Induction of death receptor ligand-mediated apoptosis in epithelial ovarian carcinoma: The search for sensitizing agents

Objective To assess the abilities of cisplatin, paclitaxel, and flexible heteroarotinoid (Flex-Het) compound (SHetA2) to sensitize ovarian cancer cells to induction of the extrinsic apoptosis pathway by death receptor ligands, tumor necrosis factor α (TNFα), and TNF-related apoptosis-inducing ligand (TRAIL). Study design The effects of various combinations of TNFα, TRAIL, cisplatin, paclitaxel, and SHetA2 on viability and apoptosis in two established ovarian cancer cell lines, A2780 and SK-OV-3, and normal human primary endometrial cultures were measured with a cytotoxicity assay, flow cytometric analysis of annexin-V, and propidium iodide staining and Western blot analysis of caspase 8 and 3 activation. Results Ovarian cancer and normal cells were resistant to TNFα and TRAIL. Cisplatin and paclitaxel did not increase sensitivity to these agents in either cell type. In contrast, combination of SHetA2 with TNFα or TRAIL induced a synergistic induction of apoptosis in cancer cells that involved activation of the extrinsic pathway caspase 8 and executioner caspase 3. The TRAIL combination was more potent than the TNFα combination. SHetA2 did not harm the viability of normal cells as a single agent or in combination with the death receptor ligands. Conclusions SHetA2, but not cisplatin or paclitaxel, can overcome resistance of ovarian cancer cells to TNFα and TRAIL without increasing sensitivity of normal cells to these death receptor ligands.