bms-214662 and bryostatin-1

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.

Topics: ADP-ribosyl Cyclase 1; Antigens, CD34; Apoptosis; bcl-2-Associated X Protein; Benzodiazepines; Bryostatins; Caspases; Cyclin A; Cyclin-Dependent Kinase 2; E2F1 Transcription Factor; Enzyme Activation; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Imidazoles; In Vitro Techniques; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Membrane Glycoproteins; Microscopy, Electron, Transmission; Mitochondria; Neoplastic Stem Cells; Protein Kinase C; Protein Kinase C beta