effectiveness of gasotransmitters in chemotherapeutic drug treatment

Following the crucial discovery of gasotransmitters as fundamental biological molecules, their physiological significance has become a debated topic in recent decades. Utilizing gasotransmitters as therapeutic aids is justified by their roles in carcinogenesis, including enhancement of apoptotic stimuli, inhibition of metastasis and inhibition of angiogenesis. Therefore, using them alone or in combination with cytotoxic agents is an essential research platform for researchers and clinicians in cancer therapy (6,140–142).

Platinum compounds have been investigated extensively, and several studies have demonstrated that tumor cells are sensitized to cisplatin compounds by NO donors (143,144). In vitro, combination of cisplatin with natural NO gas or the NO donors diethylamine NONOate (DEA NONOate) or 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) NONOate increased the killing efficacy of cisplatin by 50–1,000 times compared with cisplatin alone, and the effect lasted for a number of hours (145). Furthermore, the combination treatment of cisplatin and diethylenetriamine NONOate reverses resistance and induces apoptosis in prostate cancer cell lines (146) and metastatic human colon carcinoma cell lines (147). NO-producing aspirin compounds that can emit NO for several hours have also been investigated. For example, in a clonogenic assay, nitroaspirin exhibited dose-dependent cytotoxicity and greatly boosted cisplatin cytotoxicity in both resistant and susceptible cells (148).

Carmustine is a chemotherapeutic drug that is combined with a NO source (the donor drug DEA NONOate), and the combination of chlorotoxin-NO, carmustine, or temozolomide enhances glioma cell death. Two variables that contributed to the enhanced cytotoxic activity of these cells were the production of active levels of the cytoprotective enzyme O6-methylguanine-DNA methyltransferase activity and altered p53 activity (149).

In the same year, Shami, Saavedra, Wang, Bonifant, Diwan, Singh, Gu, Fox, Buzard, Citro, Waterhouse, Davies, Ji and Keefer (150) created glutathione/glutathione S-transferase-activated nitric oxide (JS-K), a selective targeted NO donor that was active in vitro and in vivo against human HL60 leukemia cells, following its reaction with glutathione to produce NO in vivo. JS-K acts as a chemosensitizer for doxorubicin-induced cytotoxicity in renal (151), prostate (152) and bladder cancer cells (153).

NF-κB and NOS activation make HT29 human colon cancer cells more sensitive to doxorubicin cytotoxicity (154). Simvastatin increases NF-κB activity and NO production, while also increasing doxorubicin intracellular accumulation and cytotoxicity (154). The enhanced intracellular accumulation of doxorubicin is caused by tyrosine nitration in P-glycoprotein and multidrug resistance protein 1 by NO (155). In mice with triple-negative breast cancer, NO-releasing nanoparticles in combination with doxorubicin or a doxorubicin nanoparticle carrier decreased cell survival, caused apoptosis, elevated doxorubicin intracellularly, compromised lysosomal membrane integrity and suppressed tumor growth (156). Subsequently, an S class nanocarrier of NO (Nano-NO) was developed, and successfully targeted NO to hepatocellular cancer (157). Nano-NO has improved the administration and efficacy of chemotherapy. Additionally, combining nanomaterials with NO donors, as shown by Housein et al (78) and others (158), has improved the method of NO delivery. The aforementioned Nano-NO make tumor cells more susceptible to chemotherapy.

GTN in combination with vinorelbine and cisplatin increases the response in patients with lung cancer and reduces the median time to tumor progression (159). Additionally, the combination treatment of GTN and valproic acid results in the inhibition of Bcl-2 as well as the expression of Bax and caspase-3 in human K562 cells (160). STAT3 is associated with a number of the substituted NO-releasing quinolone-1,2,4-triazole/oxime derivatives (161). In melanoma with the B-Raf V600E mutation and vemurafenib-resistant melanoma, STAT3 inhibitors have shown efficacy (161). Poly-S nitrosylated human albumin alters colon cancer cell resistance to bevacizumab (162). Furthermore, the combination of bevacizumab with S-nitrosylated human albumin exhibits antitumor effects both in vitro and in vivo (163).

Long-term (3–5 days) exposure of cancer cells to low levels of H2S (30 M; sustained >7 days) using the slow-releasing H2S donor GYY4137 causes cancer cell death in vitro by activating caspase activity and causing apoptosis (164,165). In a mouse xenograft model, GYY4137 caused a reduction in tumor volume, and this had no apparent deleterious effects on physiological functions (165). A previous study, which was performed on 11 cancer cell lines, revealed that H2S-releasing non-steroidal anti-inflammatory drugs inhibited the proliferation of all 11 cancer cell lines that were tested (102), providing further evidence of the potential of H2S as an anticancer agent. Using sulfide salt NaHS, which releases large amounts of H2S instantaneously in an aqueous solution (≤400 µM; detected within first 1.5 h), caused only a minimal growth inhibitory effect in cancer cell lines, indicating the possibility that a long period of continuous, low-level H2S exposure is required for its efficient anticancer function (118). Based on these findings, it is hypothesized that the anti-proliferative effect of H2S is selective, meaning it affects cancer cells but not normal cells.

One must remember that the three gasotransmitters do not work alone. Instead, they work together. This cooperation occasionally occurs using overlapping signaling pathways (for instance, both NO and CO stimulate the sGC pathway). NO directly stimulates the sGC pathway, and H2S concurrently blocks cGMP via inhibition of cGMP phosphodiesterase (166). One of the few studies of this contest demonstrated the anticancer effect of a combined NO- and H2S-donating compound, nitric oxide and hydrogen sulfide-releasing hybrid-aspirin, both in vitro and in vivo (6). The impact of NO and H2S on the TME is displayed in Fig. 4, and several gasotransmitter-based drugs targeting the TME are currently being investigated in clinical studies (167–169). To further investigate and understand the nature of these interactions, more comprehensive studies are required, mainly in the context of cancer, which may be utilized for therapeutic benefits in the future.

Figure 4.

Impact of NO and H2S on the TME. Several gasotransmitter-based drugs targeting the TME are currently being tested in clinical trials. DEA NONOate, PAPA NONOate, DETA NONOate, JS-K, Nano-NO and GTN are NO-releasing drugs, GYY4137 and NaHS are H2S-releasing drugs, and NOSH-aspirin releases NOSH into the TME. When used in combination, these drugs increase the cytotoxic activity of various chemotherapeutic drugs. 3-MST, 3-mercaptopyruvate sulfurtransferase; CBS, cystathionine-β-synthase; CSE, cystathionine-γ-lyase; DEA NONOate, diethylamine NONOate; DETA NONOate, diethylenetriamine NONOate; GTN, nitroglycerin; H2S, hydrogen sulfide; JS-K, glutathione/glutathione S-transferase-activated nitric oxide; NaHS, sodium hydrosulfide; Nano-NO, nitric oxide nanoparticles; NO, nitric oxide; NOS, nitric oxide synthase; NOSH, nitric oxide and hydrogen sulfide-releasing hybrid; PAPA NONOate, 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino); TME, tumor microenvironment.

Conclusions

More than three decades of studies in the field of the three gasotransmitters NO, CO and H2S have resulted in the identification of several pathophysiological paradigms and associated experimental therapeutic approaches that may be ultimately suitable for clinical translation. In particular, the initial perplexing observation that both gasotransmitter-synthesis inhibitors and donors appear to have anticancer effects, which the complex biology and bell-shaped pharmacology of NO, CO and H2S can explain, should not be considered as a barrier to translation into clinical settings. Their critical functions in normal cells compared with cancer cells open avenues for combinatorial treatment approaches together with chemotherapeutic drugs, aiming for improved clinical significance.

Supplementary Material

Supporting Data

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

MAAN, ZOK, ZH, HAH, RMA and BMH wrote the manuscript and designed the figures. AS and TA wrote the manuscript and critically revised the paper. Data authentication is not applicable. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

CAF	cancer-associated fibroblast
CBS	cystathionine-β-synthase
CO	carbon monoxide
CRPC	castration-resistant prostate cancer
DEA NONOate	diethylamine NONOate
ECM	extracellular matrix
EDRF	endothelium-derived relaxing factor
eNOS	endothelial NOS
GLT-1	glutamine transporter-1
GSNO	S-nitroso glutathione
GTN	nitroglycerin
H₂S	hydrogen sulfide
HIF-1	hypoxia-inducible factor 1
HO	heme oxygenase
iNOS	inducible NOS
MOPP	mechlorethamine, oncovin, procarbazine and prednisone
N₂O₃	dinitrogen trioxide
NaHS	sodium hydrosulfide
nNOS	neuronal NOS
NO	nitric oxide
NOS	NO synthases
NRF2	nuclear factor erythroid 2
ONOO	peroxynitrite
RNS	reactive nitrogen species
sGC	soluble guanylyl cyclase
TAM	tumor-associated macrophage
TME	tumor microenvironment

