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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Moxley
Katherine Marie
KM
Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Chengedza
Shylet
S
Benbrook
Doris Mangiaracina
DM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D013871:Thiones / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
C476105:(((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione; D002839:Chromans; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013871:Thiones; D014409:Tumor Necrosis Factor-alpha; D017239:Paclitaxel; D002945:Cisplatin