Blueberries inhibit cyclooxygenase-1 and cyclooxygenase-2 activity in human epithelial ovarian cancer
- Authors:
- Published online on: April 25, 2017 https://doi.org/10.3892/ol.2017.6094
- Pages: 4897-4904
Abstract
Introduction
Ovarian cancer (OC) begins in the ovary and can result in abnormal cells invading numerous other parts of the body. Symptoms are often vague and unapparent when the disorder begins. There are numerous symptoms for OC, such as bloating (1), pelvic pain (2) and abdominal swelling (3). A number of areas of the body can be affected by OC by the metastasis of abnormal cells, including the abdomen (4), bowel (5), bladder (6), lymph nodes (7) and liver (8). In 2012, there were 239,000 females affected by OC, which caused 152,000 mortalities worldwide (9). OC is the sixth and eighth leading cause of cancer mortality among women in developed and developing countries, respectively (10).
Medical therapy is the most widely used type of treatment for OC; examples include olaparib a biological therapy agent and taxol a chemotherapy agent (10–13). However, the majority of medicines used exhibit unwanted cell toxicity (14–17). Chemotherapy can cause different side effects, such as nausea and vomiting, distress, sexual dysfunction, fatigue and memory loss (18). The toxicity and side effects limit the usage and effectiveness of the aforementioned treatments for OC. It is therefore necessary to find an effective therapeutic method with fewer side effects for OC. Non-pharmaceutical treatment has become a novel therapy for various types of cancer. Blueberries (Vaccinium spp.), a type of fruit, have been identified to exhibit therapeutic effects on several types of cancer (19,20). For example, blueberries inhibit the progression of triple negative breast cancer and triple negative breast cancer-associated metastasis by the inhibition of inflammation via specific cytokine-mediated signaling pathways (21). Blueberries have been revealed to suppress tumor growth and metastasis (21), and are becoming an important fruit due to the associated chemopreventative and therapeutic potential against the tumorigenesis of numerous types of cancer. A blueberry-supplemented diet protects against 17β-estradiol-mediated mammary tumorigenesis (22). However, the molecular mechanisms of blueberries with respect to the inhibition of various types of cancer are unclear, and the therapeutic effect on OC remains unknown.
Cyclooxygenase (COX), termed prostaglandin-endoperoxide synthase (23), is an enzyme responsible for the formation of prostaglandins. A previous study reported the presence of high levels of COX-1 mRNA in high-grade serous ovarian cancer (24). COX-2 is also overexpressed in human ovarian cancer cells, and targeting COX-2 may be a potential approach for the treatment of OC (25). Blueberries may exhibit a therapeutic effect on OC, and COX-1 and COX-2 may be involved in the process. The present study aimed to explore the protective effect of a blueberry diet against the development of OC, which is hypothesized to act via the regulation of COX-mediated pathways.
Materials and methods
Materials
The blueberries were purchased from the Blueberry Production Field (Guizhou, China). The blueberries were frozen upon arrival at −20°C. A total of 100 g blueberries were homogenized in a homogenizer (GYB60-65; Shanghai Donghua High Pressure Homogenizer Factory, Shanghai, China). The blueberry juice was obtained by centrifuge at 10,000 × g, 40°C for 10 min (1 ml blueberry juice was produced from 2 g blueberry).
Cell culture
The human ovarian cancer SKOV3 cell line was purchased from the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China) and cultured with McCoy's 5A medium without serum (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, USA). The medium was supplemented with 4 µg/ml transferrin (Chemicon International Inc.; EMD Millipore, Billerica, MA, USA), 5 µg/ml insulin (Sigma-Aldrich, St. Louis, MO, USA). and 10 ng/ml vascular endothelial growth factor (Chemicon International Inc.; EMD Millipore). The cells were cultured in 5% CO2 at 37°C and 100% humidity, and transferred to fresh medium every 2 days.
Evaluation of cell viability by MTT assay
Cell viability was determined using an MTT assay. The SKOV3 cells were seeded into 96-well plates at a concentration of 1×104 cells per well in 100 µl McCoy's 5A medium. The cells were treated for 24, 48 or 72 h with 0, 1, 2, 4, 8 or 16 mg/ml blueberry juice. At the end of the culture, 5 µl MTT (10 mg/ml in PBS) was added to each well and incubated for an additional 3 h at room temperature. Untreated cells were used as control groups. The purple formazan was dissolved in dimethyl sulfoxide. Absorbance was recorded at 570 nm using an ELISA reader (Elisa Reader KD600; Shanghai Tongge Medical Devices Co., Ltd., Shanghai, China).