References

1	Leaf C: Why we're losing the war on cancer (and how to win it). Fortune. 149:76–82. 84–86. 882004.PubMed/NCBI
2	Debela DT, Muzazu SG, Heraro KD, Ndalama MT, Mesele BW, Haile DC, Kitui SK and Manyazewal T: New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med. 9:205031212110343662021. View Article : Google Scholar : PubMed/NCBI
3	Ke X and Shen L: Molecular targeted therapy of cancer: The progress and future prospect. Front Laboratory Med. 1:69–75. 2017. View Article : Google Scholar
4	Liang XJ, Chen C, Zhao Y and Wang PC: Circumventing tumor resistance to chemotherapy by nanotechnology. Methods Mol Biol. 596:467–488. 2010. View Article : Google Scholar : PubMed/NCBI
5	Iyer AK, Khaled G, Fang J and Maeda H: Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today. 11:812–818. 2006. View Article : Google Scholar : PubMed/NCBI
6	Szabo C: Gasotransmitters in cancer: From pathophysiology to experimental therapy. Nat Rev Drug Discov. 15:185–203. 2016. View Article : Google Scholar : PubMed/NCBI
7	Xu W, Liu LZ, Loizidou M, Ahmed M and Charles IG: The role of nitric oxide in cancer. Cell Res. 12:311–320. 2002. View Article : Google Scholar : PubMed/NCBI
8	Ngowi EE, Afzal A, Sarfraz M, Khattak S, Zaman SU, Khan NH, Li T, Jiang QY, Zhang X, Duan SF, et al: Role of hydrogen sulfide donors in cancer development and progression. Int J Biol Sci. 17:73–88. 2021. View Article : Google Scholar : PubMed/NCBI
9	Hellmich MR and Szabo C: Hydrogen sulfide and cancer. Handb Exp Pharmacol. 230:233–241. 2015. View Article : Google Scholar : PubMed/NCBI
10	Wegiel B, Gallo D, Csizmadia E, Harris C, Belcher J, Vercellotti GM, Penacho N, Seth P, Sukhatme V, Ahmed A, et al: Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth. Cancer Res. 73:7009–7021. 2013. View Article : Google Scholar : PubMed/NCBI
11	Vannini F, Kashfi K and Nath N: The dual role of iNOS in cancer. Redox Biol. 6:334–343. 2015. View Article : Google Scholar : PubMed/NCBI
12	Kashfi K: The dichotomous role of H₂S in cancer cell biology? Déjà vu all over again. Biochem Pharmacol. 149:205–223. 2018. View Article : Google Scholar : PubMed/NCBI
13	Tien Vo TT, Vo QC, Tuan VP, Wee Y, Cheng HC and Lee IT: The potentials of carbon monoxide-releasing molecules in cancer treatment: An outlook from ROS biology and medicine. Redox Biol. 46:1021242021. View Article : Google Scholar : PubMed/NCBI
14	Gensini GF, Conti AA and Lippi D: The contributions of Paul Ehrlich to infectious disease. J Infection. 54:221–224. 2007. View Article : Google Scholar : PubMed/NCBI
15	Riddell S: The emperor of all maladies: A biography of cancer. J Clin Invest. 121:52011. View Article : Google Scholar
16	Bosch F and Rosich L: The contributions of Paul Ehrlich to pharmacology: A tribute on the occasion of the centenary of his Nobel Prize. Pharmacology. 82:171–179. 2008. View Article : Google Scholar : PubMed/NCBI
17	Valent P, Groner B, Schumacher U, Superti-Furga G, Busslinger M, Kralovics R, Zielinski C, Penninger JM, Kerjaschki D, Stingl G, et al: Paul Ehrlich (1854–1915) and his contributions to the foundation and birth of translational medicine. J Innate Immun. 8:111–120. 2016. View Article : Google Scholar : PubMed/NCBI
18	Faguet GB: A brief history of cancer: Age-old milestones underlying our current knowledge database. Int J Cancer. 136:2022–2036. 2015. View Article : Google Scholar : PubMed/NCBI
19	Baselga J, Bhardwaj N, Cantley LC, DeMatteo R, DuBois RN, Foti M, Gapstur SM, Hahn WC, Helman LJ, Jensen RA, et al: AACR cancer progress report 2015. Clin Cancer Res. 21 (Suppl 19):S1–S128. 2015. View Article : Google Scholar : PubMed/NCBI
20	Farber S and Diamond LK: Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 238:787–793. 1948. View Article : Google Scholar : PubMed/NCBI
21	Kotecha RS, Gottardo NG, Kees UR and Cole CH: The evolution of clinical trials for infant acute lymphoblastic leukemia. Blood Cancer J. 4:e2002014. View Article : Google Scholar : PubMed/NCBI
22	Kinjo J, Nakano D, Fujioka T and Okabe H: Screening of promising chemotherapeutic candidates from plants extracts. J Nat Med. 70:335–360. 2016. View Article : Google Scholar : PubMed/NCBI
23	Freireich EJ, Karon M and Frei III E: Quadruple combination therapy (VAMP) for acute lymphocytic leukemia of childhood. Proc Am Assoc Cancer Res. 5:201964.
24	Liebman HA, Hum GJ, Sheehan WW, Ryden VM and Bateman JR: Randomized study for the treatment of adult advanced Hodgkin's disease: Mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) versus lomustine, vinblastine, and prednisone. Cancer Treat Rep. 67:413–419. 1983.PubMed/NCBI
25	Bonadonna G, Zucali R, Monfardini S, De Lena M and Uslenghi C: Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 36:252–259. 1975. View Article : Google Scholar : PubMed/NCBI
26	Arruebo M, Vilaboa N, Sáez-Gutierrez B, Lambea J, Tres A, Valladares M and González-Fernández A: Assessment of the evolution of cancer treatment therapies. Cancers (Basel). 3:3279–3330. 2011. View Article : Google Scholar : PubMed/NCBI
27	Bonadonna G, Valagussa P, Moliterni A, Zambetti M and Brambilla C: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med. 332:901–906. 1995. View Article : Google Scholar : PubMed/NCBI
28	Fisher B, Sherman B, Rockette H, Redmond C, Margolese R and Fisher ER: 1-phenylalanine mustard (L-PAM) in the management of premenopausal patients with primary breast cancer: lack of association of disease-free survival with depression of ovarian function. National Surgical Adjuvant Project for Breast and Bowel Cancers. Cancer. 44:847–857. 1979. View Article : Google Scholar : PubMed/NCBI
29	Early Breast Cancer Trialists' Collaborative Group (EBCTCG), . Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: Meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 19:27–39. 2018. View Article : Google Scholar : PubMed/NCBI
30	Mansoori B, Mohammadi A, Davudian S, Shirjang S and Baradaran B: The different mechanisms of cancer drug resistance: A Brief Review. Adv Pharm Bull. 7:339–348. 2017. View Article : Google Scholar : PubMed/NCBI
31	Roma-Rodrigues C, Mendes R, Baptista PV and Fernandes AR: Targeting tumor microenvironment for cancer therapy. Int J Mol Sci. 20:8402019. View Article : Google Scholar : PubMed/NCBI
32	Bagnyukova TV, Serebriiskii IG, Zhou Y, Hopper-Borge EA, Golemis EA and Astsaturov I: Chemotherapy and signaling: How can targeted therapies supercharge cytotoxic agents? Cancer Biol Ther. 10:839–853. 2010. View Article : Google Scholar : PubMed/NCBI
33	Whiteside TL: The tumor microenvironment and its role in promoting tumor growth. Oncogene. 27:5904–5912. 2008. View Article : Google Scholar : PubMed/NCBI
34	Alkasalias T, Moyano-Galceran L, Arsenian-Henriksson M and Lehti K: Fibroblasts in the Tumor Microenvironment: Shield or Spear? Int J Mol Sci. 19:15322018. View Article : Google Scholar : PubMed/NCBI
35	Klemm F and Joyce JA: Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 25:198–213. 2015. View Article : Google Scholar : PubMed/NCBI
36	Vaupel P and Multhoff G: Hypoxia-/HIF-1α-Driven factors of the tumor microenvironment impeding antitumor immune responses and promoting malignant progression. Adv Exp Med Biol. 1072:171–175. 2018. View Article : Google Scholar : PubMed/NCBI
37	Jing X, Yang F, Shao C, Wei K, Xie M, Shen H and Shu Y: Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 18:1572019. View Article : Google Scholar : PubMed/NCBI
38	Luo W and Wang Y: Hypoxia mediates tumor malignancy and therapy resistance. Adv Exp Med Biol. 1136:1–18. 2019. View Article : Google Scholar : PubMed/NCBI
39	Jarosz-Biej M, Smolarczyk R, Cichoń T and Kułach N: Tumor Microenvironment as A ‘Game Changer’ in cancer radiotherapy. Int J Mol Sci. 20:32122019. View Article : Google Scholar : PubMed/NCBI
40	Befani C and Liakos P: The role of hypoxia-inducible factor-2 alpha in angiogenesis. J Cell Physiol. 233:9087–9098. 2018. View Article : Google Scholar : PubMed/NCBI
41	Senthebane DA, Rowe A, Thomford NE, Shipanga H, Munro D, Mazeedi MAMA, Almazyadi HAM, Kallmeyer K, Dandara C, Pepper MS, et al: The role of tumor microenvironment in chemoresistance: to survive, keep your enemies closer. Int J Mol Sci. 18:15862017. View Article : Google Scholar : PubMed/NCBI
42	Hass R, von der Ohe J and Ungefroren H: Impact of the tumor microenvironment on tumor heterogeneity and consequences for cancer cell plasticity and stemness. Cancers (Basel). 12:37162020. View Article : Google Scholar : PubMed/NCBI
43	Vitale I, Manic G, Coussens LM, Kroemer G and Galluzzi L: Macrophages and Metabolism in the Tumor Microenvironment. Cell Metab. 30:36–50. 2019. View Article : Google Scholar : PubMed/NCBI
44	Bu L, Baba H, Yoshida N, Miyake K, Yasuda T, Uchihara T, Tan P and Ishimoto T: Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene. 38:4887–4901. 2019. View Article : Google Scholar : PubMed/NCBI
45	Wang R: The Evolution of Gasotransmitter Biology and Medicine. Signal Transduction and the Gasotransmitters: NO, CO, and H2S in Biology and Medicine. Wang R: Humana Press; Totowa, NJ: pp. 3–31. 2004, View Article : Google Scholar
46	Andrew PJ and Mayer B: Enzymatic function of nitric oxide synthases. Cardiovasc Res. 43:521–531. 1999. View Article : Google Scholar : PubMed/NCBI
47	Ryter SW and Choi AMK: Heme oxygenase-1/carbon monoxide: From metabolism to molecular therapy. Am J Respir Cell Mol Biol. 41:251–260. 2009. View Article : Google Scholar : PubMed/NCBI
48	Naik JS, O'Donaughy TL and Walker BR: Endogenous carbon monoxide is an endothelial-derived vasodilator factor in the mesenteric circulation. Am J Physiol Heart Circ Physiol. 284:H838–H845. 2003. View Article : Google Scholar : PubMed/NCBI
49	Wang R: The gasotransmitter role of hydrogen sulfide. Antioxid Redox Signal. 5:493–501. 2003. View Article : Google Scholar : PubMed/NCBI
50	Tang G, Wu L, Liang W and Wang R: Direct stimulation of K(ATP) channels by exogenous and endogenous hydrogen sulfide in vascular smooth muscle cells. Mol Pharmacol. 68:1757–1764. 2005. View Article : Google Scholar : PubMed/NCBI
51	Salihi A: Activation of inward rectifier potassium channels in high salt impairment of hydrogen sulfide-induced aortic relaxation in rats. Physiol Pharmacol. 19:263–273. 2016.
52	Wang L, Xie X, Ke B, Huang W, Jiang X and He G: Recent advances on endogenous gasotransmitters in inflammatory dermatological disorders. J Adv Res. (In Press).
53	West JB: Joseph Priestley, oxygen, and the enlightenment. Am J Physiol Lung Cell Mol Physiol. 306:L111–L119. 2014. View Article : Google Scholar : PubMed/NCBI
54	Gruetter CA, Barry BK, McNamara DB, Gruetter DY, Kadowitz PJ and Ignarro L: Relaxation of bovine coronary artery and activation of coronary arterial guanylate cyclase by nitric oxide, nitroprusside and a carcinogenic nitrosoamine. J Cyclic Nucleotide Res. 5:211–224. 1979.PubMed/NCBI
55	Furchgott RF and Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 288:373–376. 1980. View Article : Google Scholar : PubMed/NCBI
56	Ignarro LJ, Buga GM, Wood KS, Byrns RE and Chaudhuri G: Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA. 84:9265–9269. 1987. View Article : Google Scholar : PubMed/NCBI
57	Palmer RM, Ferrige AG and Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 327:524–526. 1987. View Article : Google Scholar : PubMed/NCBI
58	Moncada S, Palmer RM and Higgs EA: The discovery of nitric oxide as the endogenous nitrovasodilator. Hypertension. 12:365–372. 1988. View Article : Google Scholar : PubMed/NCBI
59	Murad F, Mittal CK, Arnold WP, Katsuki S and Kimura H: Guanylate cyclase: Activation by azide, nitro compounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin. Adv Cyclic Nucleotide Res. 9:145–158. 1978.PubMed/NCBI
60	Koshland DE Jr: The molecule of the year. Science. 258:18611992. View Article : Google Scholar : PubMed/NCBI
61	Marsh N and Marsh A: A short history of nitroglycerine and nitric oxide in pharmacology and physiology. Clin Exp Pharmacol Physiol. 27:313–319. 2000. View Article : Google Scholar : PubMed/NCBI
62	Xu WM and Liu LZ: Nitric Oxide: Nitric oxide: From a mysterious labile factor to the molecule of the Nobel Prize. Recent progress in nitric oxide research. Cell Res. 8:251–258. 1998. View Article : Google Scholar : PubMed/NCBI
63	Yetik-Anacak G and Catravas JD: Nitric oxide and the endothelium: History and impact on cardiovascular disease. Vascul Pharmacol. 45:268–276. 2006. View Article : Google Scholar : PubMed/NCBI
64	Kennedy J: Account of the phænomena produced by a large quantity of nitric oxide of quicksilver, swallowed by mistake; and of the means employed to counteract its deleterious influence. Med Chir J Rev. 1:189–196. 1816.PubMed/NCBI
65	Thomsen LL, Lawton FG, Knowles RG, Beesley JE, Riveros-Moreno V and Moncada S: Nitric oxide synthase activity in human gynecological cancer. Cancer Res. 54:1352–1354. 1994.PubMed/NCBI
66	Hidy GM, Mueller PK, Altshuler SL, Chow JC and Watson JG: Air quality measurements-From rubber bands to tapping the rainbow. J Air Waste Manag Assoc. 67:637–668. 2017. View Article : Google Scholar : PubMed/NCBI
67	Kinnicutt LP and Sanford GR: The iodometric determination of small quantities of carbon monoxide. Public Health Pap Rep. 25:600–604. 1899.PubMed/NCBI
68	Luden G: THE carbon monoxide menace and the cancer problem. Can Med Assoc J. 17:43–48. 1927.PubMed/NCBI
69	Roughton FJW: The Kinetics of Haemoglobin V-The Combination of Carbon Monoxide with Reduced Haemoglobin. Proc R Soc London Series B, Containing Papers Biol Character. 115:464–473. 1934. View Article : Google Scholar
70	Roughton FJW and Darling RC: The effect of carbon monoxide on the oxyhemoglobin dissociation curve. Am J Physiol Legacy Content. 141:17–31. 1944. View Article : Google Scholar
71	Roughton FJ: The equilibrium between carbon monoxide and sheep haemoglobin at very high percentage saturations. J Physiol. 126:359–383. 1954. View Article : Google Scholar : PubMed/NCBI
72	Sjostrand T: Endogenous formation of carbon monoxide in man. Nature. 164:5801949. View Article : Google Scholar : PubMed/NCBI
73	Tenhunen R, Marver HS and Schmid R: Microsomal heme oxygenase. Characterization of the enzyme. J Biol Chem. 244:6388–6394. 1969. View Article : Google Scholar : PubMed/NCBI
74	Zhao Y, Biggs TD and Xian M: Hydrogen sulfide (H2S) releasing agents: Chemistry and biological applications. Chem Commun (Camb). 50:11788–11805. 2014. View Article : Google Scholar : PubMed/NCBI
75	Tanner FW: Studies on the bacterial metabolism of sulfur: I. Formation of hydrogen sulfide from certain sulfur compounds under aerobic conditions. J Bacteriol. 2:585–593. 1917. View Article : Google Scholar : PubMed/NCBI
76	Rose P, Moore PK, Ming SH, Nam OC, Armstrong JS and Whiteman M: Hydrogen sulfide protects colon cancer cells from chemopreventative agent beta-phenylethyl isothiocyanate induced apoptosis. World J Gastroenterol. 11:3990–3997. 2005. View Article : Google Scholar : PubMed/NCBI
77	Wang R: Signaling pathways for the vascular effects of hydrogen sulfide. Curr Opin Nephrol Hypertens. 20:107–112. 2011. View Article : Google Scholar : PubMed/NCBI
78	Housein Z, Kareem TS and Salihi A: In vitro anticancer activity of hydrogen sulfide and nitric oxide alongside nickel nanoparticle and novel mutations in their genes in CRC patients. Sci Rep. 11:25362021. View Article : Google Scholar : PubMed/NCBI
79	Shen Y, Shen Z, Luo S, Guo W and Zhu YZ: The cardioprotective effects of hydrogen sulfide in heart diseases: From molecular mechanisms to therapeutic potential. Oxid Med Cell Longev. 2015:9251672015. View Article : Google Scholar : PubMed/NCBI
80	Coleman JW: Nitric oxide in immunity and inflammation. Int Immunopharmacol. 1:1397–1406. 2001. View Article : Google Scholar : PubMed/NCBI
81	Esplugues JV: NO as a signalling molecule in the nervous system. Br J Pharmacol. 135:1079–1095. 2002. View Article : Google Scholar : PubMed/NCBI
82	Sen S, Jensen K, Brennan K, Ramadoss S and Chaudhuri G: Chapter 10-Chemoprotective and chemosensitizing effects of nitric oxide and other biologically active gases in breast cancer chemotherapy: Potential implications. Nitric Oxide (Donor/Induced) in Chemosensitizing. Bonavida B: Academic Press; pp. 169–178. 2017, View Article : Google Scholar
83	Choudhari SK, Chaudhary M, Bagde S, Gadbail AR and Joshi V: Nitric oxide and cancer: A review. World J Surg Oncol. 11:1182013. View Article : Google Scholar : PubMed/NCBI
84	Burke AJ, Sullivan FJ, Giles FJ and Glynn SA: The yin and yang of nitric oxide in cancer progression. Carcinogenesis. 34:503–512. 2013. View Article : Google Scholar : PubMed/NCBI
85	Ying L and Hofseth LJ: An Emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Cancer Res. 67:1407–1410. 2007. View Article : Google Scholar : PubMed/NCBI
86	Tennyson Andrew G and Lippard Stephen J: Generation, translocation, and action of nitric oxide in living systems. Chem Biol. 18:1211–1220. 2011. View Article : Google Scholar : PubMed/NCBI
87	Grisham MB, Jourd'Heuil D and Wink DA: Nitric oxide. I. Physiological chemistry of nitric oxide and its metabolites: Implications in inflammation. Am J Physiol. 276:G315–G321. 1999.PubMed/NCBI
88	Subapriya R, Kumaraguruparan R, Ramachandran CR and Nagini S: Oxidant-antioxidant status in patients with oral squamous cell carcinomas at different intraoral sites. Clin Biochem. 35:489–493. 2002. View Article : Google Scholar : PubMed/NCBI
89	Cheng H, Wang L, Mollica M, Re AT, Wu S and Zuo L: Nitric oxide in cancer metastasis. Cancer Lett. 353:1–7. 2014. View Article : Google Scholar : PubMed/NCBI
90	Frérart F, Sonveaux P, Rath G, Smoos A, Meqor A, Charlier N, Jordan BF, Saliez J, Noël A, Dessy C, et al: The acidic tumor microenvironment promotes the reconversion of nitrite into nitric oxide: Towards a new and safe radiosensitizing strategy. Clin Cancer Res. 14:2768–2774. 2008. View Article : Google Scholar : PubMed/NCBI
91	Tanese K, Grimm EA and Ekmekcioglu S: The role of melanoma tumor-derived nitric oxide in the tumor inflammatory microenvironment: Its impact on the chemokine expression profile, including suppression of CXCL10. Int J Cancer. 131:891–901. 2012. View Article : Google Scholar : PubMed/NCBI
92	Decker NK, Abdelmoneim SS, Yaqoob U, Hendrickson H, Hormes J, Bentley M, Pitot H, Urrutia R, Gores GJ and Shah VH: Nitric oxide regulates tumor cell cross-talk with stromal cells in the tumor microenvironment of the liver. Am J Pathol. 173:1002–1012. 2008. View Article : Google Scholar : PubMed/NCBI
93	PeNarando J, Aranda E and RodrIguez-Ariza A: Immunomodulatory roles of nitric oxide in cancer: Tumor microenvironment says ‘NO’ to antitumor immune response. Transl Res. 210:99–108. 2019. View Article : Google Scholar : PubMed/NCBI
94	Arora H, Panara K, Kuchakulla M, Kulandavelu S, Burnstein KL, Schally AV, Hare JM and Ramasamy R: Alterations of tumor microenvironment by nitric oxide impedes castration-resistant prostate cancer growth. Proc Natl Acad Sci USA. 115:11298–11303. 2018. View Article : Google Scholar : PubMed/NCBI
95	Yang G: Hydrogen sulfide in cell survival: A double-edged sword. Exp Rev Clin Pharmacol. 4:33–47. 2011. View Article : Google Scholar
96	Pei Y, Wu B, Cao Q, Wu L and Yang G: Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells. Toxicol Appl Pharmacol. 257:420–428. 2011. View Article : Google Scholar : PubMed/NCBI
97	Bhattacharyya S, Saha S, Giri K, Lanza IR, Nair KS, Jennings NB, Rodriguez-Aguayo C, Lopez-Berestein G, Basal E, Weaver AL, et al: Cystathionine beta-synthase (CBS) contributes to advanced ovarian cancer progression and drug resistance. PLoS One. 8:e791672013. View Article : Google Scholar : PubMed/NCBI
98	Hellmich MR, Coletta C, Chao C and Szabo C: The therapeutic potential of cystathionine β-synthetase/hydrogen sulfide inhibition in cancer. Antioxid Redox Signal. 22:424–448. 2015. View Article : Google Scholar : PubMed/NCBI
99	Zhu H, Blake S, Chan KT, Pearson RB and Kang J: Cystathionine β-synthase in physiology and cancer. Biomed Res Int. 2018:32051252018. View Article : Google Scholar : PubMed/NCBI
100	Hellmich MR and Szabo C: Hydrogen sulfide and cancer. Chemistry, Biochemistry and Pharmacology of Hydrogen Sulfide. Springer; New York, NY: pp. 233–241. 2015, View Article : Google Scholar : PubMed/NCBI
101	Sen N: Functional and molecular insights of hydrogen sulfide signaling and protein sulfhydration. J Mol Biol. 429:543–561. 2017. View Article : Google Scholar : PubMed/NCBI
102	Chattopadhyay M, Kodela R, Nath N, Dastagirzada YM, Velázquez-Martínez CA, Boring D and Kashfi K: Hydrogen sulfide-releasing NSAIDs inhibit the growth of human cancer cells: A general property and evidence of a tissue type-independent effect. Biochem Pharmacol. 83:715–722. 2012. View Article : Google Scholar : PubMed/NCBI
103	Szabo C, Ransy C, Módis K, Andriamihaja M, Murghes B, Coletta C, Olah G, Yanagi K and Bouillaud F: Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms. Br J Pharmacol. 171:2099–2122. 2014. View Article : Google Scholar : PubMed/NCBI
104	Rose P, Moore PK and Zhu YZ: H₂S biosynthesis and catabolism: New insights from molecular studies. Cell Mol Life Sci. 74:1391–1412. 2017. View Article : Google Scholar : PubMed/NCBI
105	Cao X, Ding L, Xie ZZ, Yang Y, Whiteman M, Moore PK and Bian JS: A review of hydrogen sulfide synthesis, metabolism, and measurement: Is modulation of hydrogen sulfide a novel therapeutic for cancer? Antioxid Redox Signal. 31:1–38. 2019. View Article : Google Scholar : PubMed/NCBI
106	Giuffrè A, Tomé CS, Fernandes DGF, Zuhra K and Vicente JB: Hydrogen sulfide metabolism and signaling in the tumor microenvironment. Adv Exp Med Biol. 1219:335–353. 2020. View Article : Google Scholar : PubMed/NCBI
107	Wang RH, Chu YH and Lin KT: The hidden role of hydrogen sulfide metabolism in cancer. Int J Mol Sci. 22:65622021. View Article : Google Scholar : PubMed/NCBI
108	Watnick RS: The role of the tumor microenvironment in regulating angiogenesis. Cold Spring Harb Perspect Med. 2:a0066762012. View Article : Google Scholar : PubMed/NCBI
109	Zhou Y, Li XH, Zhang CC, Wang MJ, Xue WL, Wu DD, Ma FF, Li WW, Tao BB and Zhu YC: Hydrogen sulfide promotes angiogenesis by downregulating miR-640 via the VEGFR2/mTOR pathway. Am J Physiol Cell Physiol. 310:C305–C317. 2016. View Article : Google Scholar : PubMed/NCBI
110	Wang M, Yan J, Cao X, Hua P and Li Z: Hydrogen sulfide modulates epithelial-mesenchymal transition and angiogenesis in non-small cell lung cancer via HIF-1α activation. Biochem Pharmacol. 172:1137752020. View Article : Google Scholar : PubMed/NCBI
