title: Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump.
abstract: Imatinib mesylate (STI571), a potent tyrosine kinase inhibitor, is successfully used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. However, the intended chronic oral administration of imatinib may lead to development of cellular resistance and subsequent treatment failure. Indeed, several molecular mechanisms leading to imatinib resistance have already been reported, including overexpression of the MDR1/ABCB1 drug pump. We examined whether imatinib is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump that is frequently overexpressed in human tumors. Using a panel of well-defined BCRP-overexpressing cell lines, we provide the first evidence that imatinib is a substrate for BCRP, that it competes with mitoxantrone for drug export, and that BCRP-mediated efflux can be reversed by the fumitremorgin C analog Ko-143. Since BCRP is highly expressed in the gastrointestinal tract, BCRP might not only play a role in cellular resistance of tumor cells but also influence the gastrointestinal absorption of imatinib.
authors.affiliation: Department of Medical Oncology, Erasmus Medical Center Rotterdam, Daniel den Hoed Kliniek/Josephine Nefkens Institute, Rotterdam, The Netherlands. h.burger@erasmusmc.nl
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.forename: Hans
authors.initials: H
authors.lastname: van Tol
authors.forename: Antonius W M
authors.initials: AW
authors.lastname: Boersma
authors.forename: Mariël
authors.initials: M
authors.lastname: Brok
authors.forename: Erik A C
authors.initials: EA
authors.lastname: Wiemer
authors.forename: Gerrit
authors.initials: G
authors.lastname: Stoter
authors.forename: Kees
authors.initials: K
authors.lastname: Nooter
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001549:Benzamides; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D008942:Mitoxantrone / Q000378:metabolism; D009183:Mycotoxins / Q000031:analogs & derivatives / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D002250:Carbon Radioisotopes; D009183:Mycotoxins; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D008942:Mitoxantrone