title: Release of intracellular calcium primes chronic myeloid leukaemia cells for tyrosine kinase inhibitor-induced apoptosis.
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.
authors: Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK.
authors: S L
authors: SL
authors: Forchap
authors: M
authors: M
authors: Pirmohamed
authors: R E
authors: RE
authors: Clark
mesh_terms: D000547:Amantadine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D000547:Amantadine; D020169:Caspases; D002118:Calcium; D011224:Prazosin