2-methoxyestradiol mediates apoptosis through caspase-dependent and independent mechanisms in ovarian cancer cells but not in normal counterparts.

OBJECTIVE: The estrogen metabolite 2-methoxyestradiol has shown antitumorigenic action in some epithelial tumors. In the present work we investigate its effects in ovarian cancer used alone or in combination with other apoptotic-inducing reagents such as tumor necrosis factor-related apoptosis-inducing ligand. METHODS: To assess the effect of 2-methoxyestradiol, dose response and time courses in ovarian cancer and normal cells were conducted. Apoptosis was confirmed through DNA laddering, by flow cytometry, and Western blotting of proteins involved in the apoptotic cascade. RESULTS: 2-Methoxyestradiol induced apoptosis in ovarian cancer cells but not in normal counterparts. 2-Methoxyestradiol activates both the intrinsic and extrinsic apoptotic pathways. 2-Methoxyestradiol-mediated apoptosis involves reactive oxygen species generation and caspase-dependent and caspase-independent mechanisms. We also demonstrate that 2-methoxyestradiol selectively induces an additive/synergistic apoptotic response in ovarian cancer cells when used in combination with tumor necrosis factor-related apoptosis-inducing ligand. CONCLUSIONS: 2-Methoxyestradiol, alone or in combination with tumor necrosis factor-related apoptosis-inducing ligand, should be considered as a potential treatment for ovarian cancer.

TRAIL mediates apoptosis in cancerous but not normal primary cultured cells of the human reproductive tract.

Cancer of the reproductive tract encompasses malignancies of the uterine corpus, cervix, ovary, Fallopian tube, among others and accounts for 15% of female cancer mortalities. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates apoptosis by binding to death receptors and offers a promising cancer treatment. The goal of this study was to investigate and characterize the effect of TRAIL in endometrial cancer cell lines and normal (non-cancerous) epithelial cells of endometrial origin. We also examined the effect of TRAIL in other primary cultured cancers and normal cells of the human female reproductive tract and evaluated if TRAIL mediated apoptosis correlated with death receptors and decoy receptors 1 and 2.Herein, we demonstrate that TRAIL at concentrations which kill cancerous cells, does not mediate apoptosis or alter cell viability in normal human endometrium, ovary, cervix or Fallopian tube. The partial inhibition by a caspase 9 inhibitor and the total inhibition by a caspase 8 inhibitor demonstrates the dependency on the extrinsic apoptotic pathway. The selective mortality does not correlate with the presence of death or decoy receptors. These results suggest that TRAIL may be an effective treatment for endometrial cancer and other female reproductive cancers, with minimal secondary effects on healthy tissue.