RESUMO
OBJECTIVE: 2-Methoxyestradiol, one of the natural 17ß-estradiol derivatives, is a novel, potent anticancer agent currently being evaluated in advanced phases of clinical trials. The main goal of the study was to investigate the anticancer activity of 2-methoxy-estradiol towards osteosarcoma cells and its possible neurodegenerative effects. We used an experimental model of neurotoxicity and anticancer activity of the physiological agent, 2-methoxyestradiol. Thus, we used highly metastatic osteosarcoma 143B and mouse immortalized hippocampal HT22 cell lines. The cells were treated with pharmacological (1 µM, 10 µM) concentrations of 2-methoxyestradiol. EXPERIMENTAL: Neuronal nitric oxide synthase and 3-nitrotyrosine protein levels were determined by western blotting. Cell viability and induction of cell death were measured by MTT and PI/Annexin V staining and a DNA fragmentation ELISA kit, respectively. Intracellular levels of nitric oxide were determined by flow cytometry. RESULTS: Here we demonstrated that the signaling pathways of neurodegenerative diseases and cancer may overlap. We presented evidence that 2-methoxyestradiol, in contrast to 17ß-estradiol, specifically affects neuronal nitric oxide synthase and augments 3-nitrotyrosine level leading to osteosarcoma and immortalized hippocampal cell death. CONCLUSIONS: We report the dual facets of 2-methoxyestradiol, that causes cancer cell death, but on the other hand may play a key role as a neurotoxin.
Assuntos
Antineoplásicos/farmacologia , Estradiol/análogos & derivados , Óxido Nítrico Sintase Tipo I/genética , 2-Metoxiestradiol , Antineoplásicos/toxicidade , Apoptose , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Indução Enzimática/efeitos dos fármacos , Estradiol/farmacologia , Estradiol/toxicidade , Hipocampo/patologia , Humanos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Óxido Nítrico Sintase Tipo I/biossíntese , Osteossarcoma/tratamento farmacológico , Estresse OxidativoRESUMO
2-Methoxyestradiol (2-ME) is a physiological metabolite of 17ß-estradiol. At pharmacological concentrations, 2-ME inhibits colon, breast and lung cancer in tumor models. Here we investigated the effect of physiologically relevant concentrations of 2-ME in osteosarcoma cell model. We demonstrated that 2-ME increased nuclear localization of neuronal nitric oxide synthase, resulting in nitro-oxidative DNA damage. This in turn caused cell cycle arrest and apoptosis in osteosarcoma cells. We suggest that 2-ME is a naturally occurring hormone with potential anti-cancer properties.