COX-1 and COX-2 expression construction
COX-1 and COX-2 genes were amplified and cloned into the Nhel-EcoRI sites of pcDNA3.1 plasmid (Invitrogen; Thermo Fisher Scientific, Inc.), which were termed pcDNA3.1-COX-1 and pcDNA3.1-COX-2. The details of the CPX primers are as follows: COX-1 accession number, BC029840.1, sense, 5′-GTGAGCTAGCATGAGCCGGAGTCTCTTGC-3′ and antisense primers, 5′-CTGAGAATTCTCAGAGCTCTGTGGATGGTC-3′, generating a 1820-base pair (bp) product; COX-2 accession number, AY462100.1, sense, 5′-GTGAGCTAGCATGCTCGCCCGCGCCCTGC-3′ and antisense primers, 5′-CTGAGAATTCCTACAGTTCAGTCGAACGTTC-3′, generating an 1835-bp product. The constructed plasmids were amplified in Escherichia coli (Takara Biotechnology Co., Ltd., Dalian, China), isolated using a plasmid Miniprep Kit (Beijing TransGen Biotech Co., Ltd., Beijing, China) and were verified by sequencing (Takara Biotechnology Co., Ltd.). The classical Sanger sequencing was used. PCR reaction mixture was prepared using the following: 1 µl 100 ng plasmid, 1 µl primer (5 pmol; 5′ Sequencing 1 Primer, CMV-F; 3′ Sequencing 1 Primer, BGH-rev), 2 µl BigDye, 4 µl 5X buffer, 0.5 µl Taq DNA polymerase and ddH2O added to 20 µl. The PCR reaction begins at 95°C 1 min, then 35 cycles of 96°C 10 sec, 52°C 15 sec and 72°C 1 min.
COX-1 and COX-2 RNAi
The lentivector pLKO.1 l was purchased from Academia Sinica (Taipei, Taiwan). The siRNA sequence targeting COX-1, 5′-GTGAGCTATTACACTCGTATT-3′ and COX-2, 5′-GATTGACAGTCCACCAACTTA-3′ was synthesized by Takara Biotechnology Co., Ltd., and linked to the lentivector pLKO.1, and therefore termed pLKO.1-COX-1-siRNA and pLKO.1-COX-2-siRNA. The SKOV3 cells were cotransfected by the reconstructed vectors by Lipofectamine® 2000 (Shanghai Yijie Biotechnology Co., Ltd., Shanghai, China) and pPACK Packaging Plasmid Mix (System Biosciences, Palo Alto, CA, USA).
Orthotopic implantation
All procedures were approved by the Animal Care and Ethics Committee of Guangdong General Hospital (Guangzhou, China). A total of 40 BALB/c 3-week-old nude mice (male:female=1:1; 15–20 g; height, 2–2.5 cm) purchased from the Animal Center of Guangdong Academy of Medical Sciences (Guangzhou, China) were raised in a high-efficiency particulate arrestance-filtered environment with a 12-h light/dark cycle. The SKOV3 cells were subcutaneously injected into 32 nude mice. At ~1 cm3, the xenograft was excised and minced, and implanted into other 4-week old BALB/c nude mice according to the protocol of a previous study (26). A total of 4 days subsequent to the implantation of the OC tumors, the effects of blueberries on the mice was tested.
Experimental design
All the mice were assigned into either control or model group, with the model group being administered different concentrations of blueberry juice (100, 200 and 400 mg daily). The control and model groups were fed a normal diet and water, and all the model groups were administered a normal diet plus the corresponding blueberry juice. Subsequent to 2 weeks, the mice were sacrificed via cervical dislocation. Tumors were isolated under sterile conditions on a nutrient culture medium. Tumor size was determined using the ellipsoid formula v=4/3π abc, where v is volume, a and c are equal to half tumor height, and b is half tumor length. All the procedures for animal studies were consistent with the Animal Care and Use Guidance of Guangdong Academy of Medical Sciences (Guangzhou, China).
Quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR)
Total RNA was purified from ovarian tumors of animal models or healthy mice using an RNA purification kit (cat. no. 74106; Qiagen, Inc., Valencia, CA, USA). Tumor tissues were cut into slices <2 mm and homogenized in 500 µl TRIzol. Phase was separated by the addition of 500 µl chloroform, and centrifuged at 12,000 × g for 10 min. The RNA was precipitated by adding 500 µl isopropyl alcohol. RNA was purified using a purification column. A total of 1 µg RNA from each sample was reverse-transcribed using the High-Capacity cDNA Reverse Transcription kit (cat. no. 4368813; Thermo Fisher Scientific, Inc., Carlsbad, CA, USA). A total of 1 µl purified RNA, poly(A)+-selected RNA primed with oligo (deoxy-thymidine) 100 nM, 1X annealing buffer and water were heated to 65°C for 5 min and placed on ice for 1 min. This reaction mix and 0.5 µl reverse transcriptase were added to the reaction for a final volume of 40 µl, and the mixture was incubated at 50°C for 50 min. The mixture was then heated to 95°C for 5. The SYBR Green DNA PCR kit was purchased from Applied Biosystems (Thermo Fisher Scientific, Inc.) and used for RT-qPCR using Applied Biosystems® 7500 Real-Time PCR Systems (Thermo Fisher Scientific, Inc.). The PCR primers were as follows: COX-1 forward, 5′-CAGAGCCAGATGGCTGTGGG-3′ and reverse, 5′-AAGCTGCTCATCGCCCCAGG-3′; COX-2 forward, 5′-AAGTGCGATTGTACCCGGAC-3′ and reverse, 5′-ACGTTCCAAAATCCCTTGAA-3′; GAP DH forward, 5′-AACTACATGGTTTACATGTT-3′ and reverse, 5′-CACTTGATTTTGGAGGGATC-3′. After 1 min enzyme activation at 95°C, the reaction was cycled 45 times at 95°C for 10 s, 55°C for 10 s, and 72°C for 20 s. The values of the target genes were calculated utilizing the 2−ΔΔCq method (27) for the fold change compared with GAPDH. The mRNA levels of the target genes were presented as relative increases compared with GAPDH. All experiments were performed in triplicate.
ELISA analysis
The concentrations of COX-1 and COX-2 in the treated and untreated samples were measured using Human COX-1 ELISA kit (cat. no. MBS026381) and Human COX-2 ELISA kit (cat. no. MBS043833; MyBioSource, San Diego, CA, USA), respectively.
Statistical analysis
Data were analyzed using one-way analysis of variance in SPSS 20 (IBM SPSS, Armonk, NY, USA). Quantitative data are shown as the mean ± standard deviation. P<0.05 was considered to indicate a statistically significant difference.
Results
Effect of blueberry on the growth of SKOV3 cells
To investigate the effects of blueberries on SKOV3 cells, the concentration-dependent effects of blueberry juice was explored. It was found that blueberries inhibited cell growth in a dose-dependent way. Subsequent to the exposure of SKOV3 cells to 16 mg/ml blueberry, the cell growth rate was reduced by up to 28% compared with the control following the 3-day culture (P=0.018; Fig. 1). Based on these results, the present study used a higher blueberry concentration (16 mg/ml) to treat the OC mouse models (400 mg daily for a 25 g mouse).
Effects of COX-1 and COX-2 on the growth rate of SKOV3 cells
To investigate the effects of COX-1 and COX-2 on SKOV3 cells, the genes were overexpressed by gene transformation or inhibited by RNAi in the cells. Exposure of SKOV3 cells to 16 mg/l blueberry resulted in a reduction of cell concentration detected by MTT when compared with the control (P=0.019; Fig. 1). When COX-1 or COX-2 was inhibited by RNAi in SKOV3 cells and treated with 16 mg/ml blueberry juice, the growth rate of the cells was reduced by up to 50% compared with the growth rate of the control group subsequent to 72 h culture (Fig. 1). By contrast, if COX-1 or COX-2 was overexpressed in SKOV3 cells, the growth rate increased by up to 66% compared with the growth rate of the control group subsequent to 72 h culture (Fig. 1). The increase was inhibited completely when 16 mg/ml blueberry juice was added to the cells.
mRNA level of COX-1 and COX-2 in SKOV3
The mRNA level of COX-1 was significantly affected by blueberry juice and was reduced by up to 50% when 16 mg/ml blueberry juice was added compared with the control without the blueberry treatment (P=0.002; Fig. 2). The mRNA level of COX-1 increased by up to 50% when SKOV3 cells were transfected with COX-1, compared with the control without COX-1 transfection (P=0.002; Fig. 2). The increase was inhibited by the addition of blueberry juice in a dose-dependent way. The mRNA level of COX-1 was reduced to 0 when SKOV3 cells were transfected with COX-1 RNAi (Fig. 2). Neither the overexpression nor gene silencing of COX-2 affected the mRNA level of COX-1 (P=0.235; Fig. 2).