111	Szabo C and Hellmich MR: Endogenously produced hydrogen sulfide supports tumor cell growth and proliferation. Cell Cycle. 12:2915–2916. 2013. View Article : Google Scholar : PubMed/NCBI
112	Holwerda KM, Burke SD, Faas MM, Zsengeller Z, Stillman IE, Kang PM, van Goor H, McCurley A, Jaffe IZ, Karumanchi SA and Lely AT: Hydrogen sulfide attenuates sFlt1-Induced hypertension and renal damage by upregulating vascular endothelial growth factor. J Am Soc Nephrol. 25:717–725. 2014. View Article : Google Scholar : PubMed/NCBI
113	Szabo C, Coletta C, Chao C, Módis K, Szczesny B, Papapetropoulos A and Hellmich MR: Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci USA. 110:12474–12479. 2013. View Article : Google Scholar : PubMed/NCBI
114	Liu D, Liu M, Wan Y, Zhou X, Yang S, An L, Huang G and Tian Q: Remodeling endogenous H₂S microenvironment in colon cancer to enhance chemodynamic therapy. Chem Engineering J. 422:1300982021. View Article : Google Scholar
115	Wan M, Liu Z, Li T, Chen H, Wang Q, Chen T, Tao Y and Mao C: Zwitterion-Based hydrogen sulfide nanomotors induce multiple acidosis in tumor cells by destroying tumor metabolic symbiosis. Angew Chem Int Ed Engl. 60:16139–16148. 2021. View Article : Google Scholar : PubMed/NCBI
116	Li D, Xiong Q, Peng J, Hu B, Li W, Zhu Y and Shen X: Hydrogen Sulfide Up-Regulates the expression of ATP-Binding cassette transporter A1 via promoting nuclear translocation of PPARα. Int J Mol Sci. 17:6352016. View Article : Google Scholar : PubMed/NCBI
117	Schulze A and Harris AL: How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 491:3642012. View Article : Google Scholar : PubMed/NCBI
118	Lee ZW, Teo XY, Tay EY, Tan CH, Hagen T, Moore PK and Deng LW: Utilizing hydrogen sulfide as a novel anti-cancer agent by targeting cancer glycolysis and pH imbalance. Br J Pharmacol. 171:4322–4336. 2014. View Article : Google Scholar : PubMed/NCBI
119	Niland S, Riscanevo AX and Eble JA: Matrix metalloproteinases shape the tumor microenvironment in cancer progression. Int J Mol Sci. 23:1462021. View Article : Google Scholar : PubMed/NCBI
120	Harjunpää H, Llort Asens M, Guenther C and Fagerholm SC: Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment. Front Immunol. 10:10782019. View Article : Google Scholar : PubMed/NCBI
121	Mao Y, Keller ET, Garfield DH, Shen K and Wang J: Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev. 32:303–315. 2013. View Article : Google Scholar : PubMed/NCBI
122	Zhen Y, Pan W, Hu F, Wu H, Feng J, Zhang Y and Chen J: Exogenous hydrogen sulfide exerts proliferation/anti-apoptosis/angiogenesis/migration effects via amplifying the activation of NF-κB pathway in PLC/PRF/5 hepatoma cells. Int J Oncol. 46:2194–2204. 2015. View Article : Google Scholar : PubMed/NCBI
123	Li H, Xu F, Gao G, Gao X, Wu B, Zheng C, Wang P, Li Z, Hua H and Li D: Hydrogen sulfide and its donors: Novel antitumor and antimetastatic therapies for triple-negative breast cancer. Redox Biol. 34:1015642020. View Article : Google Scholar : PubMed/NCBI
124	Wu D, Li M, Tian W, Wang S, Cui L, Li H, Wang H, Ji A and Li Y: Hydrogen sulfide acts as a double-edged sword in human hepatocellular carcinoma cells through EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways. Sci Rep. 7:51342017. View Article : Google Scholar : PubMed/NCBI
125	Wu D, Li J, Zhang Q, Tian W, Zhong P, Liu Z, Wang H, Wang H, Ji A and Li Y: Exogenous hydrogen sulfide regulates the growth of human thyroid carcinoma cells. Oxid Med Cell Longev. 2019:69272982019. View Article : Google Scholar : PubMed/NCBI
126	Zhang L, Qi Q, Yang J, Sun D, Li C, Xue Y, Jiang Q, Tian Y, Xu C and Wang R: An anticancer role of hydrogen sulfide in human gastric cancer cells. Oxid Med Cell Longev. 2015:6364102015. View Article : Google Scholar : PubMed/NCBI
127	Rose JJ, Wang L, Xu Q, McTiernan CF, Shiva S, Tejero J and Gladwin MT: Carbon monoxide poisoning: Pathogenesis, management, and future directions of therapy. Am J Respir Crit Care Med. 195:596–606. 2017. View Article : Google Scholar : PubMed/NCBI
128	Motterlini R and Otterbein LE: The therapeutic potential of carbon monoxide. Nat Rev Drug Discov. 9:728–743. 2010. View Article : Google Scholar : PubMed/NCBI
129	Wegiel B, Nemeth Z, Correa-Costa M, Bulmer AC and Otterbein LE: Heme Oxygenase-1: A Metabolic Nike. Antioxid Redox Signal. 20:1709–1722. 2014. View Article : Google Scholar : PubMed/NCBI
130	Ismailova A, Kuter D, Bohle DS and Butler IS: An overview of the potential therapeutic applications of CO-Releasing molecules. Bioinorg Chem Appl. 2018:85473642018. View Article : Google Scholar : PubMed/NCBI
131	Ji X, Damera K, Zheng Y, Yu B, Otterbein LE and Wang B: Toward carbon monoxide-based therapeutics: Critical drug delivery and developability issues. J Pharm Sci. 105:406–416. 2016. View Article : Google Scholar : PubMed/NCBI
132	McCoubrey WK Jr, Huang T and Maines MD: Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem. 247:725–732. 1997. View Article : Google Scholar : PubMed/NCBI
133	Otterbein LE, Soares MP, Yamashita K and Bach FH: Heme oxygenase-1: Unleashing the protective properties of heme. Trends Immunol. 24:449–455. 2003. View Article : Google Scholar : PubMed/NCBI
134	Ryter SW, Alam J and Choi AMK: Heme Oxygenase-1/Carbon monoxide: From basic science to therapeutic applications. Physiol Rev. 86:583–650. 2006. View Article : Google Scholar : PubMed/NCBI
135	Chen S, Wang X, Nisar MF, Lin M and Zhong JL: Heme Oxygenases: Cellular multifunctional and protective molecules against UV–Induced oxidative stress. Oxid Med Cell Longev. 2019:54167282019. View Article : Google Scholar : PubMed/NCBI
136	Goebel U and Wollborn J: Carbon monoxide in intensive care medicine-time to start the therapeutic application? Intensive Care Med Exp. 8:22020. View Article : Google Scholar : PubMed/NCBI
137	Zuckerbraun BS, Chin BY, Bilban M, d'Avila JC, Rao J, Billiar TR and Otterbein LE: Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J. 21:1099–1106. 2007. View Article : Google Scholar : PubMed/NCBI
138	Chin BY, Jiang G, Wegiel B, Wang HJ, Macdonald T, Zhang XC, Gallo D, Cszimadia E, Bach FH, Lee PJ and Otterbein LE: Hypoxia-inducible factor 1alpha stabilization by carbon monoxide results in cytoprotective preconditioning. Proc Natl Acad Sci USA. 104:5109–5114. 2007. View Article : Google Scholar : PubMed/NCBI
139	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
140	Shefa U, Yeo SG, Kim MS, Song IO, Jung J, Jeong NY and Huh Y: Role of gasotransmitters in oxidative stresses, neuroinflammation, and neuronal repair. Biomed Res. 2017:16893412017.PubMed/NCBI
141	Yang C, Jeong S, Ku S, Lee K and Park MH: Use of gasotransmitters for the controlled release of polymer-based nitric oxide carriers in medical applications. J Control Release. 279:157–170. 2018. View Article : Google Scholar : PubMed/NCBI
142	Hassan AY, Maulood IM and Salihi A: The vasodilatory mechanism of nitric oxide and hydrogen sulfide in the human mesenteric artery in patients with colorectal cancer. Exp Ther Med. 21:2142021. View Article : Google Scholar : PubMed/NCBI
143	Konovalova NP, Goncharova SA, Volkova LM, Rajewskaya TA, Eremenko LT and Korolev AM: Nitric oxide donor increases the efficiency of cytostatic therapy and retards the development of drug resistance. Nitric Oxide. 8:59–64. 2003. View Article : Google Scholar : PubMed/NCBI
144	Weyerbrock A, Baumer B and Papazoglou A: Growth inhibition and chemosensitization of exogenous nitric oxide released from NONOates in glioma cells in vitro. J Neurosurg. 110:128–136. 2009. View Article : Google Scholar : PubMed/NCBI
145	Wink DA, Cook JA, Christodoulou D, Krishna MC, Pacelli R, Kim S, DeGraff W, Gamson J, Vodovotz Y, Russo A and Mitchell JB: Nitric oxide and some nitric oxide donor compounds enhance the cytotoxicity of cisplatin. Nitric Oxide. 1:88–94. 1997. View Article : Google Scholar : PubMed/NCBI
146	Huerta-Yepez S, Vega M, Escoto-Chavez SE, Murdock B, Sakai T, Baritaki S and Bonavida B: Nitric oxide sensitizes tumor cells to TRAIL-induced apoptosis via inhibition of the DR5 transcription repressor Yin Yang 1. Nitric Oxide. 20:39–52. 2009. View Article : Google Scholar : PubMed/NCBI
147	Huerta S, Baay-Guzman G, Gonzalez-Bonilla CR, Livingston EH, Huerta-Yepez S and Bonavida B: In vitro and in vivo sensitization of SW620 metastatic colon cancer cells to CDDP-induced apoptosis by the nitric oxide donor DETANONOate: Involvement of AIF. Nitric Oxide. 20:182–194. 2009. View Article : Google Scholar : PubMed/NCBI
148	Bratasz A, Selvendiran K, Wasowicz T, Bobko A, Khramtsov VV, Ignarro LJ and Kuppusamy P: NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols. J Transl Med. 6:92008. View Article : Google Scholar : PubMed/NCBI
149	Safdar S, Payne CA, Tu NH and Taite LJ: Targeted nitric oxide delivery preferentially induces glioma cell chemosensitivity via altered p53 and O(6)-methylguanine-DNA methyltransferase activity. Biotechnol Bioengering. 110:1211–1220. 2013. View Article : Google Scholar : PubMed/NCBI
150	Shami PJ, Saavedra JE, Wang LY, Bonifant CL, Diwan BA, Singh SV, Gu Y, Fox SD, Buzard GS and Citro ML: JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity. Mol Cancer Ther. 2:409–417. 2003.PubMed/NCBI
151	Qiu M, Ke L, Zhang S, Zeng X, Fang Z and Liu J: JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin. Cancer Chemother Pharmacol. 80:275–286. 2017. View Article : Google Scholar : PubMed/NCBI
152	Laschak M, Spindler KD, Schrader AJ, Hessenauer A, Streicher W, Schrader M and Cronauer MV: JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells. BMC Cancer. 12:1302012. View Article : Google Scholar : PubMed/NCBI
153	Qiu M, Chen L, Tan G, Ke L, Zhang S, Chen H and Liu J: A reactive oxygen species activation mechanism contributes to JS-K-induced apoptosis in human bladder cancer cells. Sci Rep. 5:151042015. View Article : Google Scholar : PubMed/NCBI
154	Riganti C, Doublier S, Costamagna C, Aldieri E, Pescarmona G, Ghigo D and Bosia A: Activation of nuclear factor-kappa B pathway by simvastatin and RhoA silencing increases doxorubicin cytotoxicity in human colon cancer HT29 cells. Mol Pharmacol. 74:476–484. 2008. View Article : Google Scholar : PubMed/NCBI
155	De Boo S, Kopecka J, Brusa D, Gazzano E, Matera L, Ghigo D, Bosia A and Riganti C: iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells. Mol Cancer. 8:1082009. View Article : Google Scholar : PubMed/NCBI
156	Alimoradi H, Greish K, Barzegar-Fallah A, Alshaibani L and Pittalà V: Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity. Int J Nanomedicine. 13:7771–7787. 2018. View Article : Google Scholar : PubMed/NCBI
157	Sung YC, Jin PR, Chu LA, Hsu FF, Wang MR, Chang CC, Chiou SJ, Qiu JT, Gao DY, Lin CC, et al: Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies. Nat Nanotechnol. 14:1160–1169. 2019. View Article : Google Scholar : PubMed/NCBI
158	Pieretti JC, Pelegrino MT, Nascimento MHM, Tortella GR, Rubilar O and Seabra AB: Small molecules for great solutions: Can nitric oxide-releasing nanomaterials overcome drug resistance in chemotherapy? Biochem Pharmacol. 176:1137402020. View Article : Google Scholar : PubMed/NCBI
159	Yasuda H, Nakayama K, Watanabe M, Suzuki S, Fuji H, Okinaga S, Kanda A, Zayasu K, Sasaki T, Asada M, et al: Nitroglycerin treatment may enhance chemosensitivity to docetaxel and carboplatin in patients with lung adenocarcinoma. Clin Cancer Res. 12:6748–6757. 2006. View Article : Google Scholar : PubMed/NCBI
160	Aalaei S, Mohammadzadeh M and Pazhang Y: Synergistic induction of apoptosis in a cell model of human leukemia K562 by nitroglycerine and valproic acid. EXCLI J. 18:619–630. 2019.PubMed/NCBI
161	Kaoud TS, Mohassab AM, Hassan HA, Yan C, Van Ravenstein SX, Abdelhamid D, Dalby KN and Abdel-Aziz M: NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth. Eur J Med Chem. 186:1118852020. View Article : Google Scholar : PubMed/NCBI
162	Ishima Y, Kragh-Hansen U, Maruyama T and Otagiri M: Poly-s-nitrosated albumin as a safe and effective multifunctional antitumor agent: Characterization, biochemistry and possible future therapeutic applications. Biomed Res Int. 2013:3538922013. View Article : Google Scholar : PubMed/NCBI
163	Ishima Y, Inoue A, Fang J, Kinoshita R, Ikeda M, Watanabe H, Maeda H, Otagiri M and Maruyama T: Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide. Cancer Sci. 106:194–200. 2015. View Article : Google Scholar : PubMed/NCBI
164	Li L, Whiteman M, Guan YY, Neo KL, Cheng Y, Lee SW, Zhao Y, Baskar R, Tan CH and Moore PK: Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): New insights into the biology of hydrogen sulfide. Circulation. 117:2351–2360. 2008. View Article : Google Scholar : PubMed/NCBI
165	Lee ZW, Zhou J, Chen CS, Zhao Y, Tan CH, Li L, Moore PK and Deng LW: The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effects in vitro and in vivo. PLoS One. 6:e210772011. View Article : Google Scholar : PubMed/NCBI
166	Nalli AD, Bhattacharya S, Wang H, Kendig DM, Grider JR and Murthy KS: Augmentation of cGMP/PKG pathway and colonic motility by hydrogen sulfide. Am J Physiol Gastrointest Liver Physiol. 313:G330–G341. 2017. View Article : Google Scholar : PubMed/NCBI
167	Liu B, Huang X, Li Y, Liao W, Li M, Liu Y, He R, Feng D, Zhu R and Kurihara H: JS-K, a nitric oxide donor, induces autophagy as a complementary mechanism inhibiting ovarian cancer. BMC Cancer. 19:6452019. View Article : Google Scholar : PubMed/NCBI
168	Fonseca MD, Cunha FQ, Kashfi K and Cunha TM: NOSH-aspirin (NBS-1120), a dual nitric oxide and hydrogen sulfide-releasing hybrid, reduces inflammatory pain. Pharmacol Res Perspect. 3:e001332015. View Article : Google Scholar : PubMed/NCBI
169	Rose P, Dymock BW and Moore PK: GYY4137, a novel water-soluble, H2S-releasing molecule. Methods Enzymol. 554:143–167. 2015. View Article : Google Scholar : PubMed/NCBI
170	Aaltoma SH, Lipponen PK and Kosma VM: Inducible nitric oxide synthase (iNOS) expression and its prognostic value in prostate cancer. Anticancer Res. 21:3101–3106. 2001.PubMed/NCBI
171	Aaltomaa SH, Lipponen PK, Viitanen J, Kankkunen JP, Ala-Opas MY and Kosma VM: The prognostic value of inducible nitric oxide synthase in local prostate cancer. BJU Int. 86:234–239. 2000. View Article : Google Scholar : PubMed/NCBI
172	Bhowmick R and Girotti AW: Pro-survival and pro-growth effects of stress-induced nitric oxide in a prostate cancer photodynamic therapy model. Cancer Lett. 343:115–122. 2014. View Article : Google Scholar : PubMed/NCBI
173	Coulter JA, Page NL, Worthington J, Robson T, Hirst DG and McCarthy HO: Transcriptional regulation of inducible nitric oxide synthase gene therapy: Targeting early stage and advanced prostate cancer. J Gene Med. 12:755–765. 2010. View Article : Google Scholar : PubMed/NCBI
174	Cronauer MV, Ince Y, Engers R, Rinnab L, Weidemann W, Suschek CV, Burchardt M, Kleinert H, Wiedenmann J, Sies H, et al: Nitric oxide-mediated inhibition of androgen receptor activity: Possible implications for prostate cancer progression. Oncogene. 26:1875–1884. 2007. View Article : Google Scholar : PubMed/NCBI
175	Erlandsson A, Carlsson J, Andersson SO, Vyas C, Wikström P, Andrén O, Davidsson S and Rider JR: High inducible nitric oxide synthase in prostate tumor epithelium is associated with lethal prostate cancer. Scand J Urol. 52:129–133. 2018. View Article : Google Scholar : PubMed/NCBI
176	McCarthy HO, Coulter JA, Worthington J, Robson T and Hirst DG: Human osteocalcin: A strong promoter for nitric oxide synthase gene therapy, with specificity for hormone refractory prostate cancer. J Gene Med. 9:511–520. 2007. View Article : Google Scholar : PubMed/NCBI
177	Fahey JM and Girotti AW: Accelerated migration and invasion of prostate cancer cells after a photodynamic therapy-like challenge: Role of nitric oxide. Nitric Oxide. 49:47–55. 2015. View Article : Google Scholar : PubMed/NCBI
178	D'Este F, Della Pietra E, Badillo Pazmay GV, Xodo LE and Rapozzi V: Role of nitric oxide in the response to photooxidative stress in prostate cancer cells. Biochem Pharmacol. 182:1142052020. View Article : Google Scholar : PubMed/NCBI
179	Ryk C, de Verdier P, Montgomery E, Peter Wiklund N, Wiklund F and Gronberg H: Polymorphisms in the nitric-oxide synthase 2 gene and prostate cancer pathogenesis. Redox Biol. 5:4192015. View Article : Google Scholar : PubMed/NCBI
180	Uotila P, Valve E, Martikainen P, Nevalainen M, Nurmi M and Harkonen P: Increased expression of cyclooxygenase-2 and nitric oxide synthase-2 in human prostate cancer. Urol Res. 29:23–28. 2001. View Article : Google Scholar : PubMed/NCBI
181	Abdelmagid SA, Rickard JA, McDonald WJ, Thomas LN and Too CK: CAT-1-mediated arginine uptake and regulation of nitric oxide synthases for the survival of human breast cancer cell lines. J Cell Biochem. 112:1084–1092. 2011. View Article : Google Scholar : PubMed/NCBI
182	Abdelmagid SA and Too CK: Prolactin and estrogen up-regulate carboxypeptidase-d to promote nitric oxide production and survival of mcf-7 breast cancer cells. Endocrinology. 149:4821–4828. 2008. View Article : Google Scholar : PubMed/NCBI
183	Ambs S and Glynn SA: Candidate pathways linking inducible nitric oxide synthase to a basal-like transcription pattern and tumor progression in human breast cancer. Cell Cycle. 10:619–624. 2011. View Article : Google Scholar : PubMed/NCBI
184	Alalami O and Martin JH: ZR-75-1 human breast cancer cells: Expression of inducible nitric oxide synthase and effect of tamoxifen and phorbol ester on nitric oxide production. Cancer Lett. 123:99–105. 1998. View Article : Google Scholar : PubMed/NCBI
185	Basudhar D, Somasundaram V, de Oliveira GA, Kesarwala A, Heinecke JL, Cheng RY, Glynn SA, Ambs S, Wink DA and Ridnour LA: Nitric oxide synthase-2-derived nitric oxide drives multiple pathways of breast cancer progression. Antioxid Redox Signal. 26:1044–1058. 2017. View Article : Google Scholar : PubMed/NCBI
186	Bentrari F, Arnould L, Jackson AP, Jeannin JF and Pance A: Progesterone enhances cytokine-stimulated nitric oxide synthase II expression and cell death in human breast cancer cells. Lab Invest. 85:624–632. 2005. View Article : Google Scholar : PubMed/NCBI
187	Bing RJ, Miyataka M, Rich KA, Hanson N, Wang X, Slosser HD and Shi SR: Nitric oxide, prostanoids, cyclooxygenase, and angiogenesis in colon and breast cancer. Clin Cancer Res. 7:3385–3392. 2001.PubMed/NCBI
188	Deepa M, Sureshkumar T, Satheeshkumar PK and Priya S: Antioxidant rich Morus alba leaf extract induces apoptosis in human colon and breast cancer cells by the downregulation of nitric oxide produced by inducible nitric oxide synthase. Nutr Cancer. 65:305–310. 2013. View Article : Google Scholar : PubMed/NCBI
189	Duenas-Gonzalez A, Isales CM, del Mar Abad-Hernandez M, Gonzalez-Sarmiento R, Sangueza O and Rodriguez-Commes J: Expression of inducible nitric oxide synthase in breast cancer correlates with metastatic disease. Mod Pathol. 10:645–649. 1997.PubMed/NCBI
190	Evig CB, Kelley EE, Weydert CJ, Chu Y, Buettner GR and Burns CP: Endogenous production and exogenous exposure to nitric oxide augment doxorubicin cytotoxicity for breast cancer cells but not cardiac myoblasts. Nitric Oxide. 10:119–129. 2004. View Article : Google Scholar : PubMed/NCBI
191	Flaherty RL, Intabli H, Falcinelli M, Bucca G, Hesketh A, Patel BA, Allen MC, Smith CP and Flint MS: Stress hormone-mediated acceleration of breast cancer metastasis is halted by inhibition of nitric oxide synthase. Cancer letters. 459:59–71. 2019. View Article : Google Scholar : PubMed/NCBI
192	Garrido P, Shalaby A, Walsh EM, Keane N, Webber M, Keane MM, Sullivan FJ, Kerin MJ, Callagy G, Ryan AE and Glynn SA: Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways. Oncotarget. 8:80568–80588. 2017. View Article : Google Scholar : PubMed/NCBI
193	Hsu JT, Ying C and Chen CJ: Regulation of inducible nitric oxide synthase by dietary phytoestrogen in MCF-7 human mammary cancer cells. Reprod Nutr Dev. 40:11–18. 2000. View Article : Google Scholar : PubMed/NCBI
194	Kanugula AK, Gollavilli PN, Vasamsetti SB, Karnewar S, Gopoju R, Ummanni R and Kotamraju S: Statin-induced inhibition of breast cancer proliferation and invasion involves attenuation of iron transport: Intermediacy of nitric oxide and antioxidant defence mechanisms. FEBS J. 281:3719–3738. 2014. View Article : Google Scholar : PubMed/NCBI
195	Kotamraju S, Williams CL and Kalyanaraman B: Statin-induced breast cancer cell death: Role of inducible nitric oxide and arginase-dependent pathways. Cancer Res. 67:7386–7394. 2007. View Article : Google Scholar : PubMed/NCBI
196	López-Sánchez LM, Mena R, Guil-Luna S, Mantrana A, Peñarando J, Toledano-Fonseca M, Conde F, De la Haba-Rodríguez JR, Aranda E and Rodríguez-Ariza A: Nitric oxide-targeted therapy inhibits stemness and increases the efficacy of tamoxifen in estrogen receptor-positive breast cancer cells. Lab Invest. 101:292–303. 2021. View Article : Google Scholar : PubMed/NCBI
197	Loibl S, Buck A, Strank C, von Minckwitz G, Roller M, Sinn HP, Schini-Kerth V, Solbach C, Strebhardt K and Kaufmann M: The role of early expression of inducible nitric oxide synthase in human breast cancer. Eur J Cancer. 41:265–271. 2005. View Article : Google Scholar : PubMed/NCBI
198	Lahiri M and Martin JH: Reduced expression of endothelial and inducible nitric oxide synthase in a multidrug resistant variant of the MCF-7 human breast cancer cell line. Oncol Rep. 12:1007–1011. 2004.PubMed/NCBI
199	Oktem G, Karabulut B, Selvi N, Sezgin C, Sanli UA, Uslu R, Yurtseven ME and Omay SB: Differential effects of doxorubicin and docetaxel on nitric oxide production and inducible nitric oxide synthase expression in MCF-7 human breast cancer cells. Oncol Res. 14:381–386. 2004. View Article : Google Scholar : PubMed/NCBI
200	Martin JH, Alalami O and van den Berg HW: Reduced expression of endothelial and inducible nitric oxide synthase in a human breast cancer cell line which has acquired estrogen independence. Cancer Lett. 144:65–74. 1999. View Article : Google Scholar : PubMed/NCBI
201	Nafea H, Youness RA, Abou-Aisha K and Gad MZ: LncRNA HEIH/miR-939-5p interplay modulates triple-negative breast cancer progression through NOS2-induced nitric oxide production. J Cell Physiol. 236:5362–5372. 2021. View Article : Google Scholar : PubMed/NCBI
202	Oktem G, Bilir A, Selvi N, Yurtseven ME, Vatansever S, Ates U, Uysal A and Omay SB: Chemotherapy influences inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) activity on 3D breast cancer cell line. Oncol Res. 16:195–203. 2006. View Article : Google Scholar : PubMed/NCBI
203	Zeybek ND, Inan S, Ekerbicer N, Vatansever HS, Karakaya J and Muftuoglu SF: The effects of Gemcitabine and Vinorelbine on inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) distribution of MCF-7 breast cancer cells. Acta Histochem. 113:62–67. 2011. View Article : Google Scholar : PubMed/NCBI
204	Walsh EM, Keane MM, Wink DA, Callagy G and Glynn SA: Review of triple negative breast cancer and the impact of inducible nitric oxide synthase on tumor biology and patient outcomes. Crit Rev Oncog. 21:333–351. 2016. View Article : Google Scholar : PubMed/NCBI
205	Wink DA, Ridnour LA, Cheng R, Switzer CW, Glynn S and Ambs S: The oncogenic properties of the redox inflammatory protein inducible nitric oxide synthase in ER(−) breast cancer. Redox Biol. 5:4132015. View Article : Google Scholar : PubMed/NCBI
206	Tschugguel W, Schneeberger C, Unfried G, Czerwenka K, Weninger W, Mildner M, Gruber DM, Sator MO, Waldhör T and Huber JC: Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade. Breast Cancer Res Treat. 56:145–151. 1999. View Article : Google Scholar : PubMed/NCBI
207	Abadi AT and Kusters JG: Association of inducible nitric oxide synthetase genotype and Helicobacter pylori infection gastric cancer risk may be due to faulty primer design. World J Gastroenterol. 19:429–430. 2013. View Article : Google Scholar : PubMed/NCBI
208	Chen CN, Hsieh FJ, Cheng YM, Chang KJ and Lee PH: Expression of inducible nitric oxide synthase and cyclooxygenase-2 in angiogenesis and clinical outcome of human gastric cancer. J Surg Oncol. 94:226–233. 2006. View Article : Google Scholar : PubMed/NCBI
209	Doi C, Noguchi Y, Marat D, Saito A, Fukuzawa K, Yoshikawa T, Tsuburaya A and Ito T: Expression of nitric oxide synthase in gastric cancer. Cancer Lett. 144:161–167. 1999. View Article : Google Scholar : PubMed/NCBI
210	Goto T, Haruma K, Kitadai Y, Ito M, Yoshihara M, Sumii K, Hayakawa N and Kajiyama G: Enhanced expression of inducible nitric oxide synthase and nitrotyrosine in gastric mucosa of gastric cancer patients. Clin Cancer Res. 5:1411–1415. 1999.PubMed/NCBI
211	Goto Y, Ando T, Naito M, Goto H and Hamajima N: Inducible nitric oxide synthase polymorphism is associated with the increased risk of differentiated gastric cancer in a Japanese population. World J Gastroenterol. 12:6361–6365. 2006. View Article : Google Scholar : PubMed/NCBI
212	Hirst D and Robson T: Nitric oxide in cancer therapeutics: Interaction with cytotoxic chemotherapy. Curr Pharm Des. 16:411–420. 2010. View Article : Google Scholar : PubMed/NCBI
213	Hirahashi M, Koga Y, Kumagai R, Aishima S, Taguchi K and Oda Y: Induced nitric oxide synthetase and peroxiredoxin expression in intramucosal poorly differentiated gastric cancer of young patients. Pathol Int. 64:155–163. 2014. View Article : Google Scholar : PubMed/NCBI
214	Huang FY, Chan AO, Rashid A, Wong DK, Cho CH and Yuen MF: Helicobacter pylori induces promoter methylation of E-cadherin via interleukin-1β activation of nitric oxide production in gastric cancer cells. Cancer. 118:4969–4980. 2012. View Article : Google Scholar : PubMed/NCBI
215	Ikeguchi M, Ueta T and Kaibara N: Expression of inducible nitric oxide synthase during cisplatin-based chemotherapy for gastric cancer. In Vivo. 16:185–190. 2002.PubMed/NCBI
216	Jun Y, Fei G, Ebert MP and Malfertheiner P: Expression of inducible nitric oxide synthase in human gastric cancer. World J Gastroenterol. 5:430–431. 1999. View Article : Google Scholar : PubMed/NCBI
217	Jung ID, Lee JS, Yun SY, Park CG, Han JW, Lee HW and Lee HY: Doxorubicin inhibits the production of nitric oxide by colorectal cancer cells. Arch Pharm Res. 25:691–696. 2002. View Article : Google Scholar : PubMed/NCBI
218	Rafiei A, Hosseini V, Janbabai G, Fazli B, Ajami A, Hosseini-Khah Z, Gilbreath J and Merrell DS: Inducible nitric oxide synthetase genotype and helicobacter pylori infection affect gastric cancer risk. World J Gastroenterol. 18:4917–4924. 2012. View Article : Google Scholar : PubMed/NCBI
219	Rajnakova A, Moochhala S, Goh PM and Ngoi S: Expression of nitric oxide synthase, cyclooxygenase, and p53 in different stages of human gastric cancer. Cancer Lett. 172:177–185. 2001. View Article : Google Scholar : PubMed/NCBI
220	Zhang W, He XJ, Ma YY, Wang HJ, Xia YJ, Zhao ZS, Ye ZY and Tao HQ: Inducible nitric oxide synthase expression correlates with angiogenesis, lymphangiogenesis, and poor prognosis in gastric cancer patients. Hum Pathol. 42:1275–1282. 2011. View Article : Google Scholar : PubMed/NCBI
221	Sawa T, Mounawar M, Tatemichi M, Gilibert I, Katoh T and Ohshima H: Increased risk of gastric cancer in Japanese subjects is associated with microsatellite polymorphisms in the heme oxygenase-1 and the inducible nitric oxide synthase gene promoters. Cancer Lett. 269:78–84. 2008. View Article : Google Scholar : PubMed/NCBI
222	Shen J, Wang RT, Wang LW, Xu YC and Wang XR: A novel genetic polymorphism of inducible nitric oxide synthase is associated with an increased risk of gastric cancer. World J Gastroenterol. 10:3278–3283. 2004. View Article : Google Scholar : PubMed/NCBI
223	Son HJ, Kim YH, Park DI, Kim JJ, Rhee PL, Paik SW, Choi KW, Song SY and Rhee JC: Interaction between cyclooxygenase-2 and inducible nitric oxide synthase in gastric cancer. J Clin Gastroenterol. 33:383–388. 2001. View Article : Google Scholar : PubMed/NCBI
224	Song ZY, Wen SQ, Peng JP, Huang X and Qian KD: Significance of vascular endothelial growth factor expression and its correlation with inducible nitric oxide synthase in gastric cancer. World J Gastroenterol. 10:1250–1255. 2004. View Article : Google Scholar : PubMed/NCBI
225	Ambs S, Merriam WG, Bennett WP, Felley-Bosco E, Ogunfusika MO, Oser SM, Klein S, Shields PG, Billiar TR and Harris CC: Frequent nitric oxide synthase-2 expression in human colon adenomas: Implication for tumor angiogenesis and colon cancer progression. Cancer Res. 58:334–341. 1998.PubMed/NCBI
226	Bocca C, Bozzo F, Bassignana A and Miglietta A: Antiproliferative effect of a novel nitro-oxy derivative of celecoxib in human colon cancer cells: Role of COX-2 and nitric oxide. Anticancer Res. 30:2659–2666. 2010.PubMed/NCBI
227	Dabrowska M, Uram L, Zielinski Z, Rode W and Sikora E: Oxidative stress and inhibition of nitric oxide generation underlie methotrexate-induced senescence in human colon cancer cells. Mech Ageing Dev. 170:22–29. 2018. View Article : Google Scholar : PubMed/NCBI
228	Narayanan BA, Narayanan NK, Desai D, Pittman B and Reddy BS: Effects of a combination of docosahexaenoic acid and 1,4-phenylene bis(methylene) selenocyanate on cyclooxygenase 2, inducible nitric oxide synthase and beta-catenin pathways in colon cancer cells. Carcinogenesis. 25:2443–2449. 2004. View Article : Google Scholar : PubMed/NCBI
229	Narayanan BA, Narayanan NK, Simi B and Reddy BS: Modulation of inducible nitric oxide synthase and related proinflammatory genes by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells. Cancer Res. 63:972–979. 2003.PubMed/NCBI
230	Kwak JY, Han MK, Choi KS, Park IH, Park SY, Sohn MH, Kim UH, McGregor JR, Samlowski WE and Yim CY: Cytokines secreted by lymphokine-activated killer cells induce endogenous nitric oxide synthesis and apoptosis in DLD-1 colon cancer cells. Cell Immunol. 203:84–94. 2000. View Article : Google Scholar : PubMed/NCBI
231	Kapral M, Wawszczyk J, Sosnicki S and Weglarz L: Down-regulation of inducible nitric oxide synthase expression by inositol hexaphosphate in human colon cancer cells. Acta Pol Pharm. 72:705–711. 2015.PubMed/NCBI
232	Puglisi MA, Cenciarelli C, Tesori V, Cappellari M, Martini M, Di Francesco AM, Giorda E, Carsetti R, Ricci-Vitiani L and Gasbarrini A: High nitric oxide production, secondary to inducible nitric oxide synthase expression, is essential for regulation of the tumour-initiating properties of colon cancer stem cells. J Pathol. 236:479–490. 2015. View Article : Google Scholar : PubMed/NCBI
233	Williams JL, Nath N, Chen J, Hundley TR, Gao J, Kopelovich L, Kashfi K and Rigas B: Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition: Implications for chemoprevention. Cancer Res. 63:7613–7618. 2003.PubMed/NCBI
234	Tong X, Zheng S, Jin J, Zhu L, Lou Y and Yao H: Triptolide inhibits cyclooxygenase-2 and inducible nitric oxide synthase expression in human colon cancer and leukemia cells. Acta Biochim Biophys Sin (Shanghai). 39:89–95. 2007. View Article : Google Scholar : PubMed/NCBI
235	Sasahara Y, Mutoh M, Takahashi M, Fukuda K, Tanaka N, Sugimura T and Wakabayashi K: Suppression of promoter-dependent transcriptional activity of inducible nitric oxide synthase by sodium butyrate in colon cancer cells. Cancer Lett. 177:155–161. 2002. View Article : Google Scholar : PubMed/NCBI
236	Shen X, Chen J, Qiu R, Fan X and Xin Y: Effect of camptothecin on inducible nitric oxide synthase expression in the colon cancer SW480 cell line. Oncol Lett. 10:3157–3160. 2015. View Article : Google Scholar : PubMed/NCBI
237	Spiegel A, Hundley TR, Chen J, Ouyang N, Liu X, Go MF, Tsioulias GJ, Kashfi K and Rigas B: NO-donating aspirin inhibits both the expression and catalytic activity of inducible nitric oxide synthase in HT-29 human colon cancer cells. Biochem Pharmacol. 70:993–1000. 2005. View Article : Google Scholar : PubMed/NCBI
238	Eijan AM, Piccardo I, Riveros MD, Sandes EO, Porcella H, Jasnis MA, Sacerdote De Lustig E, Malagrino H, Pasik L and Casabé AR: Nitric oxide in patients with transitional bladder cancer. J Surg Oncol. 81:203–208. 2002. View Article : Google Scholar : PubMed/NCBI
239	Hosseini A, Koskela LR, Ehren I, Aguilar-Santelises M, Sirsjo A and Wiklund NP: Enhanced formation of nitric oxide in bladder carcinoma in situ and in BCG treated bladder cancer. Nitric Oxide. 15:337–343. 2006. View Article : Google Scholar : PubMed/NCBI
240	Klotz T, Bloch W, Jacobs G, Niggemann S, Engelmann U and Addicks K: Immunolocalization of inducible and constitutive nitric oxide synthases in human bladder cancer. Urology. 54:416–419. 1999. View Article : Google Scholar : PubMed/NCBI
241	Koskela LR, Poljakovic M, Ehren I, Wiklund NP and de Verdier PJ: Localization and expression of inducible nitric oxide synthase in patients after BCG treatment for bladder cancer. Nitric Oxide. 27:185–191. 2012. View Article : Google Scholar : PubMed/NCBI
242	Langle YV, Balarino NP, Belgorosky D, Cresta Morgado PD, Sandes EO, Marino L, Bilbao ER, Zambrano M, Lodillinsky C and Eiján AM: Effect of nitric oxide inhibition in Bacillus Calmette-Guerin bladder cancer treatment. Nitric Oxide. 98:50–59. 2020. View Article : Google Scholar : PubMed/NCBI
243	Lin Z, Chen S, Ye C and Zhu S: Nitric oxide synthase expression in human bladder cancer and its relation to angiogenesis. Urol Res. 31:232–235. 2003. View Article : Google Scholar : PubMed/NCBI
244	Ryk C, Steineck G, Wiklund NP, Nyberg T and de Verdier PJ: The (CCTTT)n microsatellite polymorphism in the nitric oxide synthase 2 gene may influence bladder cancer pathogenesis. J Urol. 184:2150–2157. 2010. View Article : Google Scholar : PubMed/NCBI
245	Ryk C, Wiklund NP, Nyberg T and De Verdier PJ: Ser608Leu polymorphisms in the nitric oxide synthase-2 gene may influence urinary bladder cancer pathogenesis. Scand J Urol Nephrol. 45:319–325. 2011. View Article : Google Scholar : PubMed/NCBI
246	Wolf H, Haeckel C and Roessner A: Inducible nitric oxide synthase expression in human urinary bladder cancer. Virchows Arch. 437:662–666. 2000. View Article : Google Scholar : PubMed/NCBI
247	Sandes EO, Faletti AG, Riveros MD, Vidal Mdel C, Gimenez L, Casabé AR and Eiján AM: Expression of inducible nitric oxide synthase in tumoral and non-tumoral epithelia from bladder cancer patients. Nitric Oxide. 12:39–45. 2005. View Article : Google Scholar : PubMed/NCBI
248	Sandes EO, Lodillinsky C, Langle Y, Belgorosky D, Marino L, Gimenez L, Casabé AR and Eiján AM: Inducible nitric oxide synthase and PPARγ are involved in bladder cancer progression. J Urol. 188:967–973. 2012. View Article : Google Scholar : PubMed/NCBI
249	Ambs S and Harris CC: RESPONSE: Re: Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer. J Natl Cancer Inst. 91:1510–1511. 1999. View Article : Google Scholar : PubMed/NCBI
250	Chung P, Cook T, Liu K, Vodovotz Y, Zamora R, Finkelstein S, Billiar T and Blumberg D: Overexpression of the human inducible nitric oxide synthase gene enhances radiation-induced apoptosis in colorectal cancer cells via a caspase-dependent mechanism. Nitric Oxide. 8:119–126. 2003. View Article : Google Scholar : PubMed/NCBI
251	Cianchi F, Cortesini C, Fantappie O, Messerini L, Sardi I, Lasagna N, Perna F, Fabbroni V, Di Felice A, Perigli G, et al: Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer. Clin Cancer Res. 10:2694–2704. 2004. View Article : Google Scholar : PubMed/NCBI
252	Cianchi F, Cortesini C, Fantappie O, Messerini L, Schiavone N, Vannacci A, Nistri S, Sardi I, Baroni G, Marzocca C, et al: Inducible nitric oxide synthase expression in human colorectal cancer: Correlation with tumor angiogenesis. Am J Pathol. 162:793–801. 2003. View Article : Google Scholar : PubMed/NCBI
253	Fransen K, Elander N and Soderkvist P: Nitric oxide synthase 2 (NOS2) promoter polymorphisms in colorectal cancer. Cancer Lett. 225:99–103. 2005. View Article : Google Scholar : PubMed/NCBI
254	Gallo O, Sardi I, Masini M and Franchi A: Re: Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer. J Natl Cancer Inst. 91:1509–1511. 1999. View Article : Google Scholar : PubMed/NCBI
255	Ropponen KM, Kellokoski JK, Lipponen PK, Eskelinen MJ, Alanne L, Alhava EM and Kosma VM: Expression of inducible nitric oxide synthase in colorectal cancer and its association with prognosis. Scand J Gastroenterol. 35:1204–1211. 2000. View Article : Google Scholar : PubMed/NCBI
256	Zafirellis K, Zachaki A, Agrogiannis G and Gravani K: Inducible nitric oxide synthase expression and its prognostic significance in colorectal cancer. APMIS. 118:115–124. 2010. View Article : Google Scholar : PubMed/NCBI
257	Wang Z, Cook T, Alber S, Liu K, Kovesdi I, Watkins SK, Vodovotz Y, Billiar TR and Blumberg D: Adenoviral gene transfer of the human inducible nitric oxide synthase gene enhances the radiation response of human colorectal cancer associated with alterations in tumor vascularity. Cancer Res. 64:1386–1395. 2004. View Article : Google Scholar : PubMed/NCBI
258	Delarue FL, Taylor BS and Sebti SM: Ras and RhoA suppress whereas RhoB enhances cytokine-induced transcription of nitric oxide synthase-2 in human normal liver AKN-1 cells and lung cancer A-549 cells. Oncogene. 20:6531–6537. 2001. View Article : Google Scholar : PubMed/NCBI
259	Hu C, Li G and Wu E: A study on the activity of nitric oxide in alveolar macrophages from patients with lung cancer. Hunan Yi Ke Da Xue Xue Bao. 23:157–160. 1998.(In Chinese). PubMed/NCBI
260	Li Y, Ma C, Shi X, Wen Z, Li D, Sun M and Ding H: Effect of nitric oxide synthase on multiple drug resistance is related to Wnt signaling in non-small cell lung cancer. Oncol Rep. 32:1703–1708. 2014. View Article : Google Scholar : PubMed/NCBI
261	Liu CY, Wang CH, Chen TC, Lin HC, Yu CT and Kuo HP: Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer. Br J Cancer. 78:534–541. 1998. View Article : Google Scholar : PubMed/NCBI
262	Liu CY, Wang YM, Wang CL, Feng PH, Ko HW, Liu YH, Wu YC, Chu Y, Chung FT, Kuo CH, et al: Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14-/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J Cancer Res Clin Oncol. 136:35–45. 2010. View Article : Google Scholar : PubMed/NCBI
263	Zhang J, Li B, Ding X, Sun M, Li H, Yang M, Zhou C, Yu H, Liu H and Yu G: Genetic variants in inducible nitric oxide synthase gene are associated with the risk of radiation-induced lung injury in lung cancer patients receiving definitive thoracic radiation. Radiother Oncol. 111:194–198. 2014. View Article : Google Scholar : PubMed/NCBI
264	Ye S, Yang W, Wang Y, Ou W, Ma Q, Yu C, Ren J, Zhong G, Shi H, Yuan Z, et al: Cationic liposome-mediated nitric oxide synthase gene therapy enhances the antitumor effects of cisplatin in lung cancer. Int J Mol Med. 31:33–42. 2013. View Article : Google Scholar : PubMed/NCBI
265	Sim SH, Ahn YO, Yoon J, Kim TM, Lee SH, Kim DW and Heo DS: Influence of chemotherapy on nitric oxide synthase, indole-amine-2,3-dioxygenase and CD124 expression in granulocytes and monocytes of non-small cell lung cancer. Cancer Sci. 103:155–160. 2012. View Article : Google Scholar : PubMed/NCBI
266	Franco L, Doria D, Bertazzoni E, Benini A and Bassi C: Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic cancer. Prostaglandins Other Lipid Mediat. 73:51–58. 2004. View Article : Google Scholar : PubMed/NCBI
267	Kong G, Kim E, Kim W, Lee YW, Lee JK, Paik SW, Rhee JC, Choi KW and Lee KT: Inducible nitric oxide synthase (iNOS) immunoreactivity and its relationship to cell proliferation, apoptosis, angiogenesis, clinicopathologic characteristics, and patient survival in pancreatic cancer. Int J Pancreatol. 29:133–140. 2001. View Article : Google Scholar : PubMed/NCBI
268	Kong G, Kim EK, Kim WS, Lee KT, Lee YW, Lee JK, Paik SW and Rhee JC: Role of cyclooxygenase-2 and inducible nitric oxide synthase in pancreatic cancer. J Gastroenterol Hepatol. 17:914–921. 2002. View Article : Google Scholar : PubMed/NCBI
269	Wang J, He P, Gaida M, Yang S, Schetter AJ, Gaedcke J, Ghadimi BM, Ried T, Yfantis H, Lee D, et al: Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer. Oncotarget. 7:52993–53004. 2016. View Article : Google Scholar : PubMed/NCBI
270	Vickers SM, MacMillan-Crow LA, Green M, Ellis C and Thompson JA: Association of increased immunostaining for inducible nitric oxide synthase and nitrotyrosine with fibroblast growth factor transformation in pancreatic cancer. Arch Surg. 134:245–251. 1999. View Article : Google Scholar : PubMed/NCBI
271	Takahashi M, Kitahashi T, Ishigamori R, Mutoh M, Komiya M, Sato H, Kamanaka Y, Naka M, Maruyama T, Sugimura T and Wakabayashi K: Increased expression of inducible nitric oxide synthase (iNOS) in N-nitrosobis(2-oxopropyl)amine-induced hamster pancreatic carcinogenesis and prevention of cancer development by ONO-1714, an iNOS inhibitor. Carcinogenesis. 29:1608–1613. 2008. View Article : Google Scholar : PubMed/NCBI
272	Chen HH, Su WC, Chou CY, Guo HR, Ho SY, Que J and Lee WY: Increased expression of nitric oxide synthase and cyclooxygenase-2 is associated with poor survival in cervical cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys. 63:1093–1100. 2005. View Article : Google Scholar : PubMed/NCBI
273	Dong J, Cheng M and Sun H: Function of inducible nitric oxide synthase in the regulation of cervical cancer cell proliferation and the expression of vascular endothelial growth factor. Mol Med Rep. 9:583–589. 2014. View Article : Google Scholar : PubMed/NCBI
274	Jiang N, Tian Z, Tang J, Ou R and Xu Y: Granulocyte macrophage-colony stimulating factor (GM-CSF) downregulates the expression of protumor factors cyclooxygenase-2 and inducible nitric oxide synthase in a GM-CSF receptor-independent manner in cervical cancer cells. Mediators Inflamm. 2015:6016042015. View Article : Google Scholar : PubMed/NCBI
275	Lee TS, Jeon YT, Kim JW, Park NH, Kang SB, Lee HP and Song YS: Lack of association of the cyclooxygenase-2 and inducible nitric oxide synthase gene polymorphism with risk of cervical cancer in Korean population. Ann N Y Acad Sci. 1095:134–142. 2007. View Article : Google Scholar : PubMed/NCBI
276	Ryu YK, Lee JW and Moon EY: Thymosin beta-4, actin-sequestering protein regulates vascular endothelial growth factor expression via hypoxia-inducible nitric oxide production in HeLa cervical cancer cells. Biomol Ther (Seoul). 23:19–25. 2015. View Article : Google Scholar : PubMed/NCBI
277	Sowjanya AP, Rao M, Vedantham H, Kalpana B, Poli UR, Marks MA and Sujatha M: Correlation of plasma nitrite/nitrate levels and inducible nitric oxide gene expression among women with cervical abnormalities and cancer. Nitric Oxide. 52:21–28. 2016. View Article : Google Scholar : PubMed/NCBI
278	Li L, Zhu L, Hao B, Gao W, Wang Q, Li K, Wang M, Huang M, Liu Z, Yang Q, et al: iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer. Oncotarget. 8:33047–33063. 2017. View Article : Google Scholar : PubMed/NCBI
279	Malone JM, Saed GM, Diamond MP, Sokol RJ and Munkarah AR: The effects of the inhibition of inducible nitric oxide synthase on angiogenesis of epithelial ovarian cancer. Am J Obstet Gynecol. 194:1110–1118. 2006. View Article : Google Scholar : PubMed/NCBI
280	Martins Filho A, Jammal MP, Cobo Ede C, Silveira TP, Adad SJ, Murta EF and Nomelini RS: Correlation of cytokines and inducible nitric oxide synthase expression with prognostic factors in ovarian cancer. Immunol Lett. 158:195–199. 2014. View Article : Google Scholar : PubMed/NCBI
281	Raspollini MR, Amunni G, Villanucci A, Boddi V, Baroni G, Taddei A and Taddei GL: Expression of inducible nitric oxide synthase and cyclooxygenase-2 in ovarian cancer: Correlation with clinical outcome. Gynecol Oncol. 92:806–812. 2004. View Article : Google Scholar : PubMed/NCBI
282	Zhao L, Yu C, Zhou S, Lau WB, Lau B, Luo Z, Lin Q, Yang H, Xuan Y, Yi T, et al: Epigenetic repression of PDZ-LIM domain-containing protein 2 promotes ovarian cancer via NOS2-derived nitric oxide signaling. Oncotarget. 7:1408–1420. 2016. View Article : Google Scholar : PubMed/NCBI
283	Xu L, Xie K and Fidler IJ: Therapy of human ovarian cancer by transfection with the murine interferon beta gene: Role of macrophage-inducible nitric oxide synthase. Hum Gene Ther. 9:2699–2708. 1998. View Article : Google Scholar : PubMed/NCBI
284	Trinh B, Ko SY, Haria D, Barengo N and Naora H: The homeoprotein DLX4 controls inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer. Mol Cancer. 14:972015. View Article : Google Scholar : PubMed/NCBI
285	Sanhueza C, Araos J, Naranjo L, Barros E, Toledo L, Subiabre M, Toledo F, Gutiérrez J, Chiarello DI, Pardo F, et al: Are NHE1 and inducible nitric oxide synthase involved in human ovarian cancer? Pharmacol Res. 105:183–185. 2016. View Article : Google Scholar : PubMed/NCBI
286	Jayasurya A, Dheen ST, Yap WM, Tan NG, Ng YK and Bay BH: Inducible nitric oxide synthase and bcl-2 expression in nasopharyngeal cancer: Correlation with outcome of patients after radiotherapy. Int J Radiat Oncol Biol Phys. 56:837–845. 2003. View Article : Google Scholar : PubMed/NCBI
