Complex interaction of BCRP/ABCG2 and imatinib in BCR-ABL-expressing cells: BCRP-mediated resistance to imatinib is attenuated by imatinib-induced reduction of BCRP expression.
Imatinib, a potent tyrosine kinase inhibitor, is effluxed from cells by the breast cancer resistance protein (BCRP/ABCG2), yet published studies to date fail to demonstrate resistance to imatinib cytotoxicity in BCRP-overexpressing cells in vitro. We investigated cellular resistance to imatinib in BCR-ABL-expressing cells transduced and selected to overexpress BCRP (K562/BCRP-MX10). These cells exhibited a 2- to 3-fold increase in resistance to imatinib (P < .05) and a 7- to 12-fold increase in resistance to mitoxantrone, a known BCRP substrate. Resistance to imatinib was completely abolished by the specific BCRP inhibitor fumitremorgin C. Studies of the mechanism of the diminished resistance to imatinib compared with mitoxantrone revealed that imatinib decreased the expression of BCRP in K562/BCRP-MX10 cells without affecting mRNA levels. BCRP levels in cells that do not express BCR-ABL were not affected by imatinib. Loss of BCRP expression was accompanied by imatinib-induced reduction of phosphorylated Akt in the BCRP-expressing K562 cells. The phosphoinositol-3 kinase (PI3K) inhibitor LY294002 also decreased BCRP levels in K562/BCRP-MX10 cells. These studies show that BCRP causes measurable imatinib resistance, but this effect is attenuated by imatinib-mediated inhibition of BCR-ABL, which in turn downregulates overall BCRP levels posttranscriptionally via the PI3K-Akt pathway.
Program in Experimental Therapeutics, University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCC), Baltimore, 21201, USA.
Takeo
T
Nakanishi
Ken
K
Shiozawa
Bret A
BA
Hassel
Douglas D
DD
Ross
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000473:pathology*; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D014161:Transduction, Genetic
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D007211:Indoles; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D008942:Mitoxantrone; C010522:tryptoquivaline; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D051057:Proto-Oncogene Proteins c-akt