BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cβ

Pellicano, F., Copland, M. , Jorgensen, H. G., Mountford, J., Leber, B. and Holyoake, T. L. (2009) BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cβ. Blood, 114(19), pp. 4186-4196. (doi:10.1182/blood-2009-05-219550)

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Publisher's URL: http://dx.doi.org/10.1182/blood-2009-05-219550

Abstract

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder maintained by cancer stem cells. To target this population, we investigated the mechanism of action of BMS-214662, developed as a farnesyl transferase inhibitor (FTI) and unique in inducing apoptosis in these cells. By contrast, a related congener and equally effective FTI, BMS-225975 does not induce apoptosis, indicating a novel mechanism of action. BMS-214662 significantly and selectively induced apoptosis in primitive CD34<sup>+</sup>38<sup>-</sup> CML compared with normal cells. Apoptosis proceeded via the intrinsic pathway: Bax conformational changes, loss of mitochondrial membrane potential, generation of reactive oxygen species, release of cytochrome <i>c</i>, and caspase-9/3 activation were noted. Up-regulation of protein kinase C beta (PKCβ), down-regulation of E2F1, and phosphorylation of cyclin A-associated cyclin-dependent kinase 2 preceded these changes. Cotreatment of CML CD34<sup>+</sup> and CD34<sup>+</sup>38<sup>-</sup> cells with PKC modulators, bryostatin-1, or hispidin markedly de-creased these early events and the subsequent apoptosis. None of these events was elicited by BMS-214662 in normal CD34<sup>+</sup> cells or by BMS-225975 in CML CD34<sup>+</sup> cells. These data suggest that BMS-214662 selectively elicits a latent apoptotic pathway in CML stem cells that is initiated by up-regulation of PKCβ and mediated by Bax activation, providing a molecular framework for development of novel therapeutics.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pellicano, Dr Francesca and Holyoake, Professor Tessa and Mountford, Dr Joanne and Jorgensen, Dr Heather and Copland, Professor Mhairi
Authors: Pellicano, F., Copland, M., Jorgensen, H. G., Mountford, J., Leber, B., and Holyoake, T. L.
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:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:08 September 2009
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
354131Novel drug combinations for eradication of Ph+/Bcr-Abl+ haemopoietic stem cells in chronic myeloid leukaemia (CML)Mhairi CoplandMedical Research Council (MRC)G84/6317Institute of Cancer Sciences