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Resistance reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levels

Leukemia volume 21, pages 1561–1562 (2007)Cite this article

Over the last years there has been a controversy on whether the drug efflux pump P-glycoprotein (P-gp; the gene product of MDR1) influences imatinib cellular exposure and plays a clinically significant role in the resistance to Gleevec. Moreover, uptake transporters – notably the organic cation transporter hOCT11, 2 – have been recently the focus of much attention, contributing to the heightening of the controversy on the role of efflux pumps.3 Referring to the correspondence published this year in the Journal,3 we present additional data on the cellular disposition of imatinib in Bcr–Abl tyrosine kinase target cell, which appears to result from a delicate equilibrium between drug uptake and efflux.

Overexpression of P-gp has been identified as a mechanism of resistance to imatinib in chronic myeloid leukemia (CML);4 however, this has been questioned.5, 6 The concurrent expression of other ATP-binding cassette (ABC) or solute liquid carrier (SLC) transporters, similarly mediating either influx or efflux of drug molecules, precludes in usual conditions an accurate assessment of the single contribution of one active transporter. Conversely, the specific silencing of MDR1 by RNAi provides a unique opportunity to dissect the specific contribution of P-gp to imatinib intracellular disposition. This intervention was shown to restore sensitivity to imatinib in the K562/Dox multi-drug-resistant CML cell line.7

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References

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Acknowledgements

Alexandre Béguin, Laboratory of Clinical Pharmacology, University Hospital, Lausanne, is acknowledged for excellent technical support. Imatinib mesylate and imatinib-d8 were kindly provided by Novartis Pharma (Basel, Switzerland).

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Authors and Affiliations

  1. Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland

    N Widmer, A Fayet, T Buclin & L A Decosterd

  2. Department of Hematology and Oncology, Laboratory of Molecular Genetics, Medical University Innsbruck, Innsbruck, Austria

    H Rumpold

  3. Department of Hematology and Oncology, Laboratory of Tumorbiology and Angiogenesis, Medical University Innsbruck, Innsbruck, Austria

    G Untergasser

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  1. N Widmer
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Widmer, N., Rumpold, H., Untergasser, G. et al. Resistance reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levels. Leukemia 21, 1561–1562 (2007). https://doi.org/10.1038/sj.leu.2404671

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