title: Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro.
abstract: Imatinib mesylate (Gleevec, STI571) is a kinase inhibitor selective for Bcr-Abl, activated c-Kit kinases, and platelet-derived growth factor receptor tyrosine kinase. Imatinib mesylate, similar to many other tyrosine kinase inhibitors (TKIs), such as members of the 4-anilinoquinazoline class, competes for ATP binding. Previously, 4-anilinoquinazoline TKIs have been shown to inhibit the function of the breast cancer resistance-associated drug transporter (ABCG2), reversing resistance to camptothecin derivatives topotecan and SN-38. However, the potential to inhibit ABCG2 for the 2-phenylamino-pyrimidine class of TKIs, exemplified by imatinib mesylate, has not been examined. Here, we show that imatinib mesylate potently reverses ABCG2-mediated resistance to topotecan and SN-38 and significantly increases accumulation of topotecan only in cells expressing functional ABCG2. However, overexpression of ABCG2 does not confer resistance to imatinib mesylate. Furthermore, accumulation and efflux of [(14)C]imatinib mesylate are unaltered between ABCG2-expressing and non-ABCG2-expressing cells or by ATP depletion. These results suggest that imatinib mesylate inhibits the function of ABCG2 but is not a substrate for this transporter.
authors.affiliation: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA. peter.houghton@stjude.org
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Glen S
authors.initials: GS
authors.lastname: Germain
authors.forename: Franklin C
authors.initials: FC
authors.lastname: Harwood
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Buchdunger
authors.forename: Peter
authors.initials: P
authors.lastname: Traxler
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D000077146:Irinotecan; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019772:Topotecan / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000077146:Irinotecan; D019772:Topotecan; D000068877:Imatinib Mesylate; D002166:Camptothecin