The mRNA level of COX-2 was significantly affected by blueberry juice, decreasing by up to 50% when 16 mg/ml blueberry was added compared with the control without the blueberry treatment (P=0.008; Fig. 3). The mRNA level of COX-2 also increased by up to 150% when the SKOV3 cells were transfected with COX-2 compared with the control without COX-2 transfection (P=0.002; Fig. 3). The increase was inhibited by the addition of blueberry juice in a dose-dependent way. The mRNA level of COX-2 decreased to 0 when the SKOV3 cells were transfected with COX-2 RNAi (Fig. 3). Neither the overexpression nor gene silencing of COX-1 affected the mRNA level of COX-2 (P=0.321; Fig. 3).
Levels of COX-1 and COX-2 in SKOV3
The results of the levels of COX-1 and COX-2 in SKOV3 were similar compared with the results from the mRNA levels investigation. The concentration of COX-1 was significantly affected by the blueberry juice, being reduced by up to 50% when 16 mg/ml blueberry juice was added, compared with the control without the blueberry treatment (P=0.003; Fig. 4). The concentration of COX-1 increased by up to 50% when the SKOV3 cells were transfected with COX-1, compared with the control without COX-1 transfection (P=0.002; Fig. 4). The increase was inhibited by the addition of blueberry juice in a dose-dependent way. The concentration of COX-1 decreased to 0 when the SKOV3 cells were transfected with COX-1 RNAi (Fig. 4). Neither the overexpression nor gene silencing of COX-2 affected the concentration of COX-1 (P=0.287; Fig. 4).
Similarly, the concentration of COX-2 was significantly affected by blueberry juice, being reduced by up to 50% when 16 mg/ml blueberry juice was added, compared with the control without the blueberry treatment (P=0.002; Fig. 5). The mRNA level of COX-2 increased by up to 150% when SKOV3 cells were transfected with COX-2, compared with the control without COX-2 transfection (P=0.003; Fig. 5). The increase was inhibited by the addition of blueberry juice in a dose-dependent way. The concentration of COX-2 decreased to 0 when the SKOV3 cells were transfected with COX-2 RNAi (Fig. 5). Neither the overexpression nor gene silencing of COX-1 affected the concentration of COX-2 (P=0.329; Fig. 3).
The aforementioned results suggest that blueberries reduce the concentration of COX-1 and COX-2 in a dose-dependent way. Blueberries inhibit the growth rate of SKOV3 by decreasing the levels of COX-1 and COX-2, while COX-1 and COX-2 promote the growth of SKOV3.
Effects of blueberry on tumor volume
Prior to the blueberry treatment, the volumes of the OC tumors were similar between groups. Subsequent to the blueberry treatment, the volumes of OC in the 500 mg group significantly decreased by 40% compared with the group that received no blueberry treatment (P=0.0008). The high-efficiency inhibitory concentrations of blueberry were between 8 and 16 mg. The weights of the OC tumors were 4.82±0.41, 4.25±0.35, 3.16±0.23 and 2.47±0.26 g in blank, 0, 100, 200 and 400 mg blueberry groups, respectively, yielding growth inhibitions of 12.5, 35.4, and 49.4%. From the aforementioned results, the 400 mg blueberry group showed significant inhibitory results for OC (P=0.014).
Blueberry juice affects the mRNA levels of COX-1 and COX-2 of OC in the mouse model
The present study investigated the effect of blueberries on the mRNA levels of COX-1 and COX-2 of OC in a mouse model, which are biomarkers of OC (24,28). The mRNA levels of COX-1 and COX-2 of OC in the mice were the highest in the control group compared with those in the models treated with blueberry juice (P=0.006; Fig. 6). Comparatively, the levels of COX-1 and COX-2 significantly decreased by up to 63.6 and 68.7%, respectively, when the mice were treated with 400 mg blueberry juice daily compared with those from the control without the addition of blueberry juice (P=0.002; Fig. 6). The results suggested that blueberry juice significantly affects the mRNA levels of COX-1 and COX-2 of OC in the mouse model studied.
Blueberry juice affects the levels of COX-1 and COX-2 of OC in the mouse model
In concordance with the mRNA results, ELISA analysis showed higher levels of COX-1 and COX-2 of OC in mice in the control group when compared with the groups treated with blueberry juice (P=0.012; Fig. 7). Comparatively, the levels of COX-1 and COX-2 significantly decreased by up to 57.1 and 54.5%, respectively, when the mice were treated with 400 mg blueberry juice daily compared with the protein levels of the control without the addition of blueberry juice (P=0.006; Fig. 7). The aforementioned results suggested that blueberry juice significantly affects the levels of COX-1 and COX-2 of OC in the mouse model studied.
Discussion
OC is a common cause of female mortality worldwide and blueberry therapy has been identified to be effective in the treatment of various types of carcinoma (21,22,29). The theoretical benefit of blueberry juice as a salvage therapy is associated with the anti-inflammation capacity (30,31) and ability to prevent the progression of various types of cancer (32,33). However, the molecular mechanism of the inhibition of OC by blueberries remains unclear. Therefore, the present study aimed to address the issue, and revealed a significant result with respect to the use of blueberry juice for the treatment of OC in the BALB/c nude mouse model. Based on the aforementioned information, the present study firstly reported the molecular mechanisms for the inhibition of OC by blueberry, revealing that a suitable dosage of blueberry juice decreases the expression of COX-1 and COX-2, which are 2 biomarkers for the development of OC. The aforementioned findings suggest that blueberry juice decreases the levels of COX-1 and COX-2, and inhibits the progression of OC. Furthermore, detecting the levels of COX-1 and COX-2 aid in the prediction of patients at risk for OC, as reported in previous studies (24,34). Blueberry juice therapy may therefore provide a non-pharmaceutical treatment for patients with OC.
Regarding the promotion of the growth of SKOV3 by COX-1 and COX-2, the issue that growth rate may be affected by other molecules must be considered. Therefore, the present study investigated the overexpression and gene silencing of COX-1 and COX-2, revealing that when COX-1 and COX-2 were overexpressed without blueberry treatment, the growth rate of SKOV3 reached the highest level of the present study. By contrast, when COX-1 and COX-2 were silenced by RNAi and treated with blueberry juice at a high concentration, the growth rate of SKOV3 reached the lowest level of the present study (Fig. 1). Furthermore, blueberry juice reduces the levels of COX-1 and COX-2 in a dose-dependent way (Figs. 2–5). The aforementioned results suggest that COX-1 and COX-2 promote the growth of OC while blueberry juice inhibits the development of OC by downregulating the levels of COX-1 and COX-2.
There were certain limitations of the present study. For example, blueberry juice possesses a number of different components, which were not separated or purified to identify the more effective agents for the treatment of OC. The functions of blueberries are not unique and more functions require exploration; a limitation of the present study is that the precise mechanism of blueberries with respect to the downregulation of the levels of COX-1 and COX-2 remains unknown. The components of blueberry juice should be analyzed in detail, which may offer information to understand the exact molecular mechanisms for the role of blueberry juice in the therapy of OC.
The present study revealed that the efficacy of using blueberries to treat OC is significant. To make full use of blueberries, all associated molecular mechanisms should be investigated to maximize the potential benefit of blueberries and minimize the risk of side effects. The present study demonstrated that the concentration at which blueberries exhibit significant inhibition is 16 mg/ml for OC cells. At this concentration, blueberries effectively treated the OC models. The results of the present study provide information for subsequent clinical trials and may be beneficial to utilize blueberries, effectively and safely, as a non-pharmaceutical OC therapy. Considering the effectiveness and safety of blueberries, a larger sample size and long-term follow-up test in a larger sample of mice is recommended.
In conclusion, blueberries have been demonstrated to be effective and safe in controlling the size of OC in a dose-dependent way. Blueberries inhibit the proliferation of OC cells by downregulating the levels of COX-1 and COX-2. The present study established animal models of OC by the injection of SKOV3 cells into nude mice. Blueberry (400 mg daily) consumption decreased tumor size significantly in the mice with OC compared with the controls without blueberry treatment (P<0.05). The results of the present study suggest that blueberries should be developed as a potential non-pharmaceutical therapy for OC.
