title: BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cbeta.
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(+)38(-) 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 c, and caspase-9/3 activation were noted. Up-regulation of protein kinase Cbeta (PKCbeta), down-regulation of E2F1, and phosphorylation of cyclin A-associated cyclin-dependent kinase 2 preceded these changes. Cotreatment of CML CD34(+) and CD34(+)38(-) cells with PKC modulators, bryostatin-1, or hispidin markedly decreased these early events and the subsequent apoptosis. None of these events was elicited by BMS-214662 in normal CD34(+) cells or by BMS-225975 in CML CD34(+) cells. These data suggest that BMS-214662 selectively elicits a latent apoptotic pathway in CML stem cells that is initiated by up-regulation of PKCbeta and mediated by Bax activation, providing a molecular framework for development of novel therapeutics.
authors.affiliation: Department of Medicine, Paul O'Gorman Leukaemia Research Centre, Medical Faculty, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pellicano
authors.forename: Mhairi
authors.initials: M
authors.lastname: Copland
authors.forename: Heather G
authors.initials: HG
authors.lastname: Jorgensen
authors.forename: Joanne
authors.initials: J
authors.lastname: Mountford
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology*; D054713:Bryostatins / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; C494826:BAX protein, human; D054713:Bryostatins; D019925:Cyclin A; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008562:Membrane Glycoproteins; D051028:bcl-2-Associated X Protein; D001569:Benzodiazepines; C046785:bryostatin 1; D051231:Farnesyltranstransferase; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D020169:Caspases; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine