The inhibition of constitutive androstane receptor-mediated pathway enhances the effects of anticancer agents in ovarian cancer cells

Ovarian cancer is commonly treated with anticancer agents; however, many tumors become resistant. Resistance is regulated, in part, by P-glycoprotein, which is encoded by the gene multiple drug resistance 1 (MDR1) and functions as a transmembrane efflux pump for the elimination of anticancer agents. Constitutive androstane receptor (CAR) is a nuclear receptor that regulates drug metabolism through control of MDR1 and other genes. We examined whether the inhibition of CAR-mediated pathway could influence the cytotoxicity of three anticancer drugs, cisplatin, paclitaxel, and arsenic trioxide, in ovarian cancer cells. We observed that the cell proliferation of several ovarian cell lines expressing CAR significantly increased when CITCO was combined with anticancer agents compared with any anticancer agent alone. The up-regulation of MDR1 and UGT1A1 by anticancer agents was further enhanced in the presence of CITCO. We confirmed that combining CITCO with anticancer agents induced significantly lower levels of apoptosis than those achieved with any single anticancer drug. CAR down-regulation by RNA interference caused a significant increase in cell growth inhibition and enhancement of apoptosis in the presence of anticancer agents. Combination of CITCO with any anticancer agents significantly enhanced CAR-mediated transcription compared with any anticancer agents alone and CAR down-regulation completely inhibited the transcription in the presence of CITCO and/or anticancer agents. Inhibition of CAR pathway could be a novel therapeutic approach for the augmentation of sensitivity to anticancer agents, or to overcome resistance, in the treatment of ovarian cancer.