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Statins inhibit ABCB1 and ABCG2 drug transporters activity in chronic myeloid leukemia cells and potentiate antileukemic effects of imatinib

Authors
  • Glodkowska-Mrowka, Eliza
  • Mrowka, Piotr
  • Basak, Grzegorz W.
  • Niesiobedzka-Krezel, Joanna
  • Seferynska, Ilona
  • Wlodarski, Pawel Krzysztof
  • Jakobisiak, Marek
  • Stoklosa, Tomasz1, 2, 3, 2, 4, 2, 5, 6, 2, 5, 7, 8, 2
  • 1 Department of Immunology
  • 2 Medical University of Warsaw
  • 3 Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age
  • 4 Department of Biophysics and Human Physiology
  • 5 Department of Hematology
  • 6 Oncology and Internal Diseases
  • 7 Institute of Hematology and Transfusion Medicine
  • 8 Department of Histology and Embryology
Type
Published Article
Journal
Experimental Hematology
Publisher
Elsevier
Publication Date
Jan 01, 2014
Accepted Date
Feb 24, 2014
Identifiers
DOI: 10.1016/j.exphem.2014.02.006
Source
Elsevier
Keywords
License
Unknown

Abstract

Despite undisputed success of tyrosine kinase inhibitors (TKI) in the therapy of chronic myeloid leukemia (CML), development of drug resistance and inability to cure the disease challenge clinicians and researchers. Additionally, recent reports regarding cardiovascular toxicities of 2nd and 3rd generation TKIs prove that there is still a place for novel therapeutic combinations in CML. We have previously shown that statins are able to modulate activity of chemotherapeutics or antibodies used in oncology. Therefore, we decided to verify if statins are able to potentiate antileukemic activity of imatinib, still a frontline treatment of CML. Lovastatin, a cholesterol lowering drug, synergistically potentiates antileukemic activity of imatinib in cell lines and in primary CD34+ CML cells from patients in different phases of the disease, including patients resistant to imatinib with no detectable mutations. This effect is related to increased intracellular concentration of imatinib in CD34+ CML cells and cell lines measured using uptake of 14C-labeled imatinib. Lovastatin does not influence influx but significantly inhibits efflux of imatinib mediated by ABC (ATP-binding cassette) transporters: ABCB1 and ABCG2. The addition of cholesterol completely reverses these effects. Statins do not affect expression of ABCB1 and ABCG2 genes. The effects are drug-class specific as they were also observed with other statins. Our results suggest that statins may offer a valuable addition to imatinib in a selected group of CML patients.

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