INDUCTION OF APOPTOSIS BY TAXOL AND CISPLATIN AND EFFECT ON CELL CYCLE-RELATED PROTEINS IN CISPLATIN-SENSITIVE AND CISPLATIN-RESISTANT HUMAN OVARIAN-CANCER CELLS

The effect of taxol (TX) and cisplatin (CDDP), singly or in associatio n, was assessed on two human ovarian cancer cell lines, one sensitive (A2780) and one resistant (A2780 cp8) to CDDP. Cell lines showed a sim ilar sensitivity to TX, whereas different cytotoxicity results were ob tained in the two cell lines as a function of TX and CDDP sequence. Sp ecifically, TX followed by CDDP induced simply additive effects in bot h cell lines. whereas the opposite sequence produced antagonistic effe cts in A2780 cells and synergistic effects in A2780 cp8 cells. TX, wit h or without CDDP, induced oligonucleosomal DNA fragmentation typical of the apoptotic process, but the biochemical mechanisms undergoing ap optosis were different in the two cell lines. In fact, in A2780 cells, TX (with or without CDDP) treatment markedly increased p53 as well as p21(waf1) protein expression. In A2780 cp8 cells, drug treatment enha nced p53 levels, whereas the expression of p21(waf1) was always undete ctable at mRNA and protein levels. In the latter cell line, a prematur e activation of p34(cdc2) kinase was observed in correspondence with t he drug-induced increase in the S-phase cell fraction. Such an activat ion was not ascribable to an increase in the overall expression of p34 (cdc2) or cyclin B-1 proteins, but to a dephosphorylation of p34(cdc2) kinase. Overall, our results indicate that TX-induced apoptosis in hu man ovarian cancer cells may be sustained by different events at the c ell cycle-control level.