title: The inhibition of constitutive androstane receptor-mediated pathway enhances the effects of anticancer agents in ovarian cancer cells.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Science, Japan; Department of Obstetrics and Gynecology, 1st Affiliated Hospital, Harbin Medical University, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Science, Japan. Electronic address: masuyama@cc.okayama-u.ac.jp.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Masuyama
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Science, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Nobumoto
authors.affiliation: Department of Obstetrics and Gynecology, 1st Affiliated Hospital, Harbin Medical University, China.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Science, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiramatsu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000090702:Constitutive Androstane Receptor; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008024:Ligands; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000090702:Constitutive Androstane Receptor; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear
keywords: Anticancer agents; Constitutive androstane receptor; Multiple drug resistance 1; Ovarian cancer; Uridine diphosphate-5′-glucuronosyltransferase 1A1