Cisplatin inhibits paclitaxel-induced apoptosis in cisplatin-resistant ovarian cancer cell lines: Possible explanation for failure of combination therapy

Combination chemotherapy using paclitaxel with a platinum-based regimen is currently the standard first-line therapy for ovarian cancer after surgical cytoreduction, Whereas cisplatin-paclitaxel combination chemotherapy has s hown significant efficacy over previous drug combinations in ovarian cancer , 20-30% of patients fail to respond to this combination. These patients ar e deemed cisplatin-paclitaxel resistant, although it is unclear whether the tumors are resistant to one or both drugs. Because the options available t o ovarian cancer patients for second-line therapy are limited, and knowing that mechanistic differences exist between cisplatin and paclitaxel, we ass essed the efficacy of combination drug therapy on cisplatin-resistant (cisp latin(R)) ovarian cancer cells. We found that paclitaxel induced apoptosis in cisplatin(R) cells as well as in the cisplatin-sensitive parental cell l ines. In cisplatin(R) C-13 cells, the concomitant addition of cisplatin blo cked paclitaxel-induced apoptosis as determined by DNA fragmentation assays , fluorescence microscopy, and flow cytometry, Paclitaxel-induced multimini nucleation was also inhibited when the cells were exposed sequentially to p aclitaxel and then cisplatin, Cisplatin did not block paclitaxel-induced st abilization of microtubules or prevent paclitaxel-induced loss of Bcl-2 exp ression in cisplatin(R) cells. Conversely, paclitaxel did not inhibit p53 p rotein accumulation by cisplatin. These results suggest that cisplatin bloc ks paclitaxel-induced apoptosis at a point downstream of Bcl-2 degradation and independent of microtubule stabilization. Our research shows that cispl atin can inhibit the effectiveness of paclitaxel in cisplatin(R) cell lines , Therefore, the establishment of a clinical protocol to evaluate the effic acy of paclitaxel alone versus another second-line regimen in patients with cisplatin-paclitaxel-resistant ovarian cancer is warranted.