title: Vitamin D Enhances the Efficacy of Irinotecan through miR-627-Mediated Inhibition of Intratumoral Drug Metabolism.
abstract: Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D-regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell lines. Furthermore, calcitriol (the active form of vitamin D) suppressed CYP3A4 expression by activating miR-627. As a result, calcitriol inhibited CYP3A4-mediated metabolism of irinotecan (a topoisomerase I inhibitor) in cancer cells. We show that calcitriol enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. When miR-627 is inhibited, calcitriol fails to enhance the activity of irinotecan. In addition, overexpression of miR-627 or siRNA knockdown of CYP3A4 enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. In contrast, overexpression of CYP3A4 abolished the effects of calcitriol on the activity of irinotecan. Using a nude mouse xenograft model, we demonstrated that calcitriol inhibited CYP3A4 and enhanced the in vivo antitumor activity of irinotecan without causing side effects. Our study identified a novel target for improving cancer therapy, i.e., modulating the intratumoral CYP3A4-mediated drug metabolism with vitamin D. This strategy could enhance the therapeutic efficacy without eliciting the side effects. Mol Cancer Ther; 15(9); 2086-95. ©2016 AACR.
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota.
authors.forename: Qunshu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota.
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Qian
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota. Bin.Guo@ndsu.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Guo
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004195:Disease Models, Animal; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D010597:Pharmacogenetics; D034622:RNA Interference; D014807:Vitamin D / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C583638:MIRN627 microRNA, human; D035683:MicroRNAs; D014807:Vitamin D; D000077146:Irinotecan; D051544:Cytochrome P-450 CYP3A; D002166:Camptothecin