Bcl-2 protects against beta-lapachone-mediated caspase 3 activation and apoptosis in human myeloid leukemia (HL-60) cells

We previously demonstrated that beta-lapachone (beta-lap) killed cancer cel ls solely by apoptosis. beta-Lap induced apoptosis in HL-60 cells in a dose -dependent manner as measured by flow cytometry and DNA ladder formation. C ell cycle changes, such as accumulations in S and G(2)-phases, were not obs erved. Apoptosis was accompanied by activation of caspase 3 and concomitant cleavage of poly(ADP-ribose) polymerase (PARP) to an 89 kDa polypeptide. P ARP cleavage was blocked by zDEVD-fmk or zVAD-fmk, caspase-specific cleavag e site inhibitors. Retrovirally introduced bcl-2 prevented beta-lap-mediate d caspase 3 activation and PARP cleavage and increased the viability of Bcl -2-expressing HL-60 cells compared to cells with vector alone. Various beta -lap-related analogs (e.g., dunnione and naphthoquinone derivatives) induce d equivalent apoptosis in HL-60 cells, but no compound was more effective t han beta-lap. These data provide further evidence that the primary mode of cell killing by beta-lap is by the initiation and execution of apoptosis in human cancer cells.