287	Lukes P, Pacova H, Kucera T, Vesely D, Martinek J and Astl J: Expression of endothelial and inducible nitric oxide synthase and caspase-3 in tonsillar cancer, chronic tonsillitis and healthy tonsils. Folia Biol (Praha). 54:141–145. 2008.PubMed/NCBI
288	Soler MN, Bobe P, Benihoud K, Lemaire G, Roos BA and Lausson S: Gene therapy of rat medullary thyroid cancer by naked nitric oxide synthase II DNA injection. J Gene Med. 2:344–352. 2000. View Article : Google Scholar : PubMed/NCBI
289	Rafa H, Benkhelifa S, AitYounes S, Saoula H, Belhadef S, Belkhelfa M, Boukercha A, Toumi R, Soufli I, Moralès O, et al: All-trans retinoic acid modulates TLR4/NF-κB signaling pathway targeting TNF-α and nitric oxide synthase 2 expression in colonic mucosa during ulcerative colitis and colitis associated cancer. Mediators Inflamm. 2017:73532522017. View Article : Google Scholar : PubMed/NCBI
290	Amasyali AS, Kucukgergin C, Erdem S, Sanli O, Seckin S and Nane I: Nitric oxide synthase (eNOS4a/b) gene polymorphism is associated with tumor recurrence and progression in superficial bladder cancer cases. J Urol. 188:2398–2403. 2012. View Article : Google Scholar : PubMed/NCBI
291	Polat F, Diler SB, Azazi İ and Öden A: T-786C, G894T, and intron 4 VNTR (4a/b) polymorphisms of the endothelial nitric oxide synthase gene in bladder cancer cases. Asian Pac J Cancer Prev. 16:2199–2202. 2015. View Article : Google Scholar : PubMed/NCBI
292	Ryk C, Wiklund NP, Nyberg T and de Verdier PJ: Polymorphisms in nitric-oxide synthase 3 may influence the risk of urinary-bladder cancer. Nitric Oxide. 25:338–343. 2011. View Article : Google Scholar : PubMed/NCBI
293	Abedinzadeh M, Dastgheib SA, Maleki H, Heiranizadeh N, Zare M, Jafari-Nedooshan J, Kargar S and Neamatzadeh H: Association of endothelial nitric oxide synthase gene polymorphisms with susceptibility to prostate cancer: A comprehensive systematic review and meta-analysis. Urol J. 17:329–337. 2020.PubMed/NCBI
294	Branković A, Brajušković G, Nikolić Z, Vukotić V, Cerović S, Savić-Pavićević D and Romac S: Endothelial nitric oxide synthase gene polymorphisms and prostate cancer risk in Serbian population. Int J Exp Pathol. 94:355–361. 2013. View Article : Google Scholar : PubMed/NCBI
295	Diler SB and Oden A: The T-786C, G894T, and intron 4 VNTR (4a/b) polymorphisms of the endothelial nitric oxide synthase gene in prostate cancer cases. Genetika. 52:249–254. 2016.PubMed/NCBI
296	Fu Q, Liu X, Liu Y, Yang J, Lv G and Dong S: MicroRNA-335 and −543 suppress bone metastasis in prostate cancer via targeting endothelial nitric oxide synthase. Int J Mol Med. 36:1417–1425. 2015. View Article : Google Scholar : PubMed/NCBI
297	Medeiros R, Morais A, Vasconcelos A, Costa S, Carrilho S, Oliveira J and Lopes C: Endothelial nitric oxide synthase gene polymorphisms and the shedding of circulating tumour cells in the blood of prostate cancer patients. Cancer Lett. 189:85–90. 2003. View Article : Google Scholar : PubMed/NCBI
298	Medeiros R, Morais A, Vasconcelos A, Costa S, Pinto D, Oliveira J and Lopes C: Endothelial nitric oxide synthase gene polymorphisms and genetic susceptibility to prostate cancer. Eur J Cancer Prev. 11:343–350. 2002. View Article : Google Scholar : PubMed/NCBI
299	Medeiros RM, Morais A, Vasconcelos A, Costa S, Pinto D, Oliveira J, Ferreira P and Lopes C: Outcome in prostate cancer: Association with endothelial nitric oxide synthase Glu-Asp298 polymorphism at exon 7. Clin Cancer Res. 8:3433–3437. 2002.PubMed/NCBI
300	Nikolic ZZ, Pavicevic D, Romac SP and Brajuskovic GN: Genetic variants within endothelial nitric oxide synthase gene and prostate cancer: A meta-analysis. Clin Transl Sci. 8:23–31. 2015. View Article : Google Scholar : PubMed/NCBI
301	Marangoni K, Neves AF, Cardoso AM, Santos WK, Faria PC and Goulart LR: The endothelial nitric oxide synthase Glu-298-Asp polymorphism and its mRNA expression in the peripheral blood of patients with prostate cancer and benign prostatic hyperplasia. Cancer Detect Prev. 30:7–13. 2006. View Article : Google Scholar : PubMed/NCBI
302	Polytarchou C, Hatziapostolou M, Poimenidi E, Mikelis C, Papadopoulou A, Parthymou A and Papadimitriou E: Nitric oxide stimulates migration of human endothelial and prostate cancer cells through up-regulation of pleiotrophin expression and its receptor protein tyrosine phosphatase beta/zeta. Int J Cancer. 124:1785–1793. 2009. View Article : Google Scholar : PubMed/NCBI
303	Re A, Aiello A, Nanni S, Grasselli A, Benvenuti V, Pantisano V, Strigari L, Colussi C, Ciccone S, Mazzetti AP, et al: Silencing of GSTP1, a prostate cancer prognostic gene, by the estrogen receptor-β and endothelial nitric oxide synthase complex. Mol Endocrinol. 25:2003–2016. 2011. View Article : Google Scholar : PubMed/NCBI
304	Re A, Colussi C, Nanni S, Aiello A, Bacci L, Grassi C, Pontecorvi A and Farsetti A: Nucleoporin 153 regulates estrogen-dependent nuclear translocation of endothelial nitric oxide synthase and estrogen receptor beta in prostate cancer. Oncotarget. 9:27985–27997. 2018. View Article : Google Scholar : PubMed/NCBI
305	Ziaei SA, Samzadeh M, Jamaldini SH, Afshari M, Haghdoost AA and Hasanzad M: Endothelial nitric oxide synthase Glu298Asp polymorphism as a risk factor for prostate cancer. Int J Biol Markers. 28:43–48. 2013. View Article : Google Scholar : PubMed/NCBI
306	Zhao C, Yan W, Zu X, Chen M, Liu L, Zhao S, Liu H, Hu X, Luo R, Xia Y and Qi L: Association between endothelial nitric oxide synthase 894G>T polymorphism and prostate cancer risk: A meta-analysis of literature studies. Tumour Biol. 35:11727–11733. 2014. View Article : Google Scholar : PubMed/NCBI
307	Yu S, Jia L, Zhang Y, Wu D, Xu Z, Ng CF, To KK, Huang Y and Chan FL: Increased expression of activated endothelial nitric oxide synthase contributes to antiandrogen resistance in prostate cancer cells by suppressing androgen receptor transactivation. Cancer Lett. 328:83–94. 2013. View Article : Google Scholar : PubMed/NCBI
308	Wu JH, Yang K, Ma HS and Xu Y: Association of endothelia nitric oxide synthase gene rs1799983 polymorphism with susceptibility to prostate cancer: A meta-analysis. Tumour Biol. 35:7057–7062. 2014. View Article : Google Scholar : PubMed/NCBI
309	Safarinejad MR and Safarinejad S, Shafiei N and Safarinejad S: Effects of the T-786C, G894T, and Intron 4 VNTR (4a/b) polymorphisms of the endothelial nitric oxide synthase gene on the risk of prostate cancer. Urol Oncol. 31:1132–1140. 2013. View Article : Google Scholar : PubMed/NCBI
310	Sanli O, Kucukgergin C, Gokpinar M, Tefik T, Nane I and Seckin S: Despite the lack of association between different genotypes and the presence of prostate cancer, endothelial nitric oxide synthase a/b (eNOS4a/b) polymorphism may be associated with advanced clinical stage and bone metastasis. Urol Oncol. 29:183–188. 2011. View Article : Google Scholar : PubMed/NCBI
311	Bayraktutan Z, Kiziltunc A, Bakan E and Alp HH: Determination of endothelial nitric oxide synthase gene polymorphism and plasma asymmetric dimethyl arginine concentrations in patients with lung cancer. Eurasian J Med. 52:185–190. 2020. View Article : Google Scholar : PubMed/NCBI
312	Cheon KT, Choi KH, Lee HB, Park SK, Rhee YK and Lee YC: Gene polymorphisms of endothelial nitric oxide synthase and angiotensin-converting enzyme in patients with lung cancer. Lung. 178:351–360. 2000. View Article : Google Scholar : PubMed/NCBI
313	Fujita S, Masago K, Hatachi Y, Fukuhara A, Hata A, Kaji R, Kim YH, Mio T, Mishima M and Katakami N: Genetic polymorphisms in the endothelial nitric oxide synthase gene correlate with overall survival in advanced non-small-cell lung cancer patients treated with platinum-based doublet chemotherapy. BMC Med Genet. 11:1672010. View Article : Google Scholar : PubMed/NCBI
314	Kocer C, Benlier N, Balci SO, Pehlivan S, Sanli M and Nacak M: The role of endothelial nitric oxide synthase gene polymorphisms in patients with lung cancer. Clin Respir J. 14:948–955. 2020. View Article : Google Scholar : PubMed/NCBI
315	Peddireddy V, Badabagni SP, Gundimeda SD and Mundluru HP: Association of eNOS and ACE gene polymorphisms and plasma nitric oxide with risk of non-small cell lung cancer in South India. Clin Respir J. 12:207–217. 2018. View Article : Google Scholar : PubMed/NCBI
316	Chen CH, Wu SH, Tseng YM, Hou MF, Tsai LY and Tsai SM: Distinct role of endothelial nitric oxide synthase gene polymorphisms from menopausal status in the patients with sporadic breast cancer in Taiwan. Nitric Oxide. 72:1–6. 2018. View Article : Google Scholar : PubMed/NCBI
317	Crucitta S, Restante G, Del Re M, Bertolini I, Bona E, Rofi E, Fontanelli L, Gianfilippo G, Fogli S, Stasi I, et al: Endothelial nitric oxide synthase c.-813C>T predicts for proteinuria in metastatic breast cancer patients treated with bevacizumab-based chemotherapy. Cancer Chemother Pharmacol. 84:1219–1227. 2019. View Article : Google Scholar : PubMed/NCBI
318	Basaran G, Turhal NS, Cabuk D, Yurt N, Yurtseven G, Gumus M, Teomete M, Dane F and Yumuk PF: Weight gain after adjuvant chemotherapy in patients with early breast cancer in Istanbul Turkey. Med Oncol. 28:409–415. 2011. View Article : Google Scholar : PubMed/NCBI
319	Hao Y, Montiel R and Huang Y: Endothelial nitric oxide synthase (eNOS) 894 G>T polymorphism is associated with breast cancer risk: A meta-analysis. Breast Cancer Res Treat. 124:809–813. 2010. View Article : Google Scholar : PubMed/NCBI
320	Hefler LA, Grimm C, Lantzsch T, Lampe D, Koelbl H, Lebrecht A, Heinze G, Tempfer C, Reinthaller A and Zeillinger R: Polymorphisms of the endothelial nitric oxide synthase gene in breast cancer. Breast Cancer Res Treat. 98:151–155. 2006. View Article : Google Scholar : PubMed/NCBI
321	Kafousi M, Vrekoussis T, Tsentelierou E, Pavlakis K, Navrozoglou I, Dousias V, Sanidas E, Tsiftsis D, Georgoulias V and Stathopoulos EN: Immunohistochemical study of the angiogenetic network of VEGF, HIF1α, VEGFR-2 and endothelial nitric oxide synthase (eNOS) in human breast cancer. Pathol Oncol Res. 18:33–41. 2012. View Article : Google Scholar : PubMed/NCBI
322	Loibl S, Bratengeier J, Farines V, von Minckwitz G, Spänkuch B, Schini-Kerth V, Nepveu F, Strebhardt K and Kaufmann M: Investigations on the inducible and endothelial nitric oxide synthases in human breast cancer cell line MCF-7-estrogen has an influence on e-NOS, but not on i-NOS. Pathol Res Pract. 202:1–7. 2006. View Article : Google Scholar : PubMed/NCBI
323	Loibl S, Strank C, von Minckwitz G, Sinn HP, Buck A, Solbach C, Strebhardt K and Kaufmann M: Immunohistochemical evaluation of endothelial nitric oxide synthase expression in primary breast cancer. Breast. 14:230–235. 2005. View Article : Google Scholar : PubMed/NCBI
324	Lu J, Wei Q, Bondy ML, Yu TK, Li D, Brewster A, Shete S, Sahin A, Meric-Bernstam F and Wang LE: Promoter polymorphism (−786t>C) in the endothelial nitric oxide synthase gene is associated with risk of sporadic breast cancer in non-Hispanic white women age younger than 55 years. Cancer. 107:2245–2253. 2006. View Article : Google Scholar : PubMed/NCBI
325	Mortensen K, Holck S, Christensen IJ, Skouv J, Hougaard DM, Blom J and Larsson LI: Endothelial cell nitric oxide synthase in peritumoral microvessels is a favorable prognostic indicator in premenopausal breast cancer patients. Clin Cancer Res. 5:1093–1097. 1999.PubMed/NCBI
326	Mortensen K, Skouv J, Hougaard DM and Larsson LI: Endogenous endothelial cell nitric-oxide synthase modulates apoptosis in cultured breast cancer cells and is transcriptionally regulated by p53. J Biol Chemistry. 274:37679–37684. 1999. View Article : Google Scholar : PubMed/NCBI
327	Martin JH, Begum S, Alalami O, Harrison A and Scott KW: Endothelial nitric oxide synthase: Correlation with histologic grade, lymph node status and estrogen receptor expression in human breast cancer. Tumour Biol. 21:90–97. 2000. View Article : Google Scholar : PubMed/NCBI
328	Ramírez-Patiño R, Figuera LE, Puebla-Pérez AM, Delgado-Saucedo JI, Legazpí-Macias MM, Mariaud-Schmidt RP, Ramos-Silva A, Gutiérrez-Hurtado IA, Gómez Flores-Ramos L, Zúñiga-González GM and Gallegos-Arreola MP: Intron 4 VNTR (4a/b) polymorphism of the endothelial nitric oxide synthase gene is associated with breast cancer in Mexican women. J Korean Med Sci. 28:1587–1594. 2013. View Article : Google Scholar : PubMed/NCBI
329	Zintzaras E, Grammatikou M, Kitsios GD, Doxani C, Zdoukopoulos N, Papandreou C and Patrikidou A: Polymorphisms of the endothelial nitric oxide synthase gene in breast cancer: A genetic association study and meta-analysis. J Hum Genet. 55:743–748. 2010. View Article : Google Scholar : PubMed/NCBI
330	Zhang L, Zeng M and Fu BM: Inhibition of endothelial nitric oxide synthase decreases breast cancer cell MDA-MB-231 adhesion to intact microvessels under physiological flows. Am J Physiol Heart Circ Physiol. 310:H1735–H1747. 2016. View Article : Google Scholar : PubMed/NCBI
331	Carkic J, Nikolic N, Nisevic J, Lazarevic M, Kuzmanovic-Pficer J, Jelovac D and Milasin J: Endothelial nitric oxide synthase polymorphisms/haplotypes are strong modulators of oral cancer risk in Serbian population. J Oral Sci. 62:322–326. 2020. View Article : Google Scholar : PubMed/NCBI
332	Karthik B, Shruthi DK, Singh J, Tegginamani AS and Kudva S: Do tobacco stimulate the production of nitric oxide by up regulation of inducible nitric oxide synthesis in cancer: Immunohistochemical determination of inducible nitric oxide synthesis in oral squamous cell carcinoma-a comparative study in tobacco habituers and non-habituers. J Cancer Res Ther. 10:244–250. 2014. View Article : Google Scholar : PubMed/NCBI
333	Chen Y, Li J, Guo Y and Guo XY: Nitric oxide synthase 3 gene variants and colorectal cancer: A meta-analysis. Asian Pac J Cancer Prev. 15:3811–3815. 2014. View Article : Google Scholar : PubMed/NCBI
334	Mortensen K, Christensen IJ, Nielsen HJ, Hansen U and Larsson LI: High expression of endothelial cell nitric oxide synthase in peritumoral microvessels predicts increased disease-free survival in colorectal cancer. Cancer Lett. 216:109–114. 2004. View Article : Google Scholar : PubMed/NCBI
335	Peñarando J, López-Sánchez LM, Mena R, Guil-Luna S, Conde F, Hernández V, Toledano M, Gudiño V, Raponi M, Billard C, et al: A role for endothelial nitric oxide synthase in intestinal stem cell proliferation and mesenchymal colorectal cancer. BMC Biol. 16:32018. View Article : Google Scholar : PubMed/NCBI
336	Yeh CC, Santella RM, Hsieh LL, Sung FC and Tang R: An intron 4 VNTR polymorphism of the endothelial nitric oxide synthase gene is associated with early-onset colorectal cancer. Int J Cancer. 124:1565–1571. 2009. View Article : Google Scholar : PubMed/NCBI
337	Hefler LA, Ludwig E, Lampe D, Zeillinger R, Leodolter S, Gitsch G, Koelbl H and Tempfer CB: Polymorphisms of the endothelial nitric oxide synthase gene in ovarian cancer. Gynecol Oncol. 86:134–137. 2002. View Article : Google Scholar : PubMed/NCBI
338	Krishnaveni D, Amar Chand B, Shravan Kumar P, Uma Devi M, Ramanna M, Jyothy A, Pratibha N, Balakrishna N and Venkateshwari A: Association of endothelial nitric oxide synthase gene T-786C promoter polymorphism with gastric cancer. World J Gastrointest Oncol. 7:87–94. 2015. View Article : Google Scholar : PubMed/NCBI
339	Wang L, Shi GG, Yao JC, Gong W, Wei D, Wu TT, Ajani JA, Huang S and Xie K: Expression of endothelial nitric oxide synthase correlates with the angiogenic phenotype of and predicts poor prognosis in human gastric cancer. Gastric Cancer. 8:18–28. 2005. View Article : Google Scholar : PubMed/NCBI
340	Tecder Ünal M, Karabulut HG, Gümüş-Akay G, Dölen Y, Elhan A, Tükün A and Ünal AE: Endothelial nitric oxide synthase gene polymorphism in gastric cancer. Turk J Gastroenterol. 21:338–344. 2010. View Article : Google Scholar : PubMed/NCBI
341	de Fatima A, Zambuzzi WF, Modolo LV, Tarsitano CA, Gadelha FR, Hyslop S, de Carvalho JE, Salgado I, Ferreira CV and Pilli RA: Cytotoxicity of goniothalamin enantiomers in renal cancer cells: Involvement of nitric oxide, apoptosis and autophagy. Chem Biol Interact. 176:143–150. 2008. View Article : Google Scholar : PubMed/NCBI
342	Hung WC, Wu TF, Ng SC, Lee YC, Shen HP, Yang SF and Wang PH: Involvement of endothelial nitric oxide synthase gene variants in the aggressiveness of uterine cervical cancer. J Cancer. 10:2594–2600. 2019. View Article : Google Scholar : PubMed/NCBI
343	Waheed S, Cheng RY, Casablanca Y, Maxwell GL, Wink DA and Syed V: Nitric oxide donor DETA/NO inhibits the growth of endometrial cancer cells by upregulating the expression of RASSF1 and CDKN1A. Molecules. 24:37222019. View Article : Google Scholar : PubMed/NCBI
344	Riener EK, Hefler LA, Grimm C, Galid A, Zeillinger R, Tong-Cacsire D, Gitsch G, Leodolter S and Tempfer CB: Polymorphisms of the endothelial nitric oxide synthase gene in women with vulvar cancer. Gynecol Oncol. 93:686–690. 2004. View Article : Google Scholar : PubMed/NCBI
345	Wang J, Yang S, He P, Schetter AJ, Gaedcke J, Ghadimi BM, Ried T, Yfantis HG, Lee DH, Gaida MM, et al: Endothelial Nitric oxide synthase traffic inducer (NOSTRIN) is a negative regulator of disease aggressiveness in pancreatic cancer. Clin Cancer Res. 22:5992–6001. 2016. View Article : Google Scholar : PubMed/NCBI
346	Yanar K, Cakatay U, Aydin S, Verim A, Atukeren P, Özkan NE, Karatoprak K, Cebe T, Turan S, Ozkök E, et al: Relation between endothelial nitric oxide synthase genotypes and oxidative stress markers in larynx cancer. Oxid Med Cell Longev. 2016:49850632016. View Article : Google Scholar : PubMed/NCBI
347	Chen C, Wang Y, Goh SS, Yang J, Lam DH, Choudhury Y, Tay FC, Du S, Tan WK, Purwanti YI, et al: Inhibition of neuronal nitric oxide synthase activity promotes migration of human-induced pluripotent stem cell-derived neural stem cells toward cancer cells. J Neurochem. 126:318–330. 2013. View Article : Google Scholar : PubMed/NCBI
348	Karihtala P, Soini Y, Auvinen P, Tammi R, Tammi M and Kosma VM: Hyaluronan in breast cancer: Correlations with nitric oxide synthases and tyrosine nitrosylation. J Histochem Cytochem. 55:1191–1198. 2007. View Article : Google Scholar : PubMed/NCBI
349	Lewko B, Zółtowska A, Stepiński J, Kamiński M, Skokowski J, Roszkiewicz A and Moszkowska G: Nitric oxide synthase type 1 expression in human lung cancer and its relation to p53. Med Sci Monit. 7:218–221. 2001.PubMed/NCBI
350	Ahmed HH, Metwally FM, Mahdy ES, Shosha WG and Ramadan SS: Clinical value of serum hepatocyte growth factor, B-cell lymphoma-2 and nitric oxide in primary breast cancer patients. Eur Rev Med Pharmacol Sci. 16:958–965. 2012.PubMed/NCBI
351	Al Dhaheri Y, Attoub S, Arafat K, Abuqamar S, Viallet J, Saleh A, Al Agha H, Eid A and Iratni R: Anti-metastatic and anti-tumor growth effects of Origanum majorana on highly metastatic human breast cancer cells: Inhibition of NFκB signaling and reduction of nitric oxide production. PLoS One. 8:e688082013. View Article : Google Scholar : PubMed/NCBI
352	Avtandilyan N, Javrushyan H, Petrosyan G and Trchounian A: The involvement of arginase and nitric oxide synthase in breast cancer development: Arginase and NO Synthase as therapeutic targets in cancer. Biomed Res Int. 2018:86969232018. View Article : Google Scholar : PubMed/NCBI
353	Bani D, Masini E, Bello MG, Bigazzi M and Sacchi TB: Relaxin activates the L-arginine-nitric oxide pathway in human breast cancer cells. Cancer Res. 55:5272–5275. 1995.PubMed/NCBI
354	Avtandilyan N, Javrushyan H, Karapetyan A and Trchounian A: RETRACTED ARTICLE: Inhibition of tumor progression by N^G-Nitro-L-arginine Methyl Ester in 7,12-dimethylbenz(a)anthracene induced breast cancer: Nitric oxide synthase inhibition as an antitumor prevention. J Mammary Gland Biol Neoplasia. 24:1992019. View Article : Google Scholar : PubMed/NCBI
355	Alagol H, Erdem E, Sancak B, Turkmen G, Camlibel M and Bugdayci G: Nitric oxide biosynthesis and malondialdehyde levels in advanced breast cancer. Aust N Z J Surg. 69:647–650. 1999. View Article : Google Scholar : PubMed/NCBI
356	Bhattacharjee KG, Bhattacharyya M, Halder UC, Jana P and Sinha AK: The ‘Cross Talk’ between the receptors of insulin, estrogen and progesterone in neutrophils in the synthesis of maspin through nitric oxide in breast cancer. Int J Biomed Sci. 8:129–139. 2012.PubMed/NCBI
357	Cendan JC, Souba WW, Copeland EM III and Lind DS: Increased L-arginine transport in a nitric oxide-producing metastatic colon cancer cell line. Ann Surg Oncol. 3:501–508. 1996. View Article : Google Scholar : PubMed/NCBI
358	Cendan JC, Topping DL, Pruitt J, Snowdy S, Copeland EM III and Lind DS: Inflammatory mediators stimulate arginine transport and arginine-derived nitric oxide production in a murine breast cancer cell line. J Surg Res. 60:284–288. 1996. View Article : Google Scholar : PubMed/NCBI
359	Chakraborty S, Girish GV and Sinha AK: Impaired binding of insulin to erythrocyte membrane receptor and the activation of nitric oxide synthase by the hormone in human breast cancer. J Cancer Res Clin Oncol. 130:294–300. 2004. View Article : Google Scholar : PubMed/NCBI
360	Coskun U, Gunel N, Sancak B, Günel U, Onuk E, Bayram O, Yílmaz E, Candan S and Ozkan S: Significance of serum vascular endothelial growth factor, insulin-like growth factor-I levels and nitric oxide activity in breast cancer patients. Breast. 12:104–110. 2003. View Article : Google Scholar : PubMed/NCBI
361	Coskun U, Gunel N, Sancak B, Günel U, Onuk E, Bayram O, Yílmaz E, Candan S and Ozkan S: WITHDRAWN: Significance of serum vascular endothelial growth factor, insulin-like growth factor-I levels and nitric oxide activity in breast cancer patients. Breast. Aug 20–2008.doi: 10.1054/brst.2002.0483 (Epub ahead of print). PubMed/NCBI
362	Dave B, Granados-Principal S, Zhu R, Benz S, Rabizadeh S, Soon-Shiong P, Yu KD, Shao Z, Li X, Gilcrease M, et al: Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling. Proc Natl Acad Sci USA. 111:8838–8843. 2014. View Article : Google Scholar : PubMed/NCBI
363	De Vitto H, Mendonca BS, Elseth KM, Onul A, Xue J, Vesper BJ, Gallo CV, Rumjanek FD, Paradise WA and Radosevich JA: Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): A switch from aerobic to anaerobic metabolism. Tumour Biol. 34:403–413. 2013. View Article : Google Scholar : PubMed/NCBI
364	Deliconstantinos G, Villiotou V, Stavrides JC, Salemes N and Gogas J: Nitric oxide and peroxynitrite production by human erythrocytes: A causative factor of toxic anemia in breast cancer patients. Anticancer Res. 15:1435–1446. 1995.PubMed/NCBI
365	Demircan B, Yucel B and Radosevich JA: DNA methylation in human breast cancer cell lines adapted to high nitric oxide. In Vivo. 34:169–176. 2020. View Article : Google Scholar : PubMed/NCBI
366	Duan L, Danzer B, Levenson VV and Maki CG: Critical roles for nitric oxide and ERK in the completion of prosurvival autophagy in 4OHTAM-treated estrogen receptor-positive breast cancer cells. Cancer Lett. 353:290–300. 2014. View Article : Google Scholar : PubMed/NCBI
367	El Hasasna H, Saleh A, Al Samri H, Athamneh K, Attoub S, Arafat K, Benhalilou N, Alyan S, Viallet J, Al Dhaheri Y, et al: Rhus coriaria suppresses angiogenesis, metastasis and tumor growth of breast cancer through inhibition of STAT3, NFκB and nitric oxide pathways. Scic Rep. 6:211442016. View Article : Google Scholar : PubMed/NCBI
368	Engelen M, Klimberg VS, Allasia A and Deutz NEP: Major surgery diminishes systemic arginine availability and suppresses nitric oxide response to feeding in patients with early stage breast cancer. Clin Nutr. 37:1645–1653. 2018. View Article : Google Scholar : PubMed/NCBI
369	Erbas H, Aydogdu N, Usta U and Erten O: Protective role of carnitine in breast cancer via decreasing arginase activity and increasing nitric oxide. Cell Biol Int. 31:1414–1419. 2007. View Article : Google Scholar : PubMed/NCBI
370	Gaballah HE, Abdel Salam I, Abdel Wahab N and Mansour OM: Plasma bcl-2 and nitric oxide: Possible prognostic role in patients with metastatic breast cancer. Med Oncol. 18:171–178. 2001. View Article : Google Scholar : PubMed/NCBI
371	Gajalakshmi P, Priya MK, Pradeep T, Behera J, Muthumani K, Madhuwanti S, Saran U and Chatterjee S: Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium. Toxicol Appl Pharmacol. 269:121–131. 2013. View Article : Google Scholar : PubMed/NCBI
372	Ganguly Bhattacharjee K, Bhattacharyya M, Halder UC, Jana P and Sinha AK: The role of neutrophil estrogen receptor status on maspin synthesis via nitric oxide production in human breast cancer. J Breast Cancer. 15:181–188. 2012. View Article : Google Scholar : PubMed/NCBI
373	Ganguly Bhattacharjee K, Bhattacharyya M, Halder UC, Jana P and Sinha AK: Effect of progesterone receptor status on maspin synthesis via nitric oxide production in neutrophils in human breast cancer. Breast Cancer. 21:605–613. 2014. View Article : Google Scholar : PubMed/NCBI
374	Gaspari APS, da Silva RS, Carneiro ZA, de Carvalho MR, Carvalho I, Pernomian L, Ferreira LP, Ramos LCB, de Souza GA and Formiga ALB: Improving cytotoxicity against breast cancer cells by using Mixed-Ligand Ruthenium(II) Complexes of 2,2′-Bipyridine, amino acid, and nitric oxide derivatives as potential anticancer agents. Anticancer Agents Med Chem. 21:1602–1611. 2021. View Article : Google Scholar : PubMed/NCBI
375	Guha M, Biswas J, Tirkey J and Sinha AK: Impairment of stimulation by estrogen of insulin-activated nitric oxide synthase in human breast cancer. Int J Cancer. 100:261–265. 2002. View Article : Google Scholar : PubMed/NCBI
376	Günel N, Coskun U, Sancak B, Hasdemir O, Sare M, Bayram O, Celenkoglu G and Ozkan S: Prognostic value of serum IL-18 and nitric oxide activity in breast cancer patients at operable stage. Am J Clin Oncol. 26:416–421. 2003. View Article : Google Scholar : PubMed/NCBI
377	Kampa M, Hatzoglou A, Notas G, Niniraki M, Kouroumalis E and Castanas E: Opioids are non-competitive inhibitors of nitric oxide synthase in T47D human breast cancer cells. Cell Death Differ. 8:943–952. 2001. View Article : Google Scholar : PubMed/NCBI
378	Khalkhali-Ellis Z and Hendrix MJ: Nitric oxide regulation of maspin expression in normal mammary epithelial and breast cancer cells. Am J Pathol. 162:1411–1417. 2003. View Article : Google Scholar : PubMed/NCBI
379	Konukoglu D, Turhan MS, Celik V and Turna H: Relation of serum vascular endothelial growth factor as an angiogenesis biomarker with nitric oxide & urokinase-type plasminogen activator in breast cancer patients. Indian J Med Res. 125:747–751. 2007.PubMed/NCBI
380	Kumar S and Kashyap P: Antiproliferative activity and nitric oxide production of a methanolic extract of Fraxinus micrantha on Michigan Cancer Foundation-7 mammalian breast carcinoma cell line. J Intercult Ethnopharmacol. 4:109–113. 2015. View Article : Google Scholar : PubMed/NCBI
381	Lahiri M and Martin JH: Nitric oxide decreases motility and increases adhesion in human breast cancer cells. Oncol Rep. 21:275–281. 2009.PubMed/NCBI
382	Lee SY, Rim Y, McPherson DD, Huang SL and Kim H: A novel liposomal nanomedicine for nitric oxide delivery and breast cancer treatment. Biomed Mater Eng. 24:61–67. 2014.PubMed/NCBI
383	Hewala TI, Abd El-Moneim NA, Ebied SA, Sheta MI, Soliman K and Abu-Elenean A: Diagnostic and prognostic value of serum nitric oxide, tumor necrosis factor-alpha, basic fibroblast growth factor and copper as angiogenic markers in premenopausal breast cancer patients: A case-control study. Br J Biomed Sci. 67:167–176. 2010. View Article : Google Scholar : PubMed/NCBI
384	Finkelman BS, Putt M, Wang T, Wang L, Narayan H, Domchek S, DeMichele A, Fox K, Matro J, Shah P, et al: Arginine-nitric oxide metabolites and cardiac dysfunction in patients with breast cancer. J Am Coll Cardiol. 70:152–162. 2017. View Article : Google Scholar : PubMed/NCBI
385	Jadeski LC, Chakraborty C and Lala PK: Role of nitric oxide in tumour progression with special reference to a murine breast cancer model. Can J Physiol Pharmacol. 80:125–135. 2002. View Article : Google Scholar : PubMed/NCBI
386	McCurdy MR, Wazni MW, Martinez J, McAleer MF and Guerrero T: Exhaled nitric oxide predicts radiation pneumonitis in esophageal and lung cancer patients receiving thoracic radiation. Radiother Oncol. 101:443–448. 2011. View Article : Google Scholar : PubMed/NCBI
387	Metwally FM, El-mezayen HA and Ahmed HH: Significance of vascular endothelial growth factor, interleukin-18 and nitric oxide in patients with breast cancer: Correlation with carbohydrate antigen 15.3. Med Oncol. 28 (Suppl 1):S15–S21. 2011. View Article : Google Scholar : PubMed/NCBI
388	Mishra D, Patel V and Banerjee D: Nitric Oxide and S-Nitrosylation in Cancers: Emphasis on breast cancer. Breast Cancer (Auckl). 14:11782234198826882020.PubMed/NCBI
389	Nakamura Y, Yasuoka H, Tsujimoto M, Yoshidome K, Nakahara M, Nakao K, Nakamura M and Kakudo K: Nitric oxide in breast cancer: Induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin Cancer Res. 12:1201–1207. 2006. View Article : Google Scholar : PubMed/NCBI
390	Negroni MP, Fiszman GL, Azar ME, Morgado CC, Español AJ, Pelegrina LT, de la Torre E and Sales ME: Immunoglobulin G from breast cancer patients in stage I stimulates muscarinic acetylcholine receptors in MCF7 cells and induces proliferation. Participation of nitric oxide synthase-derived nitric oxide. J Clin Immunol. 30:474–484. 2010. View Article : Google Scholar : PubMed/NCBI
391	Martin JH, Alalami O and Yaqoob F: Differential effects of retinoids on nitric oxide production by promonocytic U937 cells and ZR-75-1 human breast cancer cells. Oncol Rep. 7:219–223. 2000.PubMed/NCBI
392	Martin JH, Symonds A and Chohan S: Down-regulation of nitric oxide production by droloxifene and toremifene in human breast cancer cells. Oncol Rep. 10:979–984. 2003.PubMed/NCBI
393	Nath N, Chattopadhyay M, Rodes DB, Nazarenko A, Kodela R and Kashfi K: Nitric Oxide-releasing aspirin suppresses NF-κB signaling in estrogen receptor negative breast cancer cells in vitro and in vivo. Molecules. 20:12481–12499. 2015. View Article : Google Scholar : PubMed/NCBI
394	Pance A: Nitric oxide and hormones in breast cancer: Allies or enemies? Future Oncol. 2:275–288. 2006. View Article : Google Scholar : PubMed/NCBI
395	Parihar A, Parihar MS and Ghafourifar P: Significance of mitochondrial calcium and nitric oxide for apoptosis of human breast cancer cells induced by tamoxifen and etoposide. Int J Mol Med. 21:317–324. 2008.PubMed/NCBI
396	Pervin S, Singh R and Chaudhuri G: Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): Potential role of cyclin D1. Proc Natl Acad Sci USA. 98:3583–3588. 2001. View Article : Google Scholar : PubMed/NCBI
397	Pervin S, Singh R and Chaudhuri G: Nitric oxide, N omega-hydroxy-L-arginine and breast cancer. Nitric Oxide. 19:103–106. 2008. View Article : Google Scholar : PubMed/NCBI
398	Pervin S, Singh R, Freije WA and Chaudhuri G: MKP-1-induced dephosphorylation of extracellular signal-regulated kinase is essential for triggering nitric oxide-induced apoptosis in human breast cancer cell lines: Implications in breast cancer. Cancer Res. 63:8853–8860. 2003.PubMed/NCBI
399	Pervin S, Singh R, Gau CL, Edamatsu H, Tamanoi F and Chaudhuri G: Potentiation of nitric oxide-induced apoptosis of MDA-MB-468 cells by farnesyltransferase inhibitor: Implications in breast cancer. Cancer Res. 61:4701–4706. 2001.PubMed/NCBI
400	Pervin S, Singh R, Hernandez E, Wu G and Chaudhuri G: Nitric oxide in physiologic concentrations targets the translational machinery to increase the proliferation of human breast cancer cells: Involvement of mammalian target of rapamycin/eIF4E pathway. Cancer Res. 67:289–299. 2007. View Article : Google Scholar : PubMed/NCBI
401	Punathil T, Tollefsbol TO and Katiyar SK: EGCG inhibits mammary cancer cell migration through inhibition of nitric oxide synthase and guanylate cyclase. Biochem Biophys Res Commun. 375:162–167. 2008. View Article : Google Scholar : PubMed/NCBI
402	Radisavljevic Z: Inactivated tumor suppressor Rb by nitric oxide promotes mitosis in human breast cancer cells. J Cell Biochem. 92:1–5. 2004. View Article : Google Scholar : PubMed/NCBI
403	Rashad YA, Elkhodary TR, El-Gayar AM and Eissa LA: Evaluation of serum levels of HER2, MMP-9, Nitric Oxide, and total antioxidant capacity in egyptian breast cancer patients: Correlation with clinico-pathological parameters. Sci Pharm. 82:129–145. 2014. View Article : Google Scholar : PubMed/NCBI
404	Ray GN, Shahid M and Husain SA: Effect of nitric oxide and malondialdehyde on sister-chromatid exchanges in breast cancer. Br J Biomed Sci. 58:169–176. 2001.PubMed/NCBI
405	Reveneau S, Arnould L, Jolimoy G, Hilpert S, Lejeune P, Saint-Giorgio V, Belichard C and Jeannin JF: Nitric oxide synthase in human breast cancer is associated with tumor grade, proliferation rate, and expression of progesterone receptors. Lab Invest. 79:1215–1225. 1999.PubMed/NCBI
406	Ridnour LA, Barasch KM, Windhausen AN, Dorsey TH, Lizardo MM, Yfantis HG, Lee DH, Switzer CH, Cheng RY, Heinecke JL, et al: Nitric oxide synthase and breast cancer: Role of TIMP-1 in NO-mediated Akt activation. PLoS One. 7:e440812012. View Article : Google Scholar : PubMed/NCBI
407	Zhu W, Yang B, Fu H, Ma L, Liu T, Chai R, Zheng Z, Zhang Q and Li G: Flavone inhibits nitric oxide synthase (NOS) activity, nitric oxide production and protein S-nitrosylation in breast cancer cells. Biochem Biophys Res Commun. 458:590–595. 2015. View Article : Google Scholar : PubMed/NCBI
408	Zheng X, Fernando V, Sharma V, Walia Y, Letson J and Furuta S: Correction of arginine metabolism with sepiapterin-the precursor of nitric oxide synthase cofactor BH(4)-induces immunostimulatory-shift of breast cancer. Biochem Pharmacol. 176:1138872020. View Article : Google Scholar : PubMed/NCBI
409	Zeillinger R, Tantscher E, Schneeberger C, Tschugguel W, Eder S, Sliutz G and Huber JC: Simultaneous expression of nitric oxide synthase and estrogen receptor in human breast cancer cell lines. Breast Cancer Res Treat. 40:205–207. 1996. View Article : Google Scholar : PubMed/NCBI
410	Wang HJ, Wei XF, Jiang YY, Huang H, Yang Y, Fan SM, Zang LH, Tashiro S, Onodera S and Ikejima T: Silibinin induces the generation of nitric oxide in human breast cancer MCF-7 cells. Free Radic Res. 44:577–584. 2010. View Article : Google Scholar : PubMed/NCBI
411	Thamrongwittawatpong L, Sirivatanauksorn Y, Batten JJ, Williamson RC, Kakkar AK and Mathie RT: The effect of N(G)-monomethyl-L-arginine and tamoxifen on nitric oxide production in breast cancer cells stimulated by oestrogen and progesterone. Eur J Surg. 167:484–489. 2001. View Article : Google Scholar : PubMed/NCBI
412	Toomey D, Condron C, Wu QD, Kay E, Harmey J, Broe P, Kelly C and Bouchier-Hayes D: TGF-beta1 is elevated in breast cancer tissue and regulates nitric oxide production from a number of cellular sources during hypoxia re-oxygenation injury. Br J Biomed Sci. 58:177–183. 2001.PubMed/NCBI
413	Salaroglio IC, Gazzano E, Abdullrahman A, Mungo E, Castella B, Abd-Elrahman GEFA, Massaia M, Donadelli M, Rubinstein M, Riganti C and Kopecka J: Increasing intratumor C/EBP-β LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer. J Exp Clin Cancer Res. 37:2862018. View Article : Google Scholar : PubMed/NCBI
414	Sen S, Kawahara B and Chaudhuri G: Mitochondrial-associated nitric oxide synthase activity inhibits cytochrome c oxidase: Implications for breast cancer. Free Radic Biol Med. 57:210–220. 2013. View Article : Google Scholar : PubMed/NCBI
415	Sen S, Kawahara B, Fukuto J and Chaudhuri G: Induction of a feed forward pro-apoptotic mechanistic loop by nitric oxide in a human breast cancer model. PLoS One. 8:e705932013. View Article : Google Scholar : PubMed/NCBI
416	Shoulars K, Rodriguez MA, Thompson T, Turk J, Crowley J and Markaverich BM: Regulation of the nitric oxide pathway genes by tetrahydrofurandiols: Microarray analysis of MCF-7 human breast cancer cells. Cancer Lett. 264:265–273. 2008. View Article : Google Scholar : PubMed/NCBI
417	Simeone AM, Broemeling LD, Rosenblum J and Tari AM: HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production. Oncogene. 22:6739–6747. 2003. View Article : Google Scholar : PubMed/NCBI
418	Simeone AM, Ekmekcioglu S, Broemeling LD, Grimm EA and Tari AM: A novel mechanism by which N-(4-hydroxyphenyl)retinamide inhibits breast cancer cell growth: The production of nitric oxide. Mol Cancer Ther. 1:1009–1017. 2002.PubMed/NCBI
419	Simeone AM, McMurtry V, Nieves-Alicea R, Saavedra JE, Keefer LK, Johnson MM and Tari AM: TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cells. Breast Cancer Res. 10:R442008. View Article : Google Scholar : PubMed/NCBI
420	Singh T and Katiyar SK: Honokiol, a phytochemical from Magnolia spp., inhibits breast cancer cell migration by targeting nitric oxide and cyclooxygenase-2. Int J Oncol. 38:769–776. 2011.PubMed/NCBI
421	Smeda M, Kieronska A, Adamski MG, Proniewski B, Sternak M, Mohaissen T, Przyborowski K, Derszniak K, Kaczor D, Stojak M, et al: Nitric oxide deficiency and endothelial-mesenchymal transition of pulmonary endothelium in the progression of 4T1 metastatic breast cancer in mice. Breast Cancer Res. 20:862018. View Article : Google Scholar : PubMed/NCBI
422	Song YK, Billiar TR and Lee YJ: Role of galectin-3 in breast cancer metastasis: Involvement of nitric oxide. Am J Pathol. 160:1069–1075. 2002. View Article : Google Scholar : PubMed/NCBI
423	Switzer CH, Cheng RY, Ridnour LA, Glynn SA, Ambs S and Wink DA: Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer. Breast Cancer Res. 14:R1252012. View Article : Google Scholar : PubMed/NCBI
424	Switzer CH, Glynn SA, Ridnour LA, Cheng RY, Vitek MP, Ambs S and Wink DA: Nitric oxide and protein phosphatase 2A provide novel therapeutic opportunities in ER-negative breast cancer. Trends Pharmacol Sci. 32:644–651. 2011. View Article : Google Scholar : PubMed/NCBI
425	Ai Y, Kang F, Huang Z, Xue X, Lai Y, Peng S, Tian J and Zhang Y: Synthesis of CDDO-amino acid-nitric oxide donor trihybrids as potential antitumor agents against both drug-sensitive and drug-resistant colon cancer. J Med Chem. 58:2452–2464. 2015. View Article : Google Scholar : PubMed/NCBI
426	Babykutty S, Suboj P, Srinivas P, Nair AS, Chandramohan K and Gopala S: Insidious role of nitric oxide in migration/invasion of colon cancer cells by upregulating MMP-2/9 via activation of cGMP-PKG-ERK signaling pathways. Clin Exp Metastasis. 29:471–492. 2012. View Article : Google Scholar : PubMed/NCBI
427	Bessa X, Elizalde JI, Mitjans F, Piñol V, Miquel R, Panés J, Piulats J, Piqué JM and Castells A: Leukocyte recruitment in colon cancer: Role of cell adhesion molecules, nitric oxide, and transforming growth factor beta1. Gastroenterology. 122:1122–1132. 2002. View Article : Google Scholar : PubMed/NCBI
428	Chattopadhyay M, Kodela R, Olson KR and Kashfi K: NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model. Biochem Biophys Res Commun. 419:523–528. 2012. View Article : Google Scholar : PubMed/NCBI
429	Edes K, Cassidy P, Shami PJ and Moos PJ: JS-K, a nitric oxide prodrug, has enhanced cytotoxicity in colon cancer cells with knockdown of thioredoxin reductase 1. PLoS One. 5:e87862010. View Article : Google Scholar : PubMed/NCBI
430	Ishikawa T, Yoshida N, Higashihara H, Inoue M, Uchiyama K, Takagi T, Handa O, Kokura S, Naito Y, Okanoue T and Yoshikawa T: Different effects of constitutive nitric oxide synthase and heme oxygenase on pulmonary or liver metastasis of colon cancer in mice. Clin Exp Metastasis. 20:445–450. 2003. View Article : Google Scholar : PubMed/NCBI
431	Jarry A, Charrier L, Bou-Hanna C, Devilder MC, Crussaire V, Denis MG, Vallette G and Laboisse CL: Position in cell cycle controls the sensitivity of colon cancer cells to nitric oxide-dependent programmed cell death. Cancer Res. 64:4227–4234. 2004. View Article : Google Scholar : PubMed/NCBI
432	Jenkins DC, Charles IG, Baylis SA, Lelchuk R, Radomski MW and Moncada S: Human colon cancer cell lines show a diverse pattern of nitric oxide synthase gene expression and nitric oxide generation. Br J Cancer. 70:847–849. 1994. View Article : Google Scholar : PubMed/NCBI
433	Jeon HK, Choi SU and Jung NP: Association of the ERK1/2 and p38 kinase pathways with nitric oxide-induced apoptosis and cell cycle arrest in colon cancer cells. Cell Biol Toxicol. 21:115–125. 2005. View Article : Google Scholar : PubMed/NCBI
434	Kim MY: Sasa quelpaertensis Nakai extract induces p53-independent apoptosis via the elevation of nitric oxide production in human HCT116 colon cancer cells. Oncol Lett. 19:3027–3034. 2020.PubMed/NCBI
435	Kopecka J, Campia I, Brusa D, Doublier S, Matera L, Ghigo D, Bosia A and Riganti C: Nitric oxide and P-glycoprotein modulate the phagocytosis of colon cancer cells. J Cell Mol Med. 15:1492–1504. 2011. View Article : Google Scholar : PubMed/NCBI
436	Liu Q, Chan ST and Mahendran R: Nitric oxide induces cyclooxygenase expression and inhibits cell growth in colon cancer cell lines. Carcinogenesis. 24:637–642. 2003. View Article : Google Scholar : PubMed/NCBI
437	Liu Q, Inoue H and Mahendran R: Transcriptional regulation of the COX-2 expression by nitric oxide in colon cancer cell lines. Oncol Rep. 19:269–274. 2008.PubMed/NCBI
438	Mojic M, Mijatovic S, Maksimovic-Ivanic D, Miljkovic D, Stosic-Grujicic S, Stankovic M, Mangano K, Travali S, Donia M, Fagone P, et al: Therapeutic potential of nitric oxide-modified drugs in colon cancer cells. Mol Pharmacol. 82:700–710. 2012. View Article : Google Scholar : PubMed/NCBI
439	Millet A, Bettaieb A, Renaud F, Prevotat L, Hammann A, Solary E, Mignotte B and Jeannin JF: Influence of the nitric oxide donor glyceryl trinitrate on apoptotic pathways in human colon cancer cells. Gastroenterology. 123:235–246. 2002. View Article : Google Scholar : PubMed/NCBI
440	Oláh G, Módis K, Törö G, Hellmich MR, Szczesny B and Szabo C: Role of endogenous and exogenous nitric oxide, carbon monoxide and hydrogen sulfide in HCT116 colon cancer cell proliferation. Biochem Pharmacol. 149:186–204. 2018. View Article : Google Scholar : PubMed/NCBI
441	Prevotat L, Filomenko R, Solary E, Jeannin JF and Bettaieb A: Nitric oxide-induced down-regulation of beta-catenin in colon cancer cells by a proteasome-independent specific pathway. Gastroenterology. 131:1142–1152. 2006. View Article : Google Scholar : PubMed/NCBI
442	Rao CV: Nitric oxide signaling in colon cancer chemoprevention. Mutation Res. 555:107–119. 2004. View Article : Google Scholar : PubMed/NCBI
443	Rao CV, Reddy BS, Steele VE, Wang CX, Liu X, Ouyang N, Patlolla JM, Simi B, Kopelovich L and Rigas B: Nitric oxide-releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: Effects on molecular targets. Mol Cancer Ther. 5:1530–1538. 2006. View Article : Google Scholar : PubMed/NCBI
444	Riganti C, Miraglia E, Viarisio D, Costamagna C, Pescarmona G, Ghigo D and Bosia A: Nitric oxide reverts the resistance to doxorubicin in human colon cancer cells by inhibiting the drug efflux. Cancer Res. 65:516–525. 2005.PubMed/NCBI
445	Wang H and MacNaughton WK: Overexpressed beta-catenin blocks nitric oxide-induced apoptosis in colonic cancer cells. Cancer Res. 65:8604–8607. 2005. View Article : Google Scholar : PubMed/NCBI
446	Xie J, Xia L, Xiang W, He W, Yin H, Wang F, Gao T, Qi W, Yang Z, Yang X, et al: Metformin selectively inhibits metastatic colorectal cancer with the KRAS mutation by intracellular accumulation through silencing MATE1. Proc Natl Acad Sci USA. 117:13012–13022. 2020. View Article : Google Scholar : PubMed/NCBI
447	Wenzel U, Kuntz S, De Sousa UJ and Daniel H: Nitric oxide suppresses apoptosis in human colon cancer cells by scavenging mitochondrial superoxide anions. Int J Cancer. 106:666–675. 2003. View Article : Google Scholar : PubMed/NCBI
448	Williams JL, Borgo S, Hasan I, Castillo E, Traganos F and Rigas B: Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) alter the kinetics of human colon cancer cell lines more effectively than traditional NSAIDs: Implications for colon cancer chemoprevention. Cancer Res. 61:3285–3289. 2001.PubMed/NCBI
449	Voss NCS, Kold-Petersen H and Boedtkjer E: Enhanced nitric oxide signaling amplifies vasorelaxation of human colon cancer feed arteries. Am J Physiol Heart Circ Physiol. 316:H245–H254. 2019. View Article : Google Scholar : PubMed/NCBI
450	Tesei A, Rosetti M, Ulivi P, Fabbri F, Medri L, Vannini I, Bolla M, Amadori D and Zoli W: Study of molecular mechanisms of pro-apoptotic activity of NCX 4040, a novel nitric oxide-releasing aspirin, in colon cancer cell lines. J Transl Med. 5:522007. View Article : Google Scholar : PubMed/NCBI
451	Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG and Moncada S: Nitric oxide synthase activity in human breast cancer. Br J Cancer. 72:41–44. 1995. View Article : Google Scholar : PubMed/NCBI
