Imatinib is a substrate for various multidrug resistance proteins.
An increasing resistance to imatinib is an emerging problem in patients with chronic myeloid leukemia (CML). The aim of the study was to asses mechanisms related to cellular drug resistance in imatinib-resistant derivates of chronic myeloid leukemia K-562 cell line. A parental K-562 and its imatinib-resistant derivate cell lines were used. Cell lines were tested for cytotoxicity of imatinib, cytarabine, busulfan and etoposide by the MTT assay. The cytotoxicity was expressed as IC50, inhibitory concentration for 50% of cells. Multidrug resistance proteins expression, rhodamine retention and daunorubicin accumulation were measured for each cell line. Continuous exposition of K-562 cell line to 0.01-0.02 mM imatinib resulted in development of resistance, while exposition to 0.1 microM imatinib increased cell sensitivity to this drug. There was a high correlation between PGP, MRP1 and LRP expression and IC50 values for imatinib and etoposide. All tested cell lines were highly resistant to cytarabine. Rhodamine retention alone and in the presence of cyclosporine was the lowest in imatinib-resistant K-562R-0.1 cell line, what suggest high PGP activity in this cell line. The highest daunorubicin accumulation was observed in parental K-562 cell line, while it was lower in imatinib-resistant cell lines. These data suggest that imatinib is a substrate for multidrug resistance proteins, and an increased expression of PGP, MRP1 and LRP play a role in resistance to imatinib in CML.


BACKGROUND
imatinib, multidrug resistance proteins, chronic myeloid leukemia, PGP, MRP1, LRP.
Czyzewski
K
K
Department of Pediatric Hematology and Oncology, Nicolaus Copernicus University, Poland. k.czyzewski@cm.umk.pl
Styczynski
J
J
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D003630:Daunorubicin / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism; D020394:Vault Ribonucleoprotein Particles / Q000502:physiology; D000099187:Major Vault Protein
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D003630:Daunorubicin; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010879:Piperazines; D011743:Pyrimidines; D020112:Rhodamine 123; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C421109:multidrug resistance-associated protein 1