Effects of treatment sequence of cisplatin and paclitaxel (taxol) on cell cycle and cell death in NIHOVCAR-3 cell line

Jo, Hyun Hee; Kim, Yong Ok; Yoo, Young Ok; Park, Gee Young; Park, Chul Hoon; Ryu, Gee Sung; Na, Jong Goo; Kim, Soo Pyung; Han, Goo Taek

Abstract

The overt effects of the anticancer drugs such as cisplatin and taxol appear to be DNA modification and microtubule stabilization respectively. But the mechanism by which these drugs affect tumor cell cycle perturbation and their correlation to apoptosis and cytotoxicity are not well understood, especially in combined sequential treatment of cisplatin and paclitaxel (taxol). In this study, to elucidate the action mechanisms as a function of cell cycle changes and cytotoxicities and to determine the adequate treatment sequence of cisplatin and taxol to acquire more enhanced cytotoxic effects when they are combined, we evaluated the cell cycle perturbations and its correlation to cytotoxic effects, which is measured by the extents of apoptosis and the fractions of cellular debris and live cells after combination treatment of cisplatin and taxol changing their treatment sequences in NIHOVCAR-3 ovarian cancer cell line. Our results were as follows; (1) The accumulation in S phase inhibited the entrance of tumor cells to G2M phase when the cisplatin treatment was preceded to taxol in their combination. (2) The tumor cells were not accumulated in S phase but most of them entered to and accumulated in G2M phase and they were leading to cell death when the taxol treatment was preceded to cisplatin in their combination. (3) Apoptotic peaks in taxol pretreatment group were detected earlier and persisted longer than that of cisplatin pretreatment group. (4) The cytotoxicities represented by the decreased fractions of live cells and the increased fractions of cellular debris were higher in taxol pretreatment group than those of cisplatin pretreatment group. These results suggested that the taxol pretreatment is more effective in combination of cisplatin and taxol and the relative decrease in the cytotoxicity in cisplatin pretreatment group was considered to be derived from the inhibition of entrance of tumor cells to G2M and protected them from the action by taxol. From these results, we concluded that the taxol pretreatment will enhance the cytotoxic effects to tumor cells when cisplatin and taxol will be administered and it indicates that correlations between cell cycle perturbation, apoptosis and cell death have to be considered in the future combination treatment of other drugs and in the development of new treatment regimens.