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Chronic Myeloproliferative Neoplasias

Release of intracellular calcium primes chronic myeloid leukaemia cells for tyrosine kinase inhibitor-induced apoptosis

Leukemia volume 26, pages 490–498 (2012)Cite this article

Abstract

Imatinib is a substrate for hOCT1 (SLC22A1) and inhibitors of this influx transporter, such as amantadine and prazosin, have previously been shown to decrease cellular imatinib uptake. However, here we report that in longer term experiments, both drugs paradoxically increase the cytotoxicity of all three currently licensed tyrosine kinase inhibitors (TKIs), imatinib, nilotinib and dasatinib. This effect is due to release of intracellular calcium from the endoplasmic reticulum (ER), with changes in mitochondrial calcium and alterations in mitochondrial membrane permeability, resulting in caspase-mediated apoptosis. The effect is confined to BCR–ABL-positive cells, and is greater in primary cells than in cell lines. Furthermore, in primary cells at original diagnosis, the effect is only seen in samples from patients destined to become complete cytogenetic responders to imatinib. These results indicate that calcium release from the ER, here induced by amantadine or prazosin, may prime BCR–ABL-positive cells to TKI-induced apoptosis. Amantadine/prazosin primed TKI cytotoxicity in vitro may be a useful test for the level of ER-releasable calcium, and may be of prognostic value.

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Acknowledgements

We are indebted to Dr Alec Simpson (Department of Human Anatomy and Cell Biology, University of Liverpool) for useful discussions on calcium studies.

Author contributions

SLF carried out all of the experimental work and data analysis and wrote the paper; MP and REC supervised the project and helped with the writing of the paper.

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Authors and Affiliations

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

    S L Forchap & R E Clark

  2. Department of Pharmacology, The Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK

    M Pirmohamed

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  1. S L Forchap
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  2. M Pirmohamed
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  3. R E Clark
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Correspondence to R E Clark.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Leukemia website

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Forchap, S., Pirmohamed, M. & Clark, R. Release of intracellular calcium primes chronic myeloid leukaemia cells for tyrosine kinase inhibitor-induced apoptosis. Leukemia 26, 490–498 (2012). https://doi.org/10.1038/leu.2011.231

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