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Myricetin Induces Apoptosis and Enhances Chemosensitivity in Ovarian Cancer Cells

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Myricetin Induces Apoptosis and Enhances Chemosensitivity in Ovarian Cancer Cells 4974 ONCOLOGY LETTERS 13: 4974-4978, 2017 Myricetin induces apoptosis and enhances chemosensitivity in ovarian cancer cells AI-WEN ZHENG1, YA-QING CHEN1, LING-QIN ZHAO1 and JIAN-GUO FENG2 1Department of Gynecologic Oncology; 2Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China Received January 30, 2016; Accepted January 19, 2017 DOI: 10.3892/ol.2017.6031 Abstract. Ovarian cancer is the most lethal type of gynecological fifth leading cause of cancer‑associated mortality amongst cancer and is the fifth leading cause of cancer-associated females globally (3,4). The incidence rate of this disease is mortality in females globally. The majority of patients with high, with >225,000 females diagnosed with ovarian cancer ovarian cancer suffer from recurrent, progressive disease, due annually (5,6). Improvements have been made in the treat- to the acquisition of a resistance phenotype towards various ment of this disease, including the combination of surgery, conventional chemotherapy drugs. Although paclitaxel has radiation and chemotherapy with paclitaxel, gemcitabine and been demonstrated to be effective against ovarian tumors, cisplatin; however, the overall 5-year survival rate is <40% (7). there have been reports of the development of a resistant Recently, various platinum-based treatment regimens have phenotype against Taxol® treatment. The multidrug resistance been administered for the treatment of ovarian cancer (8), but (MDR)-1/P-glycoprotein has previously been demonstrated to no improvement in patient survival has been observed (1) due be associated with the acquisition of paclitaxel resistance in to the acquisition of chemotherapeutic drug resistance and certain ovarian tumors. Therefore, the screening of novel drug tumor recurrence. candidates able to target MDR-1 in ovarian cancer cells and Flavonoids are naturally occurring phytochemicals that increase the sensitivity to Taxol® is required in order to improve are abundant in the majority of fresh fruits, grains, green vege- the treatment of this disease. In the present study, the underlying tables and certain traditional medicinal herbs (9,10). Almost mechanisms by which the dietary flavonoid myricetin all chemically synthesized drugs currently used for cancer enhances the cytotoxic potential of paclitaxel in ovarian therapy have a significant toxicity to normal cells (11); however, cancer cells, was investigated. It was observed that myricetin various naturally-occurring flavonoids have demonstrated induced significant cytotoxicity in A2780 and OVCAR3 selective cytotoxicity in types of human cancer cells, accom- ovarian cancer cells, with the IC50 value obtained at 25 µM. panied by minimal toxicity to normal cells (10). Myricetin Myricetin treatment also resulted in the induction of apoptosis (3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone; in the two cell lines, accompanied by the modulation of certain Fig. 1A) is a dietary flavonoid present in fresh fruits (such as pro- and anti-apoptotic markers. It was also determined that grapes, oranges, berries), vegetables (including sweet potatoes, the pre-incubation of ovarian cancer cells with a lower dose of parsley, broad beans), herbs, tea and wine (12,13). The physi- myricetin was able to increase the cytotoxicity of paclitaxel, ological availability of myricetin in certain natural products is due to the significant downregulation of MDR‑1 in these cells. significant, such as 24 mg/kg in grapes, 0.2‑0.5 g/kg physical abundance in average food and 0.8-1.6 g/kg in green tea (12). Introduction The therapeutic potential of myricetin has previously been established and it is considered to have various Ovarian cancer is the most lethal type of gynecological pathophysiological properties, including antioxidant, cyto- cancer amongst females worldwide, responsible for protective, antiviral, antimicrobial, antiplatelet and anticancer ~125,000 cancer-associated mortalities annually (1,2). Ovarian properties (12,14). Myricetin has also been indicated to be cancer is the seventh most common type of cancer and the significantly effective in the treatment of various types of cancers, including prostate cancer, hepatocellular carcinoma, gastric cancer and human squamous cell carcinoma (12,15-18). Myricetin may also increase the chemotherapeutic potential of certain anticancer drugs by sensitizing the target cancer Correspondence to: Mr. Ai-Wen Zheng, Department of Gynecologic Oncology, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, cells to chemotherapy (19,20). As the currently available Zhejiang 310022, P.R. China conventional chemotherapeutic agents have not been observed E-mail: [email protected] to improve the overall survival rate of patients with ovarian cancer, novel drug regimens are required in order to combat Key words: myricetin, apoptosis, ovarian cancer, chemoresistance the disease. In the present study, the anticancer effects of myricetin were evaluated in the A2780 and OVCAR3 ovarian cancer cell lines. It was also investigated whether myricetin is ZHENG et al: MYRICETIN ENHANCES CHEMOSENSITIVITY IN OVARIAN CANCER CELLS 4975 able to sensitize these ovarian cancer cells to the frequently (Sigma-Alrich; Merck KGaA). Protein from each cell sample used chemotherapeutic drugs paclitaxel and cisplatin. (~50 µg) was loaded into each well and separated by 10% SDS‑PAGE, and then transferred to a polyvinylidene difluoride Materials and methods membrane (Bio-Rad Laboratories, Inc., Hercules, CA, USA). The membrane was blocked in Super Block blocking buffer Cell culture and maintenance. The A2780 and OVCAR3 (Thermo Fisher Scientific, Inc., Waltham, MA, USA) for 1 h human ovarian cancer cells were purchased from ATCC at room temperature and subsequently incubated with various (Manassas, VA, USA) and cultured in RPMI-1640 medium primary antibodies, including rabbit polyclonal anti-Bax (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) supple- (dilution, 1:500; N20, #sc-493; Santa Cruz Biotechnology, mented with 10% fetal bovine serum (Sigma-Aldrich; Merck Inc., Dallas, TX, USA), rabbit polyclonal anti-Bcl-2 KGaA), penicillin (100 U/ml; Sigma-Aldrich; Merck KGaA) (dilution, 1:500; N-19, sc-7382; Santa Cruz Biotechnology, and streptomycin (100 µg/ml; Sigma-Aldrich; Merck KGaA), Inc.), rabbit monoclonal anti-cleaved caspase-3 (Asp175) anti- at 37˚C in a humidified chamber. body (dilution, 1:1,000; #9661; Cell Signaling Technology, Inc., Danvers, MA, USA), mouse monoclonal anti-Mdr-1 antibody Cell viability assay. Cell viability was determined spectropho- (dilution, 1:500; G-1; sc-13131, Santa Cruz Biotechnology, tometrically using an MTT assay. A2780 and OVCAR3 cells Inc.). After blocking membranes were washed three times in were seeded into 96-well plates at a density of 1x104 cells/ml. 0.25% TBST buffer for 10 min and incubated with secondary The cells were cultured to ~70% confluency and exposed antibodies, including goat anti-mouse immunoglobulin G to various concentrations of myricetin (0, 5, 10, 25, 50 and (IgG)-horseradish peroxidase (HRP; #sc-2005; Santa 100 µM; Sigma‑Aldrich; Merck KGaA) for 48 h, at 37˚C, Cruz Biotechnology, Inc.) and mouse anti-rabbit IgG-HRP under the described cell culture conditions. Following treat- (#sc-2357; Santa Cruz Biotechnology, Inc.) for 30 min at ment, MTT (Sigma-Alrich; Merck KGaA) solution was added room temperature. The secondary antibodies were used at a to each well at a concentration of 2 mg/ml and incubated at dilution of 1:10,000. Images of the membranes were captured 37˚C for 2 h. The formazan that formed was dissolved using using the Super Signal ULTRA Chemiluminescent Substrate DMSO and the absorbance was measured at 570 nm using a (Pierce; Thermo Fisher Scientific, Inc.) using a KODAK Image microplate reader and Multiskan EX software, v3.4 (Multiskan Station 4000 (Kodak, Rochester, NY, USA). EX, Lab systems, Helsinki, Finland). Statistical analysis. The data were analyzed using GraphPad Apoptosis assay. Role of apoptosis in myricetin-induced cyto- Prism version 4.0 (GraphPad Software, Inc., La Jolla, CA, toxicity in A2780 and OVCAR3 cells was determined using a USA). All data are presented as the mean ± standard deviation. single stranded-DNA Apoptosis ELISA kit (EMD Millipore, Statistically significant differences between the groups were Billerica, MA, USA) (21). Cultured A2780 and OVCAR3 determined using a paired Student's two-tailed t-test. P<0.05 cells (1x104 cells/ml) were treated with 25 µM myricetin for was considered to indicate a statistically significant result. 48 h at 37˚C, and induction of apoptosis in untreated (control) and myricetin-treated cells were determined according to Results the manufacturer's protocol. The extent of apoptosis was determined from the absorbance measured at 405 nm using a Myricetin induces cytotoxicity in ovarian cancer cells. microplate reader and Multiskan EX software, v3.4 (Multiskan Treatment of the A2780 and OVCAR3 human ovarian cancer EX, Lab systems). cells with various concentration of myricetin resulted in the induction of cytotoxicity. Following a 48-h incubation, a Evaluation of cell migration using a Boyden chamber assay. gradual loss of cell viability was observed in myricetin-treated The migratory properties of A2780 and OVCAR3 cells in the A2780 cells, with the IC50 concentration determined to be presence and absence of myricetin were determined using ~25 µM (Fig. 1B). A similar inhibition of cellular growth was a Boyden chamber assay with track-etched polyethylene
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