title: Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo.
abstract: Breast cancer resistance protein (BCRP/ABCG2) confers resistance to anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38, an active metabolite of irinotecan), mitoxantrone, and topotecan. In this study, we examined the reversing effects of YHO-13177, a novel acrylonitrile derivative, and its water-soluble diethylaminoacetate prodrug YHO-13351 on the BCRP-mediated drug resistance. YHO-13177 potentiated the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38-resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells. In addition, YHO-13177 potentiated the cytotoxicity of SN-38 in human lung cancer NCI-H460 and NCI-H23, myeloma RPMI-8226, and pancreatic cancer AsPC-1 cells that intrinsically expressed BCRP. In contrast, it had no effect on P-glycoprotein-mediated paclitaxel resistance in MDR1-transduced human leukemia K562 cells and multidrug resistance-related protein 1-mediated doxorubicin resistance in MRP1-transfected human epidermoid cancer KB-3-1 cells. YHO-13177 increased the intracellular accumulation of Hoechst 33342, a substrate of BCRP, at 30 minutes and partially suppressed the expression of BCRP protein at more than 24 hours after its treatment in both HCT116/BCRP and A549/SN4 cells. In mice, YHO-13351 was rapidly converted into YHO-13177 after its oral or intravenous administration. Coadministration of irinotecan with YHO-13351 significantly increased the survival time of mice inoculated with BCRP-transduced murine leukemia P388 cells and suppressed the tumor growth in an HCT116/BCRP xenograft model, whereas irinotecan alone had little effect in these tumor models. These findings suggest that YHO-13351, a prodrug of YHO-13177, could be clinically useful for reversing BCRP-mediated drug resistance in cancer chemotherapy.
authors.affiliation: Yakult Central Institute for Microbiological Research, Yakult Honsha Co., Ltd., 1796 Yaho, Kunitachi-shi, Tokyo, 186-8650 Japan. ryuta-yamazaki@yakult.co.jp
authors.forename: Ryuta
authors.initials: R
authors.lastname: Yamazaki
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: Tomio
authors.initials: T
authors.lastname: Furuta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hatano
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Asakawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kodaira
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Ritsuo
authors.initials: R
authors.lastname: Aiyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsuzaki
authors.forename: Nao
authors.initials: N
authors.lastname: Yagi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D020014:K562 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; C562148:YHO-13177; C562147:YHO-13351; D000077146:Irinotecan; D000181:Acrylonitrile; D002166:Camptothecin