Optimizing the efficacy of TRAIL-induced apoptotic cell death in granulosa tumor cell lines

Human ovarian cancers of granulosa cell origin currently represent approximately 3 to 5% of diagnosed cancers involving the ovary. Nevertheless, there is little known regarding either the etiology or selective treatment of granulosa cell tumors (GCT) as compared to those originating from surface epithelial cells. The ability of TRAIL to target cancer cells for apoptosis without affecting normal cells has generated interest for its potential use in cancer therapy. However, its efficacy in the treatment of ovarian GCTs has yet to be evaluated. Recent in vitro studies have demonstrated that treatment with the naturally occurring cytokine, TRAIL, does not induce apoptosis in healthy ovarian granulosa cells, despite the expression of a functional TRAIL death receptor, DR5. Results obtained using two human GCT lines, COV434 and KGN (both of which were established to be p53 wild-type), demonstrate a slight, but significant, increase in TRAIL (100 ng/ml)-induced apoptosis (KGN, fold vs control = .90 +/.02; COV434, fold vs control = .89 +/.015; p < .05). This effect was markedly enhanced when granulosa cells were first treated with the conventional chemotherapeutic, cisplatin (25 uM; p<.001). Similarly, treatment with paclitaxel (10 nM) also significantly increased the death-inducing ability of TRAIL. Of notable interest was the finding that while treatment with paclitaxel effectively reduced cell viability in a human ovarian surface epithelial cell line (PA-1) following 48 h treatment, paclitaxel treatment alone was ineffective in mediating cell death in both GCT lines (10-100 nM). However, the combinatorial treatment with paclitaxel plus TRAIL led to a significant decrease in cell viability (p<.001). These results provide evidence that a greater efficacy in treating GCTs can be achieved with a regime of cisplatin or paclitaxel followed by treatment with TRAIL.