Siomycin A induces reactive oxygen species‑mediated cytotoxicity in ovarian cancer cells

Shao,Xiulan; Zhang,Fengying; Gao,Xiang; Xu,Fengying

doi:10.3892/ol.2021.12692

Siomycin A induces reactive oxygen species‑mediated cytotoxicity in ovarian cancer cells

Authors:
- Xiulan Shao
- Fengying Zhang
- Xiang Gao
- Fengying Xu
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Affiliations: Department of Obstetrics and Gynecology, The Hospital of Tinglin, Shanghai 201505, P.R. China
Published online on: March 31, 2021 https://doi.org/10.3892/ol.2021.12692
Article Number: 431
Copyright: © Shao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ovarian cancer is one of the leading causes of cancer‑related death among women worldwide and accounts for 4% of all cancer cases in female patients. To date, ovarian cancer has the poorest prognosis among all types of gynecological cancer; thus, it is necessary to identify prospective therapeutic options. Previous studies have demonstrated the involvement of reactive oxygen species (ROS) in the cytotoxicity of various anticancer drugs against several types of carcinoma, including ovarian cancer. The present study aimed to investigate the anticancer effects of Siomycin A, a thiopeptide antibiotic, on the ovarian cancer cell lines PA1 and OVCAR3. To determine the viability of these cells following exposure to Siomycin A, the MTT assay was used, and apoptosis was determined by ELISA. In addition, mitochondrial membrane potential was determined by JC1 staining, and cellular ROS levels were assessed by dichlorodihydrofluorescein diacetate staining in the presence and absence of antioxidant NAC. The subsequent levels of antioxidant enzymes and glutathione were also determined following Siomycin A treatment in the two cell lines. A combination study with Siomycin A and cisplatin indicated enhanced efficiency of the drugs on ovarian cancer cell viability. The results of the present study also demonstrated that Siomycin A induced ROS production, inhibited the major antioxidant enzymes, including catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and intracellular GSH in PA1 and OVCAR3 cells, and inhibited the cell viability with an IC₅₀ of ~5.0 and 2.5 µM after 72 h respectively compared with the untreated controls. Additionally, the Siomycin A‑induced ROS production further targeted apoptotic cell death by impairing the mitochondrial membrane potential and modulating the levels of pro‑ and antiapoptotic proteins compared with those in the corresponding control groups. The administration of the antioxidant N‑acetylcysteine significantly abrogated the cytotoxic effects of Siomycin A. In conclusion, the results of the present study demonstrated the role of ROS in Siomycin A‑mediated cytotoxicity in ovarian cancer cells.

