The endogenous estrogen metabolite 2-methoxyestradiol induces apoptotic neuronal cell death in vitro

We examined the effects of 2-methoxyestradiol, a metabolite of estradiol, on cell death in retinoic acid (RA)-differentiated neuroblastoma SH-SY5Y cell cultures. Cell death was induced by 2-methoxyestradiol in a concentration-dependent manner. Estradiol and 2-methoxyestriol failed to induce cell death. The cell death response to 2-methoxyestradiol was sensitive to the protein synthesis inhibitor cycloheximide and the apopain inhibitor Ac-Asp-Glu-Val-Asp-H (aldehyde). 2-Methoxyestradiol also induced internucleosomal DNA fragmentation. Hence we propose a role for an endogenous neuroactive steroid metabolite in the etiology of some neurodegenerative diseases.