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Chronic Myeloproliferative Neoplasias

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 volume 23, pages 1999–2006 (2009)Cite this article

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+ cells. One possible explanation is that CD34+ cells 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+) 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+ 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+ 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.

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Acknowledgements

We are grateful to Novartis Pharma for the supply of imatinib, nilotinib, radio-labelled nilotinib and PSC833. This work was supported by Leukaemia Research Great Britain (Grant #04034). AD, NEJ, AG, CML, SH and RJH conducted the experiments; AD, NEJ, AG, JCM and HGJ analyzed the results, compiled the figures and edited the manuscript; JCM, REC, TLH and MP designed and supervised the research; all authors contributed to the critical review of the data and preparation of the manuscript.

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  1. A Davies and N E Jordanides: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK

    A Davies, A Giannoudis, C M Lucas, R J Harris & R E Clark

  2. Division of Cancer Sciences and Molecular Pathology, Section of Experimental Haematology, Paul O'Gorman Leukaemia Research Centre, Faculty of Medicine, University of Glasgow, Glasgow, UK

    N E Jordanides, S Hatziieremia, H G Jørgensen, T L Holyoake & J C Mountford

  3. Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK

    M Pirmohamed

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Correspondence to J C Mountford.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Davies, A., Jordanides, N., Giannoudis, A. et al. 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, 1999–2006 (2009). https://doi.org/10.1038/leu.2009.166

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