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2-Methoxyestradiol Mediates Apoptosis Through Caspase-Dependent and Independent Mechanisms in Ovarian Cancer Cells But Not in Normal Counterparts

Department of Obstetrics and Gynecology, Faculty of Medicine, Universidad Católica de Chile, Santiago, Chile

Anil Sadarangani, PhD

Department of Physiology, Faculty of Biological Sciences Pontificia, Universidad Católica de Chile, Santiago, Chile

Soledad Lange

Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile

Ana M. Delpiano

Department of Obstetrics and Gynecology, Faculty of Medicine, Universidad Católica de Chile, Santiago, Chile

Macarena Vargas

Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile

Jorge Brañes, MD

Department of Obstetrics and Gynecology, Faculty of Medicine, Universidad Católica de Chile, Santiago, Chile

Jorge Carvajal, MD, PhD

Department of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

Stanley Lipkowitz, MD, PhD

Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Institute of Cancer, National Institutes of Health, Bethesda, Maryland

Gareth I. Owen, PhD

Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile

Mauricio A. Cuello, MD

Department of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile, macuello{at}med.puc.cl

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.

Key Words: AIF • 2ME • TRAIL • death receptors • chemotherapy • ovarian cancer.

Reproductive Sciences, Vol. 15, No. 9, 878-894 (2008)
DOI: 10.1177/1933719108324171


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