Inhibition of MDR1 does not sensitize primitive chronic myeloid leukemia CD34+ cells to imatinib

Hatziieremia, S., Jordanides, N.E., Holyoake, T.L., Mountford, J.C. and Jorgensen, H.G. (2009) Inhibition of MDR1 does not sensitize primitive chronic myeloid leukemia CD34+ cells to imatinib. Experimental Hematology, 37(6), pp. 692-700. (doi:10.1016/j.exphem.2009.02.006)

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Abstract

<p><b>Objective:</b> To investigate the interaction of imatinib mesylate (IM) with the clinically relevant adenosine triphosphate-binding cassette efflux transporter MDR1 (ABCB1) in cells from patients with chronic myeloid leukemia (CML) and to explore whether inhibition of this transporter would improve IM's efficacy in the elimination of CML CD34<sup>+</sup> cells by increasing cell-associated drug accumulation.</p> <p><b>Materials and Methods:</b> Cells from newly diagnosed chronic-phase CML patients were harvested by leukapheresis and enriched to >95% CD34<sup>+</sup>. Expression of the transporter gene MDR1 was performed by quantitative reverse transcription polymerase chain reaction. Interaction of IM with MDR1 was analyzed by substrate (rhodamine 123) displacement assay. Cell-associated levels of IM in CML CD34<sup>+</sup> cells were measured by high-pressure liquid chromatography. Intracellular phospho-CrkL levels, apoptosis in total CML CD34<sup>+</sup> cells and high-resolution tracking of cell division were assayed by flow cytometry.</p> <p><b>Results:</b> Measurements of cell-associated IM uptake showed significantly lower drug levels in CD34<sup>+</sup> cells, particularly the CD38<sup>-</sup> subpopulation, as compared to IM-sensitive K562 cells. MDR1 was expressed at low level and dye efflux studies demonstrated very little MDR1 activity in CML CD34<sup>+</sup> cells. Furthermore, combination treatment of primitive CML cells with IM and the MDR1 inhibitor PSC833 did not result in elevated cell-associated IM levels. Although we observed slightly enhanced cytostasis with IM when combined with PSC833, this was independent of BCR-ABL inhibition because no associated decrease in phospho-CrkL was observed.</p> <p><b>Conclusions:</b> Our findings demonstrate that inhibition of MDR1 neither enhances the effect of IM against BCR-ABL activity, nor significantly potentiates IM's efficiency in eliminating primitive CML cells.</p>

Item Type:Articles
Additional Information:NOTICE: this is the author’s version of a work that was accepted for publication in <i>Experimental Hematology</i>. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in <i>Experimental Hematology</i>, [37, 6, (2009)] DOI:10.1016/j.exphem.2009.02.006
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Mountford, Dr Jo and Jorgensen, Dr Heather
Authors: Hatziieremia, S., Jordanides, N.E., Holyoake, T.L., Mountford, J.C., and Jorgensen, H.G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Experimental Hematology
Publisher:Elsevier
ISSN:0301-472X
Copyright Holders:Copyright © 2009 International Society for Experimental Hematology
First Published:First published in Experimental Hematology 37(6):692-700
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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