title: Statins inhibit ABCB1 and ABCG2 drug transporter activity in chronic myeloid leukemia cells and potentiate antileukemic effects of imatinib.
abstract: Despite undisputed success of tyrosine kinase inhibitors 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 second and third generation tyrosine kinase inhibitors 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 that 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 (14)C-labeled imatinib. Lovastatin does not influence influx but significantly inhibits efflux of imatinib mediated by ATP-binding cassette (ABC) 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 observed with other statins. Our results suggest that statins may offer a valuable addition to imatinib in a select group of CML patients.
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland; Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Eliza
authors.initials: E
authors.lastname: Glodkowska-Mrowka
authors.affiliation: Department of Biophysics and Human Physiology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Mrowka
authors.affiliation: Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Grzegorz W
authors.initials: GW
authors.lastname: Basak
authors.affiliation: Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Niesiobedzka-Krezel
authors.affiliation: Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Ilona
authors.initials: I
authors.lastname: Seferynska
authors.affiliation: Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Pawel Krzysztof
authors.initials: PK
authors.lastname: Wlodarski
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Jakobisiak
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland. Electronic address: tomasz.stoklosa@wum.edu.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stoklosa
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D008148:Lovastatin