452	Stettner N, Rosen C, Bernshtein B, Gur-Cohen S, Frug J, Silberman A, Sarver A, Carmel-Neiderman NN, Eilam R, Biton I, et al: Induction of Nitric-Oxide metabolism in enterocytes alleviates colitis and inflammation-associated colon cancer. Cell Rep. 23:1962–1976. 2018. View Article : Google Scholar : PubMed/NCBI
453	Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM, Khan MA, Jones RT and Harris CC: Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. Br J Ccancer. 78:233–239. 1998. View Article : Google Scholar : PubMed/NCBI
454	Cembrzynska-Nowak M, Bienkowska M and Szklarz E: Exogenous interleukin 2 regulates interleukin 6 and nitric oxide but not interferon gamma and tumor necrosis factor alpha production in bronchoalveolar leukocytes from patients with small cell lung cancer. Arch Immunol Ther Exp (Warsz). 46:367–374. 1998.PubMed/NCBI
455	Cembrzyńska-Nowak M, Bieńkowska M, Weryńska B, Dyła T and Jankowska R: The contribution of endotoxins present in the respiratory tract to overproduction of nitric oxide associated with impaired interleukin 6 release in bronchoalveolar leukocytes from lung cancer patients. Arch Immunol Ther Exp (Warsz). 48:119–125. 2000.PubMed/NCBI
456	Chen Z, Huang KY, Ling Y, Goto M, Duan HQ, Tong XH, Liu YL, Cheng YY, Morris-Natschke SL, Yang PC, et al: Discovery of an Oleanolic Acid/Hederagenin-nitric oxide donor hybrid as an EGFR tyrosine kinase inhibitor for non-small-cell lung cancer. J Natural Prod. 82:3065–3073. 2019. View Article : Google Scholar : PubMed/NCBI
457	Deliu Z, Tamas T, Chowdhury J, Aqil M, Bassiony M and Radosevich JA: Expression of cross-tolerance to a wide range of conditions in a human lung cancer cell line after adaptation to nitric oxide. Tumour Biol. 39:10104283177237782017. View Article : Google Scholar : PubMed/NCBI
458	Fu J, Han J, Meng T, Hu J and Yin J: Novel α-ketoamide based diazeniumdiolates as hydrogen peroxide responsive nitric oxide donors with anti-lung cancer activity. Chem Commun (Camb). 55:12904–12907. 2019. View Article : Google Scholar : PubMed/NCBI
459	Fujimoto H, Ando Y, Yamashita T, Terazaki H, Tanaka Y, Sasaki J, Matsumoto M, Suga M and Ando M: Nitric oxide synthase activity in human lung cancer. Jpn J Cancer Res. 88:1190–1198. 1997. View Article : Google Scholar : PubMed/NCBI
460	Gao X, Xuan Y, Benner A, Anusruti A, Brenner H and Schottker B: Nitric oxide metabolites and lung cancer incidence: A matched case-control study nested in the ESTHER cohort. Oxid Med Cell Longev. 2019:64709502019. View Article : Google Scholar : PubMed/NCBI
461	Hwang JH, Park SJ, Ko WG, Kang SM, Lee DB, Bang J, Park BJ, Wee CB, Kim DJ, Jang IS and Ko JH: Cordycepin induces human lung cancer cell apoptosis by inhibiting nitric oxide mediated ERK/Slug signaling pathway. Am J Cancer Res. 7:417–432. 2017.PubMed/NCBI
462	Kaynar H, Meral M, Turhan H, Keles M, Celik G and Akcay F: Glutathione peroxidase, glutathione-S-transferase, catalase, xanthine oxidase, Cu-Zn superoxide dismutase activities, total glutathione, nitric oxide, and malondialdehyde levels in erythrocytes of patients with small cell and non-small cell lung cancer. Cancer Lett. 227:133–139. 2005. View Article : Google Scholar : PubMed/NCBI
463	Koizumi M, Yamazaki H, Toyokawa K, Yoshioka Y, Suzuki G, Ito M, Shinkawa K, Nishino K, Watanabe Y, Inoue T, et al: Influence of thoracic radiotherapy on exhaled nitric oxide levels in patients with lung cancer. Jpn J Clin Oncol. 31:142–146. 2001. View Article : Google Scholar : PubMed/NCBI
464	Munaweera I, Shi Y, Koneru B, Patel A, Dang MH, Di Pasqua AJ and Balkus KJ Jr: Nitric oxide- and cisplatin-releasing silica nanoparticles for use against non-small cell lung cancer. J Inorg Biochem. 153:23–31. 2015. View Article : Google Scholar : PubMed/NCBI
465	Maciag AE, Chakrapani H, Saavedra JE, Morris NL, Holland RJ, Kosak KM, Shami PJ, Anderson LM and Keefer LK: The nitric oxide prodrug JS-K is effective against non-small-cell lung cancer cells in vitro and in vivo: Involvement of reactive oxygen species. J Pharmacol Exp Ther. 336:313–320. 2011. View Article : Google Scholar : PubMed/NCBI
466	Maiuthed A, Prakhongcheep O and Chanvorachote P: Microarray-based analysis of genes, transcription factors, and epigenetic modifications in lung cancer exposed to nitric oxide. Cancer Genom Proteomics. 17:401–415. 2020. View Article : Google Scholar : PubMed/NCBI
467	Lee JJ, Kwon HK, Lee DS, Lee SW, Lee KK, Kim KJ and Kim JL: Mycelial extract of phellinus linteus induces cell death in A549 lung cancer cells and elevation of nitric oxide in raw 264.7 macrophage cells. Mycobiology. 34:143–147. 2006. View Article : Google Scholar : PubMed/NCBI
468	Liaw YP, Ting TF, Ho CC and Chiou ZY: Cell type specificity of lung cancer associated with nitric oxide. Sci Total Environ. 408:4931–4934. 2010. View Article : Google Scholar : PubMed/NCBI
469	Liu PF, Zhao DH, Qi Y, Wang JG, Zhao M, Xiao K and Xie LX: The clinical value of exhaled nitric oxide in patients with lung cancer. Clin Respir J. 12:23–30. 2018. View Article : Google Scholar : PubMed/NCBI
470	Luanpitpong S and Chanvorachote P: Nitric oxide and aggressive behavior of lung cancer cells. Anticancer Res. 35:4585–4592. 2015.PubMed/NCBI
471	Muto S, Takagi H, Owada Y, Inoue T, Watanabe Y, Yamaura T, Fukuhara M, Okabe N, Matsumura Y, Hasegawa T, et al: Serum nitric oxide as a predictive biomarker for bevacizumab in non-small cell lung cancer patients. Anticancer Res. 37:3169–3174. 2017.PubMed/NCBI
472	Masri F: Role of nitric oxide and its metabolites as potential markers in lung cancer. Ann Thorac Med. 5:123–127. 2010. View Article : Google Scholar : PubMed/NCBI
473	Masri FA, Comhair SA, Koeck T, Xu W, Janocha A, Ghosh S, Dweik RA, Golish J, Kinter M, Stuehr DJ, et al: Abnormalities in nitric oxide and its derivatives in lung cancer. Am J Respir Crit Care Med. 172:597–605. 2005. View Article : Google Scholar : PubMed/NCBI
474	Matsunaga T, Yamaji Y, Tomokuni T, Morita H, Morikawa Y, Suzuki A, Yonezawa A, Endo S, Ikari A, Iguchi K, et al: Nitric oxide confers cisplatin resistance in human lung cancer cells through upregulation of aldo-keto reductase 1B10 and proteasome. Free Radical Res. 48:1371–1385. 2014. View Article : Google Scholar : PubMed/NCBI
475	Powan P and Chanvorachote P: Nitric oxide mediates cell aggregation and mesenchymal to epithelial transition in anoikis-resistant lung cancer cells. Mol Cell Biochem. 393:237–245. 2014. View Article : Google Scholar : PubMed/NCBI
476	Punathil T and Katiyar SK: Inhibition of non-small cell lung cancer cell migration by grape seed proanthocyanidins is mediated through the inhibition of nitric oxide, guanylate cyclase, and ERK1/2. Mol Carcinog. 48:232–242. 2009. View Article : Google Scholar : PubMed/NCBI
477	Zhou J, Zhu Q and Yao H: Chemotherapy of non-small-cell lung cancer (NSCLC) and changes in serum sAPO-1/Fas and nitric oxide (NO) levels. Zhonghua Zhong Liu Za Zhi. 22:225–227. 2000.(In Chinese). PubMed/NCBI
478	Zhou H, Dong Y, Ma X, Xu J and Xu S: Development of a novel truncated deguelin derivative possessing nitric oxide donor as a potential anti-lung cancer agent. Fitoterapia. 146:1046702020. View Article : Google Scholar : PubMed/NCBI
479	Zhang L, Liu J, Wang X, Li Z, Zhang X, Cao P, She X, Dai Q, Tang J and Liu Z: Upregulation of cytoskeleton protein and extracellular matrix protein induced by stromal-derived nitric oxide promotes lung cancer invasion and metastasis. Curr Mol Med. 14:762–771. 2014. View Article : Google Scholar : PubMed/NCBI
480	Yongsanguanchai N, Pongrakhananon V, Mutirangura A, Rojanasakul Y and Chanvorachote P: Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells. Am J Physiol Cell Physiol. 308:C89–C100. 2015. View Article : Google Scholar : PubMed/NCBI
481	Wongvaranon P, Pongrakhananon V, Chunhacha P and Chanvorachote P: Acquired resistance to chemotherapy in lung cancer cells mediated by prolonged nitric oxide exposure. Anticancer Res. 33:5433–5444. 2013.PubMed/NCBI
482	Saisongkorh V, Maiuthed A and Chanvorachote P: Nitric oxide increases the migratory activity of non-small cell lung cancer cells via AKT-mediated integrin αv and β1 upregulation. Cell Oncol (Dordr). 39:449–462. 2016. View Article : Google Scholar : PubMed/NCBI
483	Saleem W, Suzuki Y, Mobaraki A, Yoshida Y, Noda S, Saitoh JI and Nakano T: Reduction of nitric oxide level enhances the radiosensitivity of hypoxic non-small cell lung cancer. Cancer Sci. 102:2150–2156. 2011. View Article : Google Scholar : PubMed/NCBI
484	Sanuphan A, Chunhacha P, Pongrakhananon V and Chanvorachote P: Long-term nitric oxide exposure enhances lung cancer cell migration. Biomed Res Int. 2013:1869722013. View Article : Google Scholar : PubMed/NCBI
485	Sanuphan A, Chunhacha P, Pongrakhananon V and Chanvorachote P: Corrigendum to ‘Long-term nitric oxide exposure enhances lung cancer cell migration’. Biomed Res Int. 2015:3106362015. View Article : Google Scholar : PubMed/NCBI
486	Su X, Takahashi A, Guo G, Mori E, Okamoto N, Ohnishi K, Iwasaki T and Ohnishi T: Biphasic effects of nitric oxide radicals on radiation-induced lethality and chromosome aberrations in human lung cancer cells carrying different p53 gene status. Int J Radiat Oncol Biol Phys. 77:559–565. 2010. View Article : Google Scholar : PubMed/NCBI
487	Suzuki Y, Inui N, Karayama M, Imokawa S, Yamada T, Yokomura K, Asada K, Kusagaya H, Kaida Y, Matsuda H, et al: Effect of PD-1 inhibitor on exhaled nitric oxide and pulmonary function in non-small cell lung cancer patients with and without COPD. Int J Chron Obstruct Pulmon Dis. 14:1867–1877. 2019. View Article : Google Scholar : PubMed/NCBI
488	Szejniuk WM, Nielsen MS, Brønnum D, Takács-Szabó Z, Weinreich UM, Pilegaard Thomsen L, Bøgsted M, Jensen I, McCulloch T, Falkmer UG, et al: Fractional exhaled nitric oxide as a potential biomarker for radiation pneumonitis in patients with non-small cell lung cancer: A pilot study. Clin Transl Radiat Oncol. 19:103–109. 2019. View Article : Google Scholar : PubMed/NCBI
489	Arif M, Vedamurthy BM, Choudhari R, Ostwal YB, Mantelingu K, Kodaganur GS and Kundu TK: Nitric oxide-mediated histone hyperacetylation in oral cancer: Target for a water-soluble HAT inhibitor, CTK7A. Chem Biol. 17:903–913. 2010. View Article : Google Scholar : PubMed/NCBI
490	Beevi SS, Rasheed AM and Geetha A: Evaluation of oxidative stress and nitric oxide levels in patients with oral cavity cancer. Jpn J Clin Oncol. 34:379–385. 2004. View Article : Google Scholar : PubMed/NCBI
491	Korde Choudhari S, Sridharan G, Gadbail A and Poornima V: Nitric oxide and oral cancer: A review. Oral Oncol. 48:475–483. 2012. View Article : Google Scholar : PubMed/NCBI
492	Patel JB, Shah FD, Shukla SN, Shah PM and Patel PS: Role of nitric oxide and antioxidant enzymes in the pathogenesis of oral cancer. J Cancer Res Ther. 5:247–253. 2009. View Article : Google Scholar : PubMed/NCBI
493	Brankovic B, Stanojevic G, Stojanovic I, Veljkovic A, Kocic G, Janosevic P, Nestorovic M, Petrovic D, Djindjic B, Pavlovic D and Krivokapic Z: Nitric oxide synthesis modulation-a possible diagnostic and therapeutic target in colorectal cancer. J BUON. 22:162–169. 2017.PubMed/NCBI
494	El-Mezayen HA, Toson el SA, Darwish H and El-Badry E: Discriminant function based on parameters of hyaluronic acid metabolism and nitric oxide to differentiate metastatic from non-metastatic colorectal cancer patients. Tumour Biol. 33:995–1004. 2012. View Article : Google Scholar : PubMed/NCBI
495	Gao Y, Zhou S, Pang L, Yang J, Li HJ, Huo X and Qian SY: Celastrol suppresses nitric oxide synthases and the angiogenesis pathway in colorectal cancer. Free Radic Res. 53:324–334. 2019. View Article : Google Scholar : PubMed/NCBI
496	Gao Y, Zhou S, Xu Y, Sheng S, Qian SY and Huo X: Nitric oxide synthase inhibitors 1400W and L-NIO inhibit angiogenesis pathway of colorectal cancer. Nitric Oxide. 83:33–39. 2019. View Article : Google Scholar : PubMed/NCBI
497	Jiang H, Verovski VN, Leonard W, Law KL, Vermeersch M, Storme G, Van den Berge D, Gevaert T, Sermeus A and De Ridder M: Hepatocytes determine the hypoxic microenvironment and radiosensitivity of colorectal cancer cells through production of nitric oxide that targets mitochondrial respiration. Int J Radiat Oncol Biol Phys. 85:820–827. 2013. View Article : Google Scholar : PubMed/NCBI
498	Krzystek-Korpacka M, Szczęśniak-Sięga B, Szczuka I, Fortuna P, Zawadzki M, Kubiak A, Mierzchała-Pasierb M, Fleszar MG, Lewandowski Ł, Serek P, et al: L-Arginine/Nitric oxide pathway is altered in colorectal cancer and can be modulated by novel derivatives from oxicam class of non-steroidal anti-inflammatory drugs. Cancers (Basel). 12:25942020. View Article : Google Scholar : PubMed/NCBI
499	Liu Y, Borchert GL and Phang JM: Polyoma enhancer activator 3, an ets transcription factor, mediates the induction of cyclooxygenase-2 by nitric oxide in colorectal cancer cells. J Biol Chemistry. 279:18694–18700. 2004. View Article : Google Scholar
500	McIlhatton MA, Tyler J, Burkholder S, Ruschoff J, Rigas B, Kopelovich L and Fishel R: Nitric oxide-donating aspirin derivatives suppress microsatellite instability in mismatch repair-deficient and hereditary nonpolyposis colorectal cancer cells. Cancer Res. 67:10966–10975. 2007. View Article : Google Scholar : PubMed/NCBI
501	Moochhala S, Chhatwal VJ, Chan ST, Ngoi SS, Chia YW and Rauff A: Nitric oxide synthase activity and expression in human colorectal cancer. Carcinogenesis. 17:1171–1174. 1996. View Article : Google Scholar : PubMed/NCBI
502	Muscat JE, Dyer AM, Rosenbaum RE and Rigas B: Nitric oxide-releasing medications and colorectal cancer risk: The framingham study. Anticancer Res. 25:4471–4474. 2005.PubMed/NCBI
503	Mandal P: Molecular signature of nitric oxide on major cancer hallmarks of colorectal carcinoma. Inflammopharmacology. 26:331–336. 2018. View Article : Google Scholar : PubMed/NCBI
504	Yagihashi N, Kasajima H, Sugai S, Matsumoto K, Ebina Y, Morita T, Murakami T and Yagihashi S: Increased in situ expression of nitric oxide synthase in human colorectal cancer. Virchows Archiv. 436:109–114. 2000. View Article : Google Scholar : PubMed/NCBI
505	Yu LB, Dong XS, Sun WZ, Zhao DL and Yang Y: Effect of a nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on invasion of human colorectal cancer cell line SL-174T. World J Gastroenterol. 11:6385–6388. 2005. View Article : Google Scholar : PubMed/NCBI
506	Wei B, Wei HB, Qi CL, Han XY and Wang TB: Effect of a selective inducible nitric oxide synthase inhibitor on cell growth in human colorectal cancer Lovo cell line. Zhonghua Wei Chang Wai Ke Za Zhi. 11:280–283. 2008.(In Chinese). PubMed/NCBI
507	Siedlar M, Mytar B, Hyszko M and Zembala M: Involvement of protein kinases in signalling for nitric oxide (NO) and tumour necrosis factor alpha (TNF) production by monocytes stimulated with colorectal DeTa cancer cells: The lack of evidence for the role of TNF in the regulation of NO production. Immunol Lett. 65:189–195. 1999. View Article : Google Scholar : PubMed/NCBI
508	Atala A: Re: Alterations of tumor microenvironment by nitric oxide impedes castration-resistant prostate cancer growth. J Urol. 202:35–36. 2019. View Article : Google Scholar : PubMed/NCBI
509	Dillioglugil MO, Mekik H, Muezzinoglu B, Ozkan TA, Demir CG and Dillioglugil O: Blood and tissue nitric oxide and malondialdehyde are prognostic indicators of localized prostate cancer. Int Urol Nephrol. 44:1691–1696. 2012. View Article : Google Scholar : PubMed/NCBI
510	Della Pietra E, Simonella F, Bonavida B, Xodo LE and Rapozzi V: Repeated sub-optimal photodynamic treatments with pheophorbide a induce an epithelial mesenchymal transition in prostate cancer cells via nitric oxide. Nitric Oxide. 45:43–53. 2015. View Article : Google Scholar : PubMed/NCBI
511	Huh J, Liepins A, Zielonka J, Andrekopoulos C, Kalyanaraman B and Sorokin A: Cyclooxygenase 2 rescues LNCaP prostate cancer cells from sanguinarine-induced apoptosis by a mechanism involving inhibition of nitric oxide synthase activity. Cancer Res. 66:3726–3736. 2006. View Article : Google Scholar : PubMed/NCBI
512	Lee KM, Kang D, Park SK, Berndt SI, Reding D, Chatterjee N, Chanock S, Huang WY and Hayes RB: Nitric oxide synthase gene polymorphisms and prostate cancer risk. Carcinogenesis. 30:621–625. 2009. View Article : Google Scholar : PubMed/NCBI
513	Rezakhani L, Khazaei MR, Ghanbari A and Khazaei M: Crab shell extract induces prostate cancer cell line (LNcap) apoptosis and decreases nitric oxide secretion. Cell J. 19:231–237. 2017.PubMed/NCBI
514	Royle JS, Ross JA, Ansell I, Bollina P, Tulloch DN and Habib FK: Nitric oxide donating nonsteroidal anti-inflammatory drugs induce apoptosis in human prostate cancer cell systems and human prostatic stroma via caspase-3. J Urol. 172:338–344. 2004. View Article : Google Scholar : PubMed/NCBI
515	Wang D, Lu S and Dong Z: Regulation of TGF-beta1 gene transcription in human prostate cancer cells by nitric oxide. Prostate. 67:1825–1833. 2007. View Article : Google Scholar : PubMed/NCBI
516	Tan G, Qiu M, Chen L, Zhang S, Ke L and Liu J: JS-K, a nitric oxide pro-drug, regulates growth and apoptosis through the ubiquitin-proteasome pathway in prostate cancer cells. BMC Cancer. 17:3762017. View Article : Google Scholar : PubMed/NCBI
517	Thomas LN, Morehouse TJ and Too CK: Testosterone and prolactin increase carboxypeptidase-D and nitric oxide levels to promote survival of prostate cancer cells. Prostate. 72:450–460. 2012. View Article : Google Scholar : PubMed/NCBI
518	Siemens DR, Heaton JP, Adams MA, Kawakami J and Graham CH: Phase II study of nitric oxide donor for men with increasing prostate-specific antigen level after surgery or radiotherapy for prostate cancer. Urology. 74:878–883. 2009. View Article : Google Scholar : PubMed/NCBI
519	Soni Y, Softness K, Arora H and Ramasamy R: The Yin yang role of nitric oxide in prostate cancer. Am J Mens Health. 14:15579883209031912020. View Article : Google Scholar : PubMed/NCBI
520	Caneba CA, Yang L, Baddour J, Curtis R, Win J, Hartig S, Marini J and Nagrath D: Nitric oxide is a positive regulator of the Warburg effect in ovarian cancer cells. Cell Death Dis. 5:e13022014. View Article : Google Scholar : PubMed/NCBI
521	El-Sehemy A, Chang AC, Azad AK, Gupta N, Xu Z, Steed H, Karsan A and Fu Y: Notch activation augments nitric oxide/soluble guanylyl cyclase signaling in immortalized ovarian surface epithelial cells and ovarian cancer cells. Cell Signal. 25:2780–2787. 2013. View Article : Google Scholar : PubMed/NCBI
522	El-Sehemy A, Postovit LM and Fu Y: Nitric oxide signaling in human ovarian cancer: A potential therapeutic target. Nitric Oxide. 54:30–37. 2016. View Article : Google Scholar : PubMed/NCBI
523	Kielbik M, Klink M, Brzezinska M, Szulc I and Sulowska Z: Nitric oxide donors: Spermine/NO and diethylenetriamine/NO induce ovarian cancer cell death and affect STAT3 and AKT signaling proteins. Nitric Oxide. 35:93–109. 2013. View Article : Google Scholar : PubMed/NCBI
524	Leung EL, Fraser M, Fiscus RR and Tsang BK: Cisplatin alters nitric oxide synthase levels in human ovarian cancer cells: Involvement in p53 regulation and cisplatin resistance. Br J Cancer. 98:1803–1809. 2008. View Article : Google Scholar : PubMed/NCBI
525	Thomsen LL, Sargent JM, Williamson CJ and Elgie AW: Nitric oxide synthase activity in fresh cells from ovarian tumour tissue: Relationship of enzyme activity with clinical parameters of patients with ovarian cancer. Biochem Pharmacol. 56:1365–1370. 1998. View Article : Google Scholar : PubMed/NCBI
526	Salimian Rizi B, Caneba C, Nowicka A, Nabiyar AW, Liu X, Chen K, Klopp A and Nagrath D: Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells. Cancer Res. 75:456–471. 2015. View Article : Google Scholar : PubMed/NCBI
527	Stevens EV, Carpenter AW, Shin JH, Liu J, Der CJ and Schoenfisch MH: Nitric oxide-releasing silica nanoparticle inhibition of ovarian cancer cell growth. Mol Pharm. 7:775–785. 2010. View Article : Google Scholar : PubMed/NCBI
528	Camp ER, Yang A, Liu W, Fan F, Somcio R, Hicklin DJ and Ellis LM: Roles of nitric oxide synthase inhibition and vascular endothelial growth factor receptor-2 inhibition on vascular morphology and function in an in vivo model of pancreatic cancer. Clin Cancer Res. 12:2628–2633. 2006. View Article : Google Scholar : PubMed/NCBI
529	Chen X, Jia F, Li Y, Deng Y, Huang Y, Liu W, Jin Q and Ji J: Nitric oxide-induced stromal depletion for improved nanoparticle penetration in pancreatic cancer treatment. Biomaterials. 246:1199992020. View Article : Google Scholar : PubMed/NCBI
530	Fujita M, Imadome K, Endo S, Shoji Y, Yamada S and Imai T: Nitric oxide increases the invasion of pancreatic cancer cells via activation of the PI3K-AKT and RhoA pathways after carbon ion irradiation. FEBS Lett. 588:3240–3250. 2014. View Article : Google Scholar : PubMed/NCBI
531	Fujita M, Somasundaram V, Basudhar D, Cheng RYS, Ridnour LA, Higuchi H, Imadome K, No JH, Bharadwaj G and Wink DA: Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype. Redox Biol. 22:1011582019. View Article : Google Scholar : PubMed/NCBI
532	Zhou H, Huang L, Sun Y and Rigas B: Nitric oxide-donating aspirin inhibits the growth of pancreatic cancer cells through redox-dependent signaling. Cancer Lett. 273:292–299. 2009. View Article : Google Scholar : PubMed/NCBI
533	Wang B, Wei D, Crum VE, Richardson EL, Xiong HH, Luo Y, Huang S, Abbruzzese JL and Xie K: A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis. Oncogene. 22:1771–1782. 2003. View Article : Google Scholar : PubMed/NCBI
534	Wang L and Xie K: Nitric oxide and pancreatic cancer pathogenesis, prevention, and treatment. Curr Pharm Design. 16:421–427. 2010. View Article : Google Scholar : PubMed/NCBI
535	Thomas WJ, Thomas DL, Knezetic JA and Adrian TE: The role of oxygen-derived free radicals and nitric oxide in cytokine-induced antiproliferation of pancreatic cancer cells. Pancreas. 24:161–168. 2002. View Article : Google Scholar : PubMed/NCBI
536	Stewart GD, Nanda J, Katz E, Bowman KJ, Christie JG, Brown DJ, McLaren DB, Riddick AC, Ross JA, Jones GD and Habib FK: DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions. Biochem Pharmacol. 81:203–210. 2011. View Article : Google Scholar : PubMed/NCBI
537	Sugita H, Kaneki M, Furuhashi S, Hirota M, Takamori H and Baba H: Nitric oxide inhibits the proliferation and invasion of pancreatic cancer cells through degradation of insulin receptor substrate-1 protein. Mol Cancer Res. 8:1152–1163. 2010. View Article : Google Scholar : PubMed/NCBI