References
|
Donovan KA, Donovan HS, Cella D, Gaines ME, Penson RT, Plaxe SC, von Gruenigen VE, Bruner DW, Reeve BB and Wenzel L: Recommended patient-reported core set of symptoms and quality-of-life domains to measure in ovarian cancer treatment trials. J Natl Cancer Inst. 106:pii: dju1282014. View Article : Google Scholar | |
|
Chen CH, Chiu LH, Chan C and Liu WM: Management of ovarian cancer in 14th gestational week of pregnancy by robotic approach with preservation of the fetus. Gynecol Obstet Invest. 80:139–144. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Yang XJ, Zheng FY, Xu YS and Ou RY: Ovarian cancer initially presenting with isolated ipsilateral superficial inguinal lymph node metastasis: A case study and review of the literature. J Ovarian Res. 7:202014. View Article : Google Scholar : PubMed/NCBI | |
|
Shim SH, Kim DY, Seo MJ, Lee SW, Park JY, Lee JJ, Kim JH, Kim YM, Kim YT and Nam JH: Preoperative fluorine 18 fluorodeoxyglucose tumoral uptake ratio between upper and lower abdomen in primary advanced-stage ovarian cancer. Int J Gynecol Cancer. 23:1383–1392. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Peng X, Wang P, Li S, Zhang G and Hu S: Randomized clinical trial comparing octreotide and scopolamine butylbromide in symptom control of patients with inoperable bowel obstruction due to advanced ovarian cancer. World J Surg Oncol. 13:502015. View Article : Google Scholar : PubMed/NCBI | |
|
Mir MC, Stephenson AJ, Grubb RL III, Black A, Kibel AS and Izmirlian G: Predicting risk of bladder cancer using clinical and demographic information from prostate, lung, colorectal, and ovarian cancer screening trial participants. Cancer Epidemiol Biomarkers Prev. 22:2241–2249. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Nagano H, Muraoka M and Takagi K: Recurrent ovarian cancer with multiple lymph nodes metastases successfully treated with lymphadenectomy as secondary cytoreductive surgery: A case report. Int J Surg Case Rep. 5:412–415. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Bacalbasa N and Popescu I: Ovarian cancer liver metastases-should we apply the principle of optimal cytoreduction to the liver? A review. Hepatogastroenterology. 62:355–357. 2015.PubMed/NCBI | |
|
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Frampton JE: Olaparib: A review of its use as maintenance therapy in patients with ovarian cancer. BioDrugs. 29:143–150. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Ledermann J, Harter P and Gourley C: Correction to Lancet Oncol 2014; 15: 856. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 16:e1582015.PubMed/NCBI | |
|
Fu X, Zhang Y, Wang X, Chen M, Wang Y, Nie J, Meng Y and Han W: Low dose decitabine combined with taxol and platinum chemotherapy to treat refractory/recurrent ovarian cancer: An open-label, single-arm, Phase I/II study. Curr Protein Pept Sci. 16:329–336. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
McGrail DJ, Khambhati NN, Qi MX, Patel KS, Ravikumar N, Brandenburg CP and Dawson MR: Alterations in ovarian cancer cell adhesion drive taxol resistance by increasing microtubule dynamics in a FAK-dependent manner. Sci Rep. 5:95292015. View Article : Google Scholar : PubMed/NCBI | |
|
Pettitt SJ, Rehman FL, Bajrami I, Brough R, Wallberg F, Kozarewa I, Fenwick K, Assiotis I, Chen L, Campbell J, et al: A genetic screen using the PiggyBac transposon in haploid cells identifies Parp1 as a mediator of olaparib toxicity. PLoS One. 8:e615202013. View Article : Google Scholar : PubMed/NCBI | |
|
McNeil EM, Ritchie AM and Melton DW: The toxicity of nitrofuran compounds on melanoma and neuroblastoma cells is enhanced by Olaparib and ameliorated by melanin pigment. DNA Repair (Amst). 12:1000–1006. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Bouquet W, Ceelen W, Adriaens E, Almeida A, Quinten T, de Vos F, Pattyn P, Peeters M, Remon JP and Vervaet C: In vivo toxicity and bioavailability of Taxol and a paclitaxel/beta-cyclodextrin formulation in a rat model during HIPEC. Ann Surg Oncol. 17:2510–2517. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Arany I, Clark JS, Reed D, Szabo I, Ember I and Juncos LA: The role of p66shc in taxol- and dichloroacetic acid-dependent renal toxicity. Anticancer Res. 33:3119–3122. 2013.PubMed/NCBI | |
