RESISTANCE TO APOPTOSIS INDUCED BY TOPOISOMERASE-I INHIBITORS IN MULTIDRUG-RESISTANT HL60 LEUKEMIC-CELLS

The induction of apoptosis by topoisomerase I inhibitors, camptothecin and SN38, was evaluated in drug-sensitive HL60 and multidrug-resistan t (MDR) HL60-Vinc leukemic cells. MDR cells displayed a partial resist ance to these apoptotic stimuli and this phenomenon was not modulated by verapamil. Basal free calcium concentrations were similar in both c ell sublines and were not modified during treatment. Cytoplasmic pH wa s more acidic in sensitive cells than in MDR cells. Moreover, a signif icant acidification was obtained during the early stage of apoptosis i n sensitive HL60 cells only. Basal Bcl-2 protein expression was found to be greater in MDR than in sensitive cells and was not modulated by apoptosis inducers. This increase of Bcl-2 in MDR cells could be due t o the selection process as vincristine enhances Bcl-2 phosphorylation and expression in HL60 sensitive cells. MDR HL60-Vincristine cells the refore display a resistance to apoptosis induced by non-MDR drugs, pos sibly by Bcl-2 overexpression and inability of these drugs to mediate intracellular pH changes in these drug-resistant cells. (C) 1998 Acade mic Press.