title: Transport of SN-38 by the wild type of human ABC transporter ABCG2 and its inhibition by quercetin, a natural flavonoid.
abstract: Irinotecan (CPT-11) is a widely-used potent anticancer drug that inhibits mammalian DNA topoisomerase I, however overexpression of the ATP-binding cassette transporter ABCG2 can confer cancer cells resistance to SN-38, the active form of CPT-11. In the present study, we have examined the contribution of three variant forms of ABCG2 to SN-38 resistance. Exogenous expression of the Arg482 (wild type), Gly482, and Thr482 variants of ABCG2 conferred HEK293 cells resistance to SN-38 by 15.0-, 5.0-, and 5.3-fold, respectively. In plasma membrane vesicles prepared from the ABCG2 variant cDNA-transfected HEK293 cells, [Arg482]ABCG2 transported SN-38 and its glucuronide conjugate in an ATP-dependent manner; however, only minimal transport activities were observed with the other variants (Gly482 and Thr482). In addition, we have screened natural flavonoids to find potent inhibitors of [Arg482]ABCG2. Quercetin was found to be the strongest inhibitor (Ki = 0.28 microM) among natural flavonoids tested in the plasma membrane system in this study. When [Arg482]ABCG2-transfected HEK293 cells were incubated with SN-38 in the presence of 20 microM quercetin, cellular resistance to SN-38 was partly reversed. In this context, certain flavonoid derivatives are considered to be good candidates for development of ABCG2 inhibitors.
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ikegami
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sano
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Mitomo
authors.forename: Seigo
authors.initials: S
authors.lastname: Sawada
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001692:Biological Transport; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism*; D002462:Cell Membrane; D002478:Cells, Cultured; D004351:Drug Resistance; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D009363:Neoplasm Proteins; D000077146:Irinotecan; D000255:Adenosine Triphosphate; D011794:Quercetin; D002166:Camptothecin