Abstract
ObjectiveThe 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.MethodsQuercetin 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.ResultsContrary 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.ConclusionTaken 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.
Highlights
Ovarian cancer is the most frequent invasive malignancy of the female genital tract in the United States, with an estimated 22,240 cases diagnosed annually
Quercetin at low concentrations promotes the survival of ovarian cancer C13* cells treated with Cisplatin
To determine the potential role Quercetin may play in Cisplatin resistance in ovarian cancer, C13* cells were exposed to different concentrations of Quercetin, Cisplatin, or a combination of the two
Summary
Ovarian cancer is the most frequent invasive malignancy of the female genital tract in the United States, with an estimated 22,240 cases diagnosed annually. 14,030 women die each year from ovarian cancer, representing the most common cause of death among women with gynecological malignancies [1]. Platinum drugs, such as Cisplatin and Carboplatin, are first-line chemotherapeutic agents for the treatment of ovarian cancer. Quercetin (3,39,49,5,7-pentahydroxyflavone, Quer) belongs to a class of flavonoid compounds, and is in various vegetables, fruits, seeds, nuts, tea, and red wine [2] It is the major flavonoid in the human diet, with an estimated daily dietary intake of 25 mg in the United States [3]. The role of Quercetin in ovarian cancer treatment is controversial, and the mechanism of action remains unknown
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