P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate

Leukemia. 2004 Mar;18(3):401-8. doi: 10.1038/sj.leu.2403257.

Abstract

Imatinib (Glivec), STI571) is an intracellular acting drug that demonstrates high activity against BCR-ABL-positive chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). However, many patients, especially with advanced disease, develop drug resistance. Here, we show by a novel high-performance liquid chromatography-based method that intracellular levels of imatinib decrease in P-glycoprotein (Pgp)-positive leukemic cells. In a model of K562 cells with gradually increasing Pgp expression, a Pgp-dependent decline of intracellular imatinib levels was observed. Decreased imatinib levels were associated with a retained phosphorylation pattern of the Bcr-Abl target Crkl and loss of effect of imatinib on cellular proliferation and apoptosis. The modulation of Pgp by cyclosporin A (CSA) readily restored imatinib cytotoxicity in these cells. Finally, we provide first data showing a biological effect of Pgp modulation in the imatinib treatment of a patient with BCR-ABL-positive ALL. MDR1 overexpression must therefore be considered as an important clinical mechanism in the diversity of resistance development to imatinib treatment.

Publication types

  • Comparative Study

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Adaptor Proteins, Signal Transducing*
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Benzamides
  • Cell Division / drug effects
  • Cyclosporine / pharmacology
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / pharmacology
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / physiology
  • Gene Expression Regulation, Leukemic
  • Humans
  • Imatinib Mesylate
  • Immunosuppressive Agents / pharmacology
  • K562 Cells / drug effects
  • K562 Cells / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Nuclear Proteins / metabolism
  • Piperazines / metabolism*
  • Piperazines / therapeutic use
  • Pyrimidines / metabolism*
  • Pyrimidines / therapeutic use
  • Rhodamines / metabolism*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Benzamides
  • CRKL protein
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Nuclear Proteins
  • Piperazines
  • Pyrimidines
  • Rhodamines
  • Cyclosporine
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl