Synergistic antitumor effect of tumor necrosis factor–related apoptosis-inducing ligand combined with cisplatin in ovarian carcinoma cell lines in vitro and in vivo

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to exert selectively cytotoxic activity against many tumor cells but not normal cells. In this study, we evaluated the antitumor activity of TRAIL and cisplatin (CDDP) both separately and combined in the human ovarian cancer cell lines. In vitro study showed that TRAIL elicited significant cell apoptosis of cell lines 3AO, SKOV3, and OVCAR3 in a dose- and time-dependent manner (P < 0.05), while normal ovarian epithelial cells were resistant; this toxicity-free effect may be the result of upregulation of TRAIL receptors DcR1 and DcR2. Combined TRAIL and CDDP therapy produced more profound cell killing in 3AO cells than each alone (P < 0.05), and CDDP could upregulate the expression of both death and decoy TRAIL receptors. To further evaluate the apoptosis-inducing effects of TRAIL and the combination therapy, the abdominally and subcutaneously spread tumors in nude mice via inoculation of 3AO cells were established, and treatment of TRAIL resulted in a dose- and time-dependent inhibition of tumor growth while slight damage was observed in normal tissues. Furthermore, combined TRAIL and CDDP therapy had a synergistic effect in the regression of established ovarian cancer xenografts than TRAIL treatment alone (P < 0.05). We also examined the apoptosis-related gene expression in the transplantation tumors after TRAIL treatment, and the data suggested that the intracellular mechanism of TRAIL may be associated with downregulation of Bcl-2 and upregulation of CD95 and Apo2.7.