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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2368-2373
NEOPLASIA
MDR1 gene overexpression confers resistance to
imatinib mesylate in leukemia cell line models
François-Xavier Mahon,
Francis Belloc,
Valérie Lagarde,
Claudine Chollet,
François Moreau-Gaudry,
Josy Reiffers,
John M. Goldman, and
Junia V. Melo
From the Laboratoire Greffe de Moelle, Université
Victor Segalen, Bordeaux, France; Laboratoire de
Pathologie Moléculaire et Thérapie Génique Bordeaux,
France; and Department of Haematology, Imperial College of
Science, Technology and Medicine, Hammersmith Hospital, London,
United Kingdom.
Inappropriate expression of the multidrug resistance
(MDR1) gene encoding the P-glycoprotein (Pgp) has been
frequently implicated in resistance to different chemotherapeutic
drugs. We have previously generated chronic myeloid leukemia (CML) cell
lines resistant to the tyrosine kinase inhibitor imatinib mesylate
(STI571), and one line (LAMA84-r) showed overexpression not only of the
Bcr-Abl protein but also of Pgp. In the present study, we investigated this phenomenon in other cell lines overexpressing exclusively Pgp.
Thus, cells from the K562/DOX line, described as resistant to
doxorubicin due to MDR1 gene overexpression, grew
continuously in the presence of 1 µM imatinib, but died in 4 to 5 days if the Pgp pump modulators verapamil or PSC833 were added to the
imatinib-treated culture. Analysis of cell proliferation by the
MTS
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay confirmed the differential sensitivity of K562/DOX to imatinib, which was also reversed by verapamil or PSC833. Flow cytometric analysis of the total phosphotyrosine content by intracytoplasmic staining after a 2-hour incubation with escalating doses of imatinib showed that the inhibitory concentrations of 50% (IC50)
for inhibition of cellular protein tyrosine phosphorylation were 15, 10, and 5 µM for K562/DOX, K562/DOX plus verapamil, and K562,
respectively. Retroviral-mediated transfection of the
BCR-ABL+ AR230 cell line with the
MDR1 gene decreased its sensitivity to imatinib, an effect
that was also reversed by verapamil. The possible role of MDR
overexpression in clinical resistance to imatinib remains to be
defined. We therefore confirm that imatinib should be added to the
extensive list of drugs that can be affected by the MDR phenomenon.
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Functional consequence of MDR1 expression on imatinib intracellular concentrations
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