|
Sun CC, Bodurka DC, Weaver CB, Rasu R, Wolf JK, Bevers MW, Smith JA, Wharton JT and Rubenstein EB: Rankings and symptom assessments of side effects from chemotherapy: Insights from experienced patients with ovarian cancer. Support Care Cancer. 13:219–227. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Faria A, Pestana D, Teixeira D, de Freitas V, Mateus N and Calhau C: Blueberry anthocyanins and pyruvic acid adducts: Anticancer properties in breast cancer cell lines. Phytother Res. 24:1862–1869. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Zu XY, Zhang ZY, Zhang XW, Yoshioka M, Yang YN and Li J: Anthocyanins extracted from Chinese blueberry (Vaccinium uliginosum L.) and its anticancer effects on DLD-1 and COLO205 cells. Chin Med J (Engl). 123:2714–2719. 2010.PubMed/NCBI | |
|
Kanaya N, Adams L, Takasaki A and Chen S: Whole blueberry powder inhibits metastasis of triple negative breast cancer in a xenograft mouse model through modulation of inflammatory cytokines. Nutr Cancer. 66:242–248. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Jeyabalan J, Aqil F, Munagala R, Annamalai L, Vadhanam MV and Gupta RC: Chemopreventive and therapeutic activity of dietary blueberry against estrogen-mediated breast cancer. J Agric Food Chem. 62:3963–3971. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Thuresson ED, Lakkides KM and Smith WL: PGG2, 11R-HPETE and 15R/S-HPETE are formed from different conformers of arachidonic acid in the prostaglandin endoperoxide H synthase-1 cyclooxygenase site. Adv Exp Med Biol. 507:67–72. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Wilson AJ, Fadare O, Beeghly-Fadiel A, Son DS, Liu Q, Zhao S, Saskowski J, Uddin MJ, Daniel C, Crews B, et al: Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer. Oncotarget. 6:21353–21368. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Lin Y, Cui M, Xu T, Yu W and Zhang L: Silencing of cyclooxygenase-2 inhibits the growth, invasion and migration of ovarian cancer cells. Mol Med Rep. 9:2499–2504. 2014.PubMed/NCBI | |
|
Hui X, Chen H, Zhang S, Ma X, Wang X and Huang B: Antitumor activities of recombinant human interferon (IFN)-λ1 in vitro and in xenograft models in vivo for colon cancer. Cancer Lett. 311:141–151. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Yang WL, Roland IH, Godwin AK and Xu XX: Loss of TNF-alpha-regulated COX-2 expression in ovarian cancer cells. Oncogene. 24:7991–8002. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Montales MT, Rahal OM, Kang J, Rogers TJ, Prior RL, Wu X and Simmen RC: Repression of mammosphere formation of human breast cancer cells by soy isoflavone genistein and blueberry polyphenolic acids suggests diet-mediated targeting of cancer stem-like/progenitor cells. Carcinogenesis. 33:652–660. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Esposito D, Chen A, Grace MH, Komarnytsky S and Lila MA: Inhibitory effects of wild blueberry anthocyanins and other flavonoids on biomarkers of acute and chronic inflammation in vitro. J Agric Food Chem. 62:7022–7028. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Paulis G, Cavallini G, Giorgio GD, Quattrocchi S, Brancato T and Alvaro R: Long-term multimodal therapy (verapamil associated with propolis, blueberry, vitamin E and local diclofenac) on patients with Peyronie's disease (chronic inflammation of the tunica albuginea). Results of a controlled study. Inflamm Allergy Drug Targets. 12:403–409. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Ge I, Rudolph A, Shivappa N, Flesch-Janys D, Hébert JR and Chang-Claude J: Dietary inflammation potential and postmenopausal breast cancer risk in a German case-control study. Breast. 24:491–496. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Khachatryan N and Kempen JH: Immunosuppressive therapy and cancer risk in ocular inflammation patients: Fresh evidence and more questions. Ophthalmology. 122:219–221. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Magnowska M, Zaborowski M, Surowiak P, Nowak-Markwitz E, Zabel M and Spaczyński M: COX-2 expression pattern is related to ovarian cancer differentiation and prognosis, but is not consistent with new model of pathogenesis. Ginekol Pol. 85:335–341. 2014. View Article : Google Scholar : PubMed/NCBI |
