Nilotinib concentration in cell lines and primary CD34+ chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters

Davies, A. et al. (2009) Nilotinib concentration in cell lines and primary CD34+ chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters. Leukemia, 23(11), pp. 1999-2006. (doi:10.1038/leu.2009.166)

Davies, A. et al. (2009) Nilotinib concentration in cell lines and primary CD34+ chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters. Leukemia, 23(11), pp. 1999-2006. (doi:10.1038/leu.2009.166)

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Publisher's URL: http://dx.doi.org/10.1038/leu.2009.166

Abstract

Imatinib mesylate and nilotinib are highly effective at eradicating the majority of chronic myeloid leukemia (CML) cells; however, neither agent induces apoptosis of primitive CML CD34<sup>+</sup> cells. One possible explanation is that CD34<sup>+</sup> ells do not accumulate sufficient intracellular drug levels because of either inadequate active uptake or increased efflux. To determine the interaction of nilotinib with major clinically implicated drug transporters, we analyzed their interactions with MDR1 (ABCB1), MRP1 (ABCC1), ABCG2 (BCRP) and human organic cation transporter (hOCT) 1 in CML cell lines and primitive (CD34<sup>+</sup>) primary CML cells. Nilotinib is neither dependent on active import by hOCT1, nor effluxed through the ATP-binding cassette transporters analyzed. Indeed, we found nilotinib to be an inhibitor of hOCT1, MDR1 and ABCG2. The efflux transporters MDR1, MRP1 and ABCG2 are expressed on CML CD34<sup>+</sup> cells at 13.5, 108 and 291% of control, respectively, although hOCT1 expression was absent; however, inhibition of efflux transporter activity did not potentiate the effect of nilotinib on apoptosis, Bcr-Abl inhibition or CML CD34<sup>+</sup>) cell proliferation. Therefore, we have found no evidence for either active uptake of nilotinib through hOCT1 or efflux through MDR1, MRP1 or ABCG2, and it is therefore unlikely that these transporters will have any effect on the clinical response to this drug.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Mountford, Dr Joanne and Jorgensen, Dr Heather and Hatziieremia, Dr Sophia
Authors: Davies, A., Jordanides, N.E., Giannoudis, A., Lucas, C.M., Hatziieremia, S., Harris, R.J., Jorgensen, H.G., Holyoake, T.L., Pirmohamed, M., Clark, R.E., and Mountford, J.C.
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:Leukemia
Publisher:Nature
ISSN:0887-6924
ISSN (Online):1476-5551
Copyright Holders:Copyright © 2009 Nature
First Published:First published in Leukemia 23(11):1999-2006
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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