bms-214662 and Leukemia--Lymphocytic--Chronic--B-Cell

B-cell chronic lymphocytic leukemia (B-CLL) cells develop resistance to nucleoside analogs over time. This chemoresistance may be caused by selection for B-CLL cells with defects in the particular apoptosis pathway triggered by these drugs. Therefore, anticancer agents that induce apoptosis through alternative pathways might be useful in treating chemoresistant B-CLL. Farnesyltransferase inhibitors (FTIs) are a class of synthetic drugs with definite molecular targets, which have demonstrated cytotoxicity against leukemic cell lines. We have studied the ex vivo effect of the FTI BMS-214662 on cells from 18 patients with B-CLL. Low concentrations (<1 microM) of BMS-214662 prevented farnesylation of the chaperone marker HDJ-2 and had no effect on Akt activation. BMS-214662 induced apoptosis in B-CLL cells from all patients studied, including those showing resistance to cladribine and fludarabine ex vivo and in vivo. Treatment with BMS-214662 induced loss of mitochondrial membrane potential (DeltaPsi(m)), phosphatidylserine exposure, proapoptotic conformational changes of Bax and Bak, reduction in Mcl-1 levels and activation of caspases 9 and 3. The general caspase inhibitor Z-VAD-fmk did not prevent BMS-214662-induced cell death. These results indicate that BMS-214662 may be a useful drug for treating B-CLL and, in particular, an alternative for the therapy of purine analog-resistant or relapsed B-CLL.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Apoptosis; B-Lymphocytes; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Benzodiazepines; Carrier Proteins; Caspases; Drug Resistance, Neoplasm; Enzyme Activation; Enzyme Inhibitors; Farnesyltranstransferase; Female; Heat-Shock Proteins; HSP40 Heat-Shock Proteins; Humans; Imidazoles; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Membrane Potentials; Membrane Proteins; Mitochondria; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Phosphatidylserines; Protein Conformation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Salvage Therapy; Tumor Cells, Cultured