Low concentration of quercetin antagonizes the cytotoxic effects of anti-neoplastic drugs in ovarian cancer

• Published in: PloS one 2014-07, Vol.9 (7), p.e100314
• Main Authors: Li, Na, Sun, Chaoyang, Zhou, Bo, Xing, Hui, Ma, Ding, Chen, Gang, Weng, Danhui
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Animals; Annexin V; Antineoplastic Agents - pharmacology; Antioxidants; Antioxidants - metabolism; Apoptosis; Assaying; Attenuation; Biocompatibility; Biology; Biology and Life Sciences; Cancer; Cancer therapies; Cell culture; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cisplatin; Cisplatin - pharmacology; Cytotoxicity; Deoxyribonucleic acid; DNA; Dose-Response Relationship, Drug; Drug Antagonism; Drugs; Enzymes; Female; Flavonoids; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunofluorescence; In vivo methods and tests; Injury analysis; Injury prevention; Laboratory animals; Low concentrations; Medical prognosis; Medicine and Health Sciences; Mice; Mice, Nude; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - pathology; Oxidative Stress - drug effects; Oxygen; Paclitaxel; Pharmaceuticals; Quercetin; Quercetin - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research and Analysis Methods; Science; Superoxide dismutase; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Supplementation; Supplements; Taxol; Toxicity; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100314

The role of Quercetin in ovarian cancer treatment remains controversial, and the mechanism is unknown. The aim of this study was to investigate the therapeutic effects of Quercetin in combination with Cisplatin and other anti-neoplastic drugs in ovarian cancer cells both in vitro and in vivo, along with the molecular mechanism of action. Quercetin treatment at various concentrations was examined in combination with Cisplatin, taxol, Pirarubicin and 5-Fu in human epithelial ovarian cancer C13* and SKOV3 cells. CCK8 assay and Annexin V assay were for cell viability and apoptosis analysis, immunofluorescence assay, DCFDA staining and realtime PCR were used for reactive oxygen species (ROS)-induced injury detection and endogenous antioxidant enzymes expression. Athymic BALB/c-nu nude mice were injected with C13*cells to obtain a xenograft model for in vivo studies. Immunohistochemical analysis was carried out to evaluate the ROS-induced injury and SOD1 activity of xenograft tumors. Contrary to the pro-apoptotic effect of high concentration (40 µM-100 µM) of Quercetin, low concentrations (5 µM-30 µM) of Quercetin resulted in varying degrees of attenuation of cytotoxicity of Cisplatin treatment when combined with Cisplatin. Similar anti-apoptotic effects were observed when Quercetin was combined with other anti-neoplastic agents: Taxol, Pirarubicin and 5-Fluorouracil (5-Fu). Low concentrations of Quercetin were observed to suppress ROS-induced injury, reduce intracellular ROS level and increase the expression of endogenous antioxidant enzymes, suggesting a ROS-mediated mechanism of attenuating anti-neoplastic drugs. In xenogeneic model, Quercetin led to a substantial reduction of therapeutic efficacy of Cisplatin along with enhancing the endogenous antioxidant enzyme expression and reducing ROS-induced damage in xenograft tumor tissue. Taken together, these data suggest that Quercetin at low concentrations attenuate the therapeutic effects of Cisplatin and other anti-neoplastic drugs in ovarian cancer cells by reducing ROS damage. Quercetin supplementation during ovarian cancer treatment may detrimentally affect therapeutic response.