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.
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