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Gynecol Oncol. 2009 Dec;115(3):438-42. doi: 10.1016/j.ygyno.2009.09.007. Epub 2009 Oct 4.

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

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Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Erratum in

  • Gynecol Oncol. 2010 Jun;117(3):510. Benbrook, Doris Mangiaracina [added].



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 alpha (TNFalpha), and TNF-related apoptosis-inducing ligand (TRAIL).


The effects of various combinations of TNFalpha, 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.


Ovarian cancer and normal cells were resistant to TNFalpha and TRAIL. Cisplatin and paclitaxel did not increase sensitivity to these agents in either cell type. In contrast, combination of SHetA2 with TNFalpha 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 TNFalpha combination. SHetA2 did not harm the viability of normal cells as a single agent or in combination with the death receptor ligands.


SHetA2, but not cisplatin or paclitaxel, can overcome resistance of ovarian cancer cells to TNFalpha and TRAIL without increasing sensitivity of normal cells to these death receptor ligands.

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