TY - JOUR
T1 - The inhibition of constitutive androstane receptor-mediated pathway enhances the effects of anticancer agents in ovarian cancer cells
AU - Wang, Yan
AU - Masuyama, Hisashi
AU - Nobumoto, Etsuko
AU - Zhang, Guangmei
AU - Hiramatsu, Yuji
N1 - Funding Information:
This work was supported in part by research grants (numbers 22591856 ) from the Ministry of Education, Culture, Sports, Science and Technology of Japan .
PY - 2014/8/15
Y1 - 2014/8/15
N2 - Background 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. Purpose 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. Results 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. Conclusion 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.
AB - Background 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. Purpose 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. Results 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. Conclusion 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.
KW - Anticancer agents
KW - Constitutive androstane receptor
KW - Multiple drug resistance 1
KW - Ovarian cancer
KW - Uridine diphosphate-5′-glucuronosyltransferase 1A1
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U2 - 10.1016/j.bcp.2014.06.003
DO - 10.1016/j.bcp.2014.06.003
M3 - Article
C2 - 24928535
AN - SCOPUS:84904656885
SN - 0006-2952
VL - 90
SP - 356
EP - 366
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 4
ER -
