Apoptotic events in a human ovarian cancer cell line exposed to anthracyclines

Cytotoxic drugs commonly used in cancer therapy promote tumor cell death by inducing apoptosis, but the cell death pathway(s) is likely dependent on t he mechanism of drug action. In the present study, we investigated the mech anisms of cell death induced by doxorubicin (DXR) and the novel disaccharid e anthracycline MEN 10755, in a human ovarian cancer cell line (A2780). Exp osure to either anthracycline induced the up-regulation of several genes kn own to promote cell cycle arrest and DNA repair (WAF1/p21, GADD45) or apopt osis (bax, Fas). Although the expression of Fas was increased, an antagonis tic anti-Fas antibody ZB4 did not inhibit anthracycline-induced apoptosis, suggesting that the stimulation of the Fas receptor did not play a critical role in the induction of apoptosis in this cell line. We also observed tha t neither MEN 10755 nor DXR were able to induce apoptosis in A2780 cells de prived of the nucleus but retaining an intact mitochondrial function (cytop lasts) and that apoptosis induced by either anthracycline was inhibited by cycloheximide, indicating that it is an active process requiring new protei n synthesis. Both the caspases inhibitors, ZVAD-fmk and DEVD-cho, inhibited at similar extent apoptosis induced by either DXR or MEN 10755, suggesting an involvement of caspase-3 in this response. We conclude that, in a tumor cell line of epithelial origin, the apoptosis following exposure to anthra cyclines is an active process requiring protein synthesis and drug interact ion with nuclear structures. The pathway was Fas-independent but likely inv olved bax and caspase-3 as effectors of the cascade culminating in apoptosi s.