APOPTOSIS-RESISTANT PHENOTYPE SELECTED BY ALTERNATING EXPOSURE TO CAMPTOTHECIN AND ETOPOSIDE

We selected an apoptosis-resistant subline (VC-33) in a human promyelo cytic leukemia cell line, HL-60, by alternating exposure to camptothec in (CPT) and etoposide (VP-16). When wild-type (WT) and VC-33 cells we re incubated with various concentrations of either CPT or VP-16 for 4 h, VC-33 showed several-fold resistance to apoptosis induced by these agents in comparison with WT cells, VC-33 cells also exhibited cross-r esistance to apoptosis induced by 1-beta-D-arabinofuranosylcytosine, h ydroxyurea, a calcium ionophore (A23187), cycloheximide, or UV irradia tion. The levels of protein-DNA cross-linking induced by CPT or VP-16, and the amounts of ara-CTP generation, tended to be smaller in VC-33 cells, but the difference was not sufficient to explain the difference in the sensitivity to apoptosis. The initial rise of intracellular ca lcium ions with A23181 and the expression of P-glycoprotein, Bcl-2, an d Bcl-XL were comparable between WT and VC-33 cells. This mutant may r epresent a new phenotype of resistance to apoptosis induced by a varie ty of agents, and may thus be useful in the study of the mechanisms of apoptosis. (C) 1997 Academic Press.