title: Inhibition of pregnane X receptor pathway contributes to the cell growth inhibition and apoptosis of anticancer agents in ovarian cancer cells.
abstract: Epithelial ovarian cancer remains the most devastating gynecologic cancer with drug resistance and rapid recurrence. Pregnane X receptor (PXR) is a nuclear receptor that affects drug metabolism/efflux and drug-drug interaction through control of multiple drug resistance 1 (MDR1), which implies a major role in multidrug resistance, and other genes. We examined whether the inhibition of PXR-mediated pathway using siRNA interference and an antagonist for PXR could influence the paclitaxel and cisplatin cytotoxicity in ovarian cancer cells. PXR agonists, phthalate and pregnenolone had significant positive effects on cytochrome P450 (CYP) 3A4 expression and PXR-mediated transcription through the CYP3A4 promoter, whereas MDR1 expression and PXR-mediated transcription though the MDR1 promoter were significantly increased in the presence of paclitaxel or cisplatin. Downregulation of PXR suppressed the augmented MDR1 expression and PXR-mediated transcription by PXR ligands, and significantly enhanced cell growth inhibition and apoptosis in the presence of paclitaxel or cisplatin. Additionally, ketoconazole, a PXR antagonist, suppressed the augmented MDR1 expression and PXR-mediated transactivation by paclitaxel and cisplatin, and enhanced cell growth inhibition and apoptosis in their presence. In conclusion, inhibition of PXR-mediated pathways could be a novel means of augmenting sensitivity, or overcoming resistance to anticancer agents for ovarian cancer.
authors: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Science, Okayama, Japan.
authors: Hisashi
authors: H
authors: Masuyama
authors: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Science, Okayama, Japan.
authors: Keiichiro
authors: K
authors: Nakamura
authors: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Science, Okayama, Japan.
authors: Etsuko
authors: E
authors: Nobumoto
authors: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Science, Okayama, Japan.
authors: Yuji
authors: Y
authors: Hiramatsu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology; D010795:Phthalic Acids / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011284:Pregnenolone / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D011987:Receptors, Steroid / Q000819:agonists / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D010795:Phthalic Acids; D000077297:Pregnane X Receptor; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; C032279:phthalic acid; D011284:Pregnenolone; D017239:Paclitaxel; D002945:Cisplatin; D007654:Ketoconazole