538	Caygill CP, Royston C, Charlett A, Wall CM, Gatenby PA, Ramus JR, Watson A, Winslet M, Hourigan CS and Dev Bardhan K: Barrett's, blood groups and progression to oesophageal cancer: Is nitric oxide the link? Eur J Gastroenterol Hepatol. 23:801–806. 2011. View Article : Google Scholar : PubMed/NCBI
539	Sun GG, Hu WN, Zhang J, Li CL and Yang CR: Effect of nitric oxide on esophageal cancer cell line TE-1. Chin Med Sci J. 28:44–49. 2013. View Article : Google Scholar : PubMed/NCBI
540	Gecit I, Aslan M, Gunes M, Pirincci N, Esen R, Demir H and Ceylan K: Serum prolidase activity, oxidative stress, and nitric oxide levels in patients with bladder cancer. J Cancer Res Clin Oncol. 138:739–743. 2012. View Article : Google Scholar : PubMed/NCBI
541	Gecit İ, Eryılmaz R, Kavak S, Meral İ, Demir H, Pirinççi N, Güneş M and Taken K: The prolidase activity, oxidative stress, and nitric oxide levels of bladder tissues with or without tumor in patients with bladder cancer. J Membr Biol. 250:455–459. 2017. View Article : Google Scholar : PubMed/NCBI
542	Jansson OT, Morcos E, Brundin L, Lundberg JO, Adolfsson J, Söderhäll M and Wiklund NP: The role of nitric oxide in bacillus Calmette-Guerin mediated anti-tumour effects in human bladder cancer. Br J Cancer. 78:588–592. 1998. View Article : Google Scholar : PubMed/NCBI
543	Kilic S, Bayraktar N, Beytur A, Ergin H, Bayraktar M and Egri M: Can the levels of nitric oxide in the urine, serum and tumor tissue be putative markers for bladder cancer? Int J Urol. 13:1079–1085. 2006. View Article : Google Scholar : PubMed/NCBI
544	Khalifa A, Eissa S and Aziz A: Determination of cytosolic citrulline and nitrate as indicators of nitric oxide in bladder cancer: Possible association with basic fibroblast growth factor. Clin Biochem. 32:635–638. 1999. View Article : Google Scholar : PubMed/NCBI
545	Morcos E, Jansson OT, Adolfsson J, Kratz G and Wiklund NP: Endogenously formed nitric oxide modulates cell growth in bladder cancer cell lines. Urology. 53:1252–1257. 1999. View Article : Google Scholar : PubMed/NCBI
546	Wang Z, Fu S, Chen Y and Qin D: Modulation of nitric oxide on lymphokine-activated killer cells in patients with bladder cancer. Chin Med Sci J. 16:2132001.PubMed/NCBI
547	Thiel T, Ryk C, Chatzakos V, Hallén Grufman K, Bavand-Chobot N, Flygare J, Wiklund NP and de Verdier PJ: Secondary stimulation from Bacillus Calmette-Guerin induced macrophages induce nitric oxide independent cell-death in bladder cancer cells. Cancer Lett. 348:119–125. 2014. View Article : Google Scholar : PubMed/NCBI
548	Saygili EI, Akcay T, Dincer Y, Obek C, Kural AR and Cakalir C: Methylguanine DNA methyl transferase activities, glutathione s transferase and nitric oxide in bladder cancer patients. Cancer Invest. 24:256–260. 2006. View Article : Google Scholar : PubMed/NCBI
549	Bakan E, Taysi S, Polat MF, Dalga S, Umudum Z, Bakan N and Gumus M: Nitric oxide levels and lipid peroxidation in plasma of patients with gastric cancer. Jap J Clin Oncol. 32:162–166. 2002. View Article : Google Scholar : PubMed/NCBI
550	Dincer Y, Akcay T, Tortum OB and Dogusoy G: Nitric oxide and antioxidant defense in patients with gastric cancer. Dig Dis Sci. 51:1367–1370. 2006. View Article : Google Scholar : PubMed/NCBI
551	Holian O, Wahid S, Atten MJ and Attar BM: Inhibition of gastric cancer cell proliferation by resveratrol: Role of nitric oxide. Am J Physiol Gastrointest Liver Physiol. 282:G809–G816. 2002. View Article : Google Scholar : PubMed/NCBI
552	Eroğlu A, Demirci S, Ayyildiz A, Kocaoğlu H, Akbulut H, Akgül H and Elhan HA: Serum concentrations of vascular endothelial growth factor and nitrite as an estimate of in vivo nitric oxide in patients with gastric cancer. Br J Cancer. 80:1630–1634. 1999. View Article : Google Scholar : PubMed/NCBI
553	Koh E, Noh SH, Lee YD, Lee HY, Han JW, Lee HW and Hong S: Differential expression of nitric oxide synthase in human stomach cancer. Cancer Lett. 146:173–180. 1999. View Article : Google Scholar : PubMed/NCBI
554	Oshima T, Imada T, Nagashima Y, Cho H, Shiozawa M, Rino Y and Takanashi Y: Role of nitric oxide in human gastric cancer cells treated with 5-fluorouracil. Oncol Rep. 8:847–849. 2001.PubMed/NCBI
555	Rajnakova A, Goh PM, Chan ST, Ngoi SS, Alponat A and Moochhala S: Expression of differential nitric oxide synthase isoforms in human normal gastric mucosa and gastric cancer tissue. Carcinogenesis. 18:1841–1845. 1997. View Article : Google Scholar : PubMed/NCBI
556	Yao X, Wu Y, Zhu M, Qian H and Chen Y: Nitric oxide/cyclic guanosine monophosphate inducers sodium nitroprusside and L-arginine inhibit the proliferation of gastric cancer cells via the activation of type II cyclic guanosine monophosphate-dependent protein kinase. Oncol Lett. 10:479–484. 2015. View Article : Google Scholar : PubMed/NCBI
557	Sang J, Chen Y and Tao Y: Nitric oxide inhibits gastric cancer cell growth through the modulation of the Akt pathway. Mol Med Rep. 4:1163–1167. 2011.PubMed/NCBI
558	Sang JR, Chen YC, Shao GB and Huang XJ: Effect of nitric oxide on the proliferation of AGS gastric cancer cells. Chin J Cancer. 29:158–162. 2010. View Article : Google Scholar : PubMed/NCBI
559	Li YH, Guo M, Shi SW, Zhang QL, Yang SP and Liu JG: A ruthenium-nitrosyl-functionalized nanoplatform for the targeting of liver cancer cells and NIR-light-controlled delivery of nitric oxide combined with photothermal therapy. J Mater Chem B. 5:7831–7838. 2017. View Article : Google Scholar : PubMed/NCBI
560	Muntane J, De la Rosa AJ, Marin LM and Padillo FJ: Nitric oxide and cell death in liver cancer cells. Mitochondrion. 13:257–262. 2013. View Article : Google Scholar : PubMed/NCBI
561	Sayed-Ahmad MM and Mohamad MA: Contribution of nitric oxide and epidermal growth factor receptor in anti-metastatic potential of paclitaxel in human liver cancer cell (HebG2). J Egypt Natl Canc Inst. 17:35–41. 2005.PubMed/NCBI
562	Li J, Rao H, Jin C and Liu J: Involvement of the Toll-like receptor/Nitric oxide signaling pathway in the pathogenesis of cervical cancer caused by high-risk human papillomavirus infection. Biomed Res Int. 2017:78302622017.PubMed/NCBI
563	Park IC, Woo SH, Park MJ, Lee HC, Lee SJ, Hong YJ, Lee SH, Hong SI and Rhee CH: Ionizing radiation and nitric oxide donor sensitize Fas-induced apoptosis via up-regulation of Fas in human cervical cancer cells. Oncol Rep. 10:629–633. 2003.PubMed/NCBI
564	Wei XM, Wang Q, Gao SJ and Sui L: Relationship between nitric oxide in cervical microenvironment and different HPV types and effect on cervical cancer cells. Zhonghua Fu Chan Ke Za Zhi. 46:260–265. 2011.(In Chinese). PubMed/NCBI
565	Sudhesh P, Tamilarasan K, Arumugam P and Berchmans S: Nitric oxide releasing photoresponsive nanohybrids as excellent therapeutic agent for cervical cancer cell lines. ACS Appl Mater Interfaces. 5:8263–8266. 2013. View Article : Google Scholar : PubMed/NCBI
566	Sundaram MK, Khan MA, Alalami U, Somvanshi P, Bhardwaj T, Pramodh S, Raina R, Shekfeh Z, Haque S and Hussain A: Phytochemicals induce apoptosis by modulation of nitric oxide signaling pathway in cervical cancer cells. Eur Rev Med Pharmacol Sci. 24:11827–11844. 2020.PubMed/NCBI
567	Menendez L, Juarez L, Garcia V, Hidalgo A and Baamonde A: Involvement of nitric oxide in the inhibition of bone cancer-induced hyperalgesia through the activation of peripheral opioid receptors in mice. Neuropharmacology. 53:71–80. 2007. View Article : Google Scholar : PubMed/NCBI
568	Yang Y, Zhang J, Liu Y, Zheng Y, Bo J, Zhou X, Wang J and Ma Z: Role of nitric oxide synthase in the development of bone cancer pain and effect of L-NMMA. Mol Med Rep. 13:1220–1226. 2016. View Article : Google Scholar : PubMed/NCBI
569	Giusti M, Valenti S, Guazzini B, Molinari E, Cavallero D, Augeri C and Minuto F: Circulating nitric oxide is modulated by recombinant human TSH administration during monitoring of thyroid cancer remnant. J Endocrinol Invest. 26:1192–1197. 2003. View Article : Google Scholar : PubMed/NCBI
570	Ragot T, Provost C, Prignon A, Cohen R, Lepoivre M and Lausson S: Apoptosis induction by combination of drugs or a conjugated molecule associating non-steroidal anti-inflammatory and nitric oxide donor effects in medullary thyroid cancer models: Implication of the tumor suppressor p73. Thyroid Res. 8:132015. View Article : Google Scholar : PubMed/NCBI
571	Gallo O, Masini E, Morbidelli L, Franchi A, Fini-Storchi I, Vergari WA and Ziche M: Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J Natl Cancer Inst. 90:587–596. 1998. View Article : Google Scholar : PubMed/NCBI
572	Kawakami K, Kawakami M and Puri RK: Nitric oxide accelerates interleukin-13 cytotoxin-mediated regression in head and neck cancer animal model. Clin Cancer Res. 10:5264–5270. 2004. View Article : Google Scholar : PubMed/NCBI
573	Wu HL, Chu YH, Tai YH, Tsou MY, Wu CH, Lo WL, Tai SK, Yeh CC and Lu CC: Stage-dependent angiopoietin-Tie2 and nitric oxide signaling of erythrocytes in response to surgical trauma in head and neck cancer. World J Surg Oncol. 18:2092020. View Article : Google Scholar : PubMed/NCBI
574	Utispan K and Koontongkaew S: High nitric oxide adaptation in isogenic primary and metastatic head and neck cancer cells. Anticancer Res. 40:2657–2665. 2020. View Article : Google Scholar : PubMed/NCBI
575	Taysi S, Uslu C, Akcay F and Sutbeyaz MY: Malondialdehyde and nitric oxide levels in the plasma of patients with advanced laryngeal cancer. Surg Today. 33:651–654. 2003. View Article : Google Scholar : PubMed/NCBI
576	Sanhueza C, Araos J, Naranjo L, Barros E, Subiabre M, Toledo F, Gutiérrez J, Chiarello DI, Pardo F, Leiva A and Sobrevia L: Nitric oxide and pH modulation in gynaecological cancer. J Cell Mol Med. 20:2223–2230. 2016. View Article : Google Scholar : PubMed/NCBI
577	Chattopadhyay M, Kodela R, Nath N, Barsegian A, Boring D and Kashfi K: Hydrogen sulfide-releasing aspirin suppresses NF-κB signaling in estrogen receptor negative breast cancer cells in vitro and in vivo. Biochem Pharmacol. 83:723–732. 2012. View Article : Google Scholar : PubMed/NCBI
578	Dong Q, Yang B, Han JG, Zhang MM, Liu W, Zhang X, Yu HL, Liu ZG, Zhang SH, Li T, et al: A novel hydrogen sulfide-releasing donor, HA-ADT, suppresses the growth of human breast cancer cells through inhibiting the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways. Cancer Lett. 455:60–72. 2019. View Article : Google Scholar : PubMed/NCBI
579	Li Y, Zhou J, Wang L and Xie Z: Endogenous hydrogen sulfide-triggered MOF-based nanoenzyme for synergic cancer therapy. ACS Appl Mater Interfaces. 12:30213–30220. 2020. View Article : Google Scholar : PubMed/NCBI
580	Lv M, Li Y, Ji MH, Zhuang M and Tang JH: Inhibition of invasion and epithelial-mesenchymal transition of human breast cancer cells by hydrogen sulfide through decreased phospho-p38 expression. Mol Med Rep. 10:341–346. 2014. View Article : Google Scholar : PubMed/NCBI
581	Choi KS, Song H, Kim EH, Choi JH, Hong H, Han YM and Hahm KB: Inhibition of Hydrogen Sulfide-induced angiogenesis and inflammation in vascular endothelial cells: Potential mechanisms of gastric cancer prevention by korean red ginseng. J Ginseng Res. 36:135–145. 2012. View Article : Google Scholar : PubMed/NCBI
582	Kawahara Y, Hirashita Y, Tamura C, Kudo Y, Sakai K, Togo K, Fukuda K, Matsunari O, Okamoto K, Ogawa R, et al: Helicobacter pylori infection modulates endogenous hydrogen sulfide production in gastric cancer AGS cells. Helicobacter. 25:e127322020. View Article : Google Scholar : PubMed/NCBI
583	Sekiguchi F, Sekimoto T, Ogura A and Kawabata A: Endogenous hydrogen sulfide enhances cell proliferation of human gastric cancer AGS cells. Biol Pharm Bull. 39:887–890. 2016. View Article : Google Scholar : PubMed/NCBI
584	Wang R, Tao B, Fan Q, Wang S, Chen L, Zhang J, Hao Y, Dong S, Wang Z, Wang W, et al: Fatty-acid receptor CD36 functions as a hydrogen sulfide-targeted receptor with its Cys333-Cys272 disulfide bond serving as a specific molecular switch to accelerate gastric cancer metastasis. EBioMedicine. 45:108–123. 2019. View Article : Google Scholar : PubMed/NCBI
585	Ye F, Li X, Sun K, Xu W, Shi H, Bian J, Lu R and Ye Y: Inhibition of endogenous hydrogen sulfide biosynthesis enhances the anti-cancer effect of 3,3′-diindolylmethane in human gastric cancer cells. Life Sci. 261:1183482020. View Article : Google Scholar : PubMed/NCBI
586	Chen S, Yue T, Huang Z, Zhu J, Bu D, Wang X, Pan Y, Liu Y and Wang P: Inhibition of hydrogen sulfide synthesis reverses acquired resistance to 5-FU through miR-215-5p-EREG/TYMS axis in colon cancer cells. Cancer Lett. 466:49–60. 2019. View Article : Google Scholar : PubMed/NCBI
587	Cai WJ, Wang MJ, Ju LH, Wang C and Zhu YC: Hydrogen sulfide induces human colon cancer cell proliferation: Role of Akt, ERK and p21. Cell Biol Int. 34:565–572. 2010. View Article : Google Scholar : PubMed/NCBI
588	Hale VL, Jeraldo P, Mundy M, Yao J, Keeney G, Scott N, Cheek EH, Davidson J, Greene M, Martinez C, et al: Synthesis of multi-omic data and community metabolic models reveals insights into the role of hydrogen sulfide in colon cancer. Methods. 149:59–68. 2018. View Article : Google Scholar : PubMed/NCBI
589	Hong M, Tang X and He K: Effect of hydrogen sulfide on human colon cancer SW480 cell proliferation and migration in vitro. Nan Fang Yi Ke Da Xue Xue Bao. 34:699–703. 2014.(In Chinese). PubMed/NCBI
590	Kodela R, Nath N, Chattopadhyay M, Nesbitt DE, Velázquez-Martínez CA and Kashfi K: Hydrogen sulfide-releasing naproxen suppresses colon cancer cell growth and inhibits NF-κB signaling. Drug Design Dev Ther. 9:4873–4882. 2015.PubMed/NCBI
591	Chen S, Wang P and Liu Y: Research progress of the association of hydrogen sulfide with colorectal cancer and its associated anti-tumor drugs. Zhonghua Wei Chang Wai Ke Za Zhi. 20:834–840. 2017.(In Chinese). PubMed/NCBI
592	Elsheikh W, Blackler RW, Flannigan KL and Wallace JL: Enhanced chemopreventive effects of a hydrogen sulfide-releasing anti-inflammatory drug (ATB-346) in experimental colorectal cancer. Nitric Oxide. 41:131–137. 2014. View Article : Google Scholar : PubMed/NCBI
593	Faris P, Ferulli F, Vismara M, Tanzi M, Negri S, Rumolo A, Lefkimmiatis K, Maestri M, Shekha M, Pedrazzoli P, et al: Hydrogen Sulfide-evoked intracellular Ca²⁺ signals in primary cultures of metastatic colorectal cancer cells. Cancers (Basel). 12:33382020. View Article : Google Scholar : PubMed/NCBI
594	Malagrinò F, Zuhra K, Mascolo L, Mastronicola D, Vicente JB, Forte E and Giuffrè A: Hydrogen sulfide oxidation: Adaptive changes in mitochondria of SW480 colorectal cancer cells upon exposure to hypoxia. Oxid Med Cell Longev. 2019:81029362019. View Article : Google Scholar : PubMed/NCBI
595	Sakuma S, Minamino S, Takase M, Ishiyama Y, Hosokura H, Kohda T, Ikeda Y and Fujimoto Y: Hydrogen sulfide donor GYY4137 suppresses proliferation of human colorectal cancer Caco-2 cells by inducing both cell cycle arrest and cell death. Heliyon. 5:e022442019. View Article : Google Scholar : PubMed/NCBI
596	Liu H, Chang J, Zhao Z, Li Y and Hou J: Effects of exogenous hydrogen sulfide on the proliferation and invasion of human Bladder cancer cells. J Cancer Res Ther. 13:829–832. 2017. View Article : Google Scholar : PubMed/NCBI
597	Liu M, Wu L, Montaut S and Yang G: Hydrogen sulfide signaling axis as a target for prostate cancer therapeutics. Prostate Cancer. 2016:81085492016. View Article : Google Scholar : PubMed/NCBI
598	Zhang S, Bian H, Li X, Wu H, Bi Q, Yan Y and Wang Y: Hydrogen sulfide promotes cell proliferation of oral cancer through activation of the COX2/AKT/ERK1/2 axis. Oncol Rep. 35:2825–2832. 2016. View Article : Google Scholar : PubMed/NCBI
599	Zhuang L, Li K, Wang G, Shou T, Gao C, Mao Y, Bao M and Zhao M: Preconditioning with hydrogen sulfide prevents bone cancer pain in rats through a proliferator-activated receptor gamma/p38/Jun N-terminal kinase pathway. Exp Biol Med (Maywood). 243:57–65. 2018. View Article : Google Scholar : PubMed/NCBI
600	Xu Y, Ma N, Wei P, Zeng Z and Meng J: Expression of hydrogen sulfide synthases and Hh signaling pathway components correlate with the clinicopathological characteristics of papillary thyroid cancer patients. Int J Clin Exp Pathol. 11:1818–1824. 2018.PubMed/NCBI
601	Huang CC, Ho CH, Chen YC, Hsu CC, Lin HJ, Tian YF, Wang JJ and Guo HR: Impact of carbon monoxide poisoning on the risk of breast cancer. Sci Rep. 10:204502020. View Article : Google Scholar : PubMed/NCBI
602	Kawahara B, Moller T, Hu-Moore K, Carrington S, Faull KF, Sen S and Mascharak PK: Attenuation of antioxidant capacity in human breast cancer cells by carbon monoxide through inhibition of cystathionine β-synthase activity: Implications in chemotherapeutic drug sensitivity. J Med Chem. 60:8000–8010. 2017. View Article : Google Scholar : PubMed/NCBI
603	Kim DH, Yoon HJ, Cha YN and Surh YJ: Role of heme oxygenase-1 and its reaction product, carbon monoxide, in manifestation of breast cancer stem cell-like properties: Notch-1 as a putative target. Free Radical Res. 52:1336–1347. 2018. View Article : Google Scholar : PubMed/NCBI
604	Kourti M, Westwell A, Jiang W and Cai J: Repurposing old carbon monoxide-releasing molecules towards the anti-angiogenic therapy of triple-negative breast cancer. Oncotarget. 10:1132–1148. 2019. View Article : Google Scholar : PubMed/NCBI
605	Lee WY, Chen YC, Shih CM, Lin CM, Cheng CH, Chen KC and Lin CW: The induction of heme oxygenase-1 suppresses heat shock protein 90 and the proliferation of human breast cancer cells through its byproduct carbon monoxide. Toxicol Appl Pharmacol. 274:55–62. 2014. View Article : Google Scholar : PubMed/NCBI
606	Kawahara B, Gao L, Cohn W, Whitelegge JP, Sen S, Janzen C and Mascharak PK: Diminished viability of human ovarian cancer cells by antigen-specific delivery of carbon monoxide with a family of photoactivatable antibody-photoCORM conjugates. Chem Sci. 11:467–473. 2020. View Article : Google Scholar : PubMed/NCBI
607	Kawahara B, Ramadoss S, Chaudhuri G, Janzen C, Sen S and Mascharak PK: Carbon monoxide sensitizes cisplatin-resistant ovarian cancer cell lines toward cisplatin via attenuation of levels of glutathione and nuclear metallothionein. J Inorganic Biochem. 191:29–39. 2019. View Article : Google Scholar
608	Khasag N, Sakiyama S, Toba H, Yoshida M, Nakagawa Y, Takizawa H, Kawakami Y, Kenzaki K, Ali AH, Kondo K and Tangoku A: Monitoring of exhaled carbon monoxide and carbon dioxide during lung cancer operation. Eur J Cardiothorac Surg. 45:531–536. 2014. View Article : Google Scholar : PubMed/NCBI
609	Liptay MJ, Basu S, Hoaglin MC, Freedman N, Faber LP, Warren WH, Hammoud ZT and Kim AW: Diffusion lung capacity for carbon monoxide (DLCO) is an independent prognostic factor for long-term survival after curative lung resection for cancer. J Surg Oncol. 100:703–707. 2009. View Article : Google Scholar : PubMed/NCBI
610	Nemeth Z, Csizmadia E, Vikstrom L, Li M, Bisht K, Feizi A, Otterbein S, Zuckerbraun B, Costa DB, Pandolfi PP, et al: Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth. Oncotarget. 7:23919–23932. 2016. View Article : Google Scholar : PubMed/NCBI
611	Shao L, Gu YY, Jiang CH, Liu CY, Lv LP, Liu JN and Zou Y: Carbon monoxide releasing molecule-2 suppresses proliferation, migration, invasion, and promotes apoptosis in non-small cell lung cancer Calu-3 cells. Eur Rev Med Pharmacol Sci. 22:1948–1957. 2018.PubMed/NCBI
612	Shirabe T, Mawatari S and Kuroiwa Y: Autopsy case of carbon monoxide poisoning at the Miike Coal Mine explosion-a case of lung cancer with the fatal outcome in 3 years and 4 months. Shinkei Kenkyu No Shimpo. 14:321–326. 1970.PubMed/NCBI
613	Zarogoulidis P, Kerenidi T, Huang H, Kontakiotis T, Tremma O, Porpodis K, Kalianos A, Rapti A, Foroulis C, Zissimopoulos A, et al: Six minute walking test and carbon monoxide diffusing capacity for non-small cell lung cancer: Easy performed tests in every day practice. J Thorac Dis. 4:569–576. 2012.PubMed/NCBI
614	Lian S, Xia Y, Ung TT, Khoi PN, Yoon HJ, Kim NH, Kim KK and Jung YD: Carbon monoxide releasing molecule-2 ameliorates IL-1β-induced IL-8 in human gastric cancer cells. Toxicology. 361–362. 24–38. 2016.PubMed/NCBI
615	Lv C, Su Q, Fang J and Yin H: Styrene-maleic acid copolymer-encapsulated carbon monoxide releasing molecule-2 (SMA/CORM-2) suppresses proliferation, migration and invasion of colorectal cancer cells in vitro and in vivo. Biochem Biophys Res Commun. 520:320–326. 2019. View Article : Google Scholar : PubMed/NCBI
616	Yin H, Fang J, Liao L, Maeda H and Su Q: Upregulation of heme oxygenase-1 in colorectal cancer patients with increased circulation carbon monoxide levels, potentially affects chemotherapeutic sensitivity. BMC Cancer. 14:4362014. View Article : Google Scholar : PubMed/NCBI
617	Nitta S, Kawai K, Nagumo Y, Ikeda A, Kandori S, Kojima T and Nishiyama H: Impact of hemoglobin levels on hemoglobin-adjusted carbon monoxide diffusion capacity after chemotherapy for testicular cancer. Jpn J Clin Oncol. 49:1151–1156. 2019. View Article : Google Scholar : PubMed/NCBI
618	van Osch FHM, Pauwels CGGM, Jochems SHJ, Fayokun R, James ND, Wallace DMA, Cheng KK, Bryan RT, van Schooten FJ and Zeegers MP: Tar, nicotine and carbon monoxide yield of UK cigarettes and the risk of non-muscle-invasive and muscle-invasive bladder cancer. Eur J Cancer Prev. 28:40–44. 2019. View Article : Google Scholar : PubMed/NCBI
619	Vítek L, Gbelcová H, Muchová L, Váňová K, Zelenka J, Koníčková R, Suk J, Zadinova M, Knejzlík Z, Ahmad S, et al: Antiproliferative effects of carbon monoxide on pancreatic cancer. Dig Liver Dis. 46:369–375. 2014. View Article : Google Scholar : PubMed/NCBI

July-2022
Volume 26 Issue 1

Print ISSN: 1791-2997
Online ISSN:1791-3004

Recommend to Library

Article Options
Download PDF Download XML View XML Supplementary Files
- Supplementary_Data1.pdf
- Supplementary_Data2.xlsx
View Abstract
Full Text
Citations
Cite This Article
Download Citation
Create Citation Alert
Remove Citation Alert
Cited By
Related Articles
on Spandidos Publications
Similar Articles
on Google Scholar
on Pub Med
Copyright

Journal Metrics
Impact Factor: 3.4
Ranked Medicine Research and Experimental
(total number of cites)
CiteScore: 7.6
CiteScore Rank: Q1: #82/347 Biochemistry, Genetics and Molecular Biology
Source Normalized Impact per Paper (SNIP): 0.647
SCImago Journal Rank (SJR): 0.781

Molecular
Medicine
Reports