title: Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro.
abstract: Elevated expression of multidrug efflux pumps such as P-glycoprotein (Pgp) have been associated with resistance to cytotoxic drugs used in the treatment of leukemias and other cancers. Imatinib mesylate (STI-571 or Gleevec) is a potent inhibitor of the BCR/ABL and c-KIT tyrosine kinases. It has displayed considerable efficacy in treatment of patients with Philadelphia-positive acute lymphoblastic leukemia and chronic myelogenous leukemia and those with gastrointestinal stromal tumors (GISTs). However, recently imatinib-resistant relapse has emerged as a significant problem. Although a major cause of resistance appears to be point mutation in the kinase domain of the target enzyme, the potential contribution of elevated multidrug efflux activity has not been systematically evaluated. The imatinib-sensitive human leukemic cell line K562, which is dependent on the activity of BCR/ABL for survival and growth, provides a convenient system for evaluating modulation of drug activity. By expressing Pgp at high levels in these cells, we have demonstrated that this pump provides minimal protection against cell growth inhibition and apoptosis induced by imatinib. In contrast, overexpression of Bcl-xL, which blocks apoptosis, resulted in partial protection against the drug. We conclude that Pgp up-regulation is not likely to be a significant contributor to imatinib resistance.
authors.affiliation: Rm 511, Medical Sciences Bldg, University of Newcastle, University Dr, Callaghan, New South Wales 2308, Australia. petranel.ferrao@newcastle.edu.au
authors.forename: Petranel T
authors.initials: PT
authors.lastname: Ferrao
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Frost
authors.forename: Shoo-Peng
authors.initials: SP
authors.lastname: Siah
authors.forename: Leonie K
authors.initials: LK
authors.lastname: Ashman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001692:Biological Transport; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014161:Transduction, Genetic; D051020:bcl-X Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001549:Benzamides; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D003630:Daunorubicin