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1	Zhang Y, Luo G, Li M, Guo P, Xiao Y, Ji H and Hao Y: Global patterns and trends in ovarian cancer incidence: Age, period and birth cohort analysis. BMC Cancer. 19:9842019. View Article : Google Scholar : PubMed/NCBI
2	Reid BM, Permuth JB and Sellers TA: Epidemiology of ovarian cancer: A review. Cancer Biol Med. 14:9–32. 2017. View Article : Google Scholar : PubMed/NCBI
3	Webb PM and Jordan SJ: Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 41:3–14. 2017. View Article : Google Scholar : PubMed/NCBI
4	Pavlik EJ, Smith C, Dennis TS, Harvey E, Huang B, Chen Q, Piecoro DW, Burgess BT, McDowell A, Gorski J, et al: Disease-specific survival of type I and type II epithelial ovarian cancers-stage challenges categorical assignments of indolence & aggressiveness. Diagnostics (Basel). 10:E562020. View Article : Google Scholar : PubMed/NCBI
5	Momenimovahed Z, Tiznobaik A, Taheri S and Salehiniya H: Ovarian cancer in the world: Epidemiology and risk factors. Int J Womens Health. 11:287–299. 2019. View Article : Google Scholar : PubMed/NCBI
6	Ottevanger PB: Ovarian cancer stem cells more questions than answers. Semin Cancer Biol. 44:67–71. 2017. View Article : Google Scholar : PubMed/NCBI
7	Cornelison R, Llaneza DC and Landen CN: Emerging therapeutics to overcome chemoresistance in epithelial ovarian cancer: A mini-review. Int J Mol Sci. 18:21712017. View Article : Google Scholar
8	Bast RC Jr, Hennessy B and Mills GB: The biology of ovarian cancer: New opportunities for translation. Nat Rev Cancer. 9:415–428. 2009. View Article : Google Scholar : PubMed/NCBI
9	Nakano I, Joshi K, Visnyei K, Hu B, Watanabe M, Lam D, Wexler E, Saigusa K, Nakamura Y, Laks DR, et al: Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway. Neuro Oncol. 13:622–634. 2011. View Article : Google Scholar : PubMed/NCBI
10	Koh B, Jeon H, Kim D, Kang D and Kim KR: Effect of fibroblast co-culture on the proliferation, viability and drug response of colon cancer cells. Oncol Lett. 17:2409–2417. 2019.PubMed/NCBI
11	Shen X, Mustafa M, Chen Y, Cao Y and Gao J: Natural thiopeptides as a privileged scaffold for drug discovery and therapeutic development. Med Chem Res. 28:1063–1098. 2019. View Article : Google Scholar
12	Tüfekçi Ö, Yandım MK, Ören H, İrken G and Baran Y: Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line. Leuk Res. 39:342–347. 2015. View Article : Google Scholar : PubMed/NCBI
13	Hou Y, Zhu Q, Li Z, Peng Y, Yu X, Yuan B, Liu Y, Liu Y, Yin L, Peng Y, et al: The FOXM1-ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells. Cell Death Dis. 8:e26592017. View Article : Google Scholar : PubMed/NCBI
14	Gartel AL: A new target for proteasome inhibitors: FoxM1. Expert Opin Investig Drugs. 19:235–242. 2010. View Article : Google Scholar : PubMed/NCBI
15	Nowak A, Zakłos-Szyda M, Żyżelewicz D, Koszucka A and Motyl I: Acrylamide decreases cell viability, and provides oxidative stress, DNA damage, and apoptosis in human colon adenocarcinoma cell line caco-2. Molecules. 25:3682020. View Article : Google Scholar
16	Maity G, De A, Das A, Banerjee S, Sarkar S and Banerjee SK: Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition. Lab Invest. 95:702–717. 2015. View Article : Google Scholar : PubMed/NCBI
17	Harshkova D, Zielińska E and Aksmann A: Optimization of a microplate reader method for the analysis of changes in mitochondrial membrane potential in Chlamydomonas reinhardtii cells using the fluorochrome JC-1. J Appl Phycol. 31:3691–3697. 2019. View Article : Google Scholar
18	Halliwell B and Whiteman M: Measuring reactive species and oxidative damage in vivo and in cell culture: How should you do it and what do the results mean? Br J Pharmacol. 142:231–255. 2004. View Article : Google Scholar : PubMed/NCBI
19	Beers RF Jr and Sizer IW: A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem. 195:133–140. 1952. View Article : Google Scholar : PubMed/NCBI
20	Marklund S and Marklund G: Involvement of superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem. 47:469–474. 1974. View Article : Google Scholar : PubMed/NCBI
21	Zhu H, Zhang L, Itoh K, Yamamoto M, Ross D, Trush MA, Zweier JL and Li Y: Nrf2 controls bone marrow stromal cell susceptibility to oxidative and electrophilic stress. Free Radic Biol Med. 41:132–143. 2006. View Article : Google Scholar : PubMed/NCBI
22	Forman HJ, Zhang H and Rinna A: Glutathione: Overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. 30:1–12. 2009. View Article : Google Scholar : PubMed/NCBI
23	Das A, Chakrabarty S, Choudhury D and Chakrabarti G: 1, 4-Benzoquinone (PBQ) induced toxicity in lung epithelial cells is mediated by the disruption of the microtubule network and activation of caspase-3. Chem Res Toxicol. 23:1054–1066. 2010. View Article : Google Scholar : PubMed/NCBI
24	Ishiguro T, Ishiguro M, Ishiguro R and Iwai S: Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors. Oncol Lett. 3:726–728. 2012. View Article : Google Scholar : PubMed/NCBI
25	Tipgomut C, Wongprommoon A, Takeo E, Ittiudomrak T, Puthong S and Chanchao C: Melittin induced g1 cell cycle arrest and apoptosis in chago-k1 human bronchogenic carcinoma cells and inhibited the differentiation of THP-1 cells into tumour-associated macrophages. Asian Pac J Cancer Prev. 19:3427–3434. 2018. View Article : Google Scholar : PubMed/NCBI
26	Bustamante J, Caldas Lopes E, Garcia M, Di Libero E, Alvarez E and Hajos SE: Disruption of mitochondrial membrane potential during apoptosis induced by PSC 833 and CsA in multidrug-resistant lymphoid leukemia. Toxicol Appl Pharmacol. 199:44–51. 2004. View Article : Google Scholar : PubMed/NCBI
27	Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG and Green DR: Bax-induced caspase activation and apoptosis via cytochromec release from mitochondria is inhibitable by Bcl-xL. J Biol Chem. 274:2225–2233. 1999. View Article : Google Scholar : PubMed/NCBI
28	Liou GY and Storz P: Reactive oxygen species in cancer. Free Radic Res. 44:479–496. 2010. View Article : Google Scholar : PubMed/NCBI
29	Valko M, Rhodes CJ, Moncol J, Izakovic M and Mazur M: Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 160:1–40. 2006. View Article : Google Scholar : PubMed/NCBI
30	Filomeni G, Rotilio G and Ciriolo MR: Cell signalling and the glutathione redox system. Biochem Pharmacol. 64:1057–1064. 2002. View Article : Google Scholar : PubMed/NCBI
31	Helm CW and States JC: Enhancing the efficacy of cisplatin in ovarian cancer treatment-could arsenic have a role. J Ovarian Res. 2:22009. View Article : Google Scholar : PubMed/NCBI
32	Wang B, Wang W, Meng HY, Chen J and Yuan LJ: Effects and mechanism of siomycin A on the growth and apoptosis of MiaPaCa-2 cancer cells. Oncol Lett. 18:2869–2876. 2019.PubMed/NCBI
33	Guo X, Liu A, Hua H, Lu H, Zhang D, Lin Y, Sun Q, Zhu X, Yan G and Zhao F: Siomycin a induces apoptosis in human lung adenocarcinoma A549 cells by suppressing the expression of foxm1. Nat Prod Commun. 10:1603–1606. 2015.PubMed/NCBI
34	Radhakrishnan SK, Bhat UG, Hughes DE, Wang IC, Costa RH and Gartel AL: Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1. Cancer Res. 66:9731–9735. 2006. View Article : Google Scholar : PubMed/NCBI
35	Lee VS, McRobb LS, Moutrie V, Santos ED and Siu TL: Effects of FOXM1 inhibition and ionizing radiation on melanoma cells. Oncol Lett. 16:6822–6830. 2018.PubMed/NCBI