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2-Methoxyestradiol Inhibits Proliferation and Induces Apoptosis Independently of Estrogen Receptors and ß

Discovery Research Department, EntreMed, Inc., Rockville, Maryland 20850

2-Methoxyestradiol (2ME₂) is an endogenous metabolite of 17ß-estradiol (E₂) that arises from the hydroxylation and subsequent methylation at the 2-position. In vitro 2ME₂ inhibits a large variety of tumor and nontumor cell lines from diverse origins, as well as several stages of the angiogenic cascade. In vivo it has been shown to be a very effective inhibitor of tumor growth and angiogenesis in numerous models. Although various molecular targets have been proposed for this compound, the mechanism of action is still uncertain. As this molecule emerges as a drug candidate it is important to assess the estrogen receptors (ERs) as molecular targets for 2ME₂. The purpose of this study was to investigate whether 2ME₂ is able to engage ERs as an agonist and whether its antiproliferative activities are mediated through ERs. We confirm that 2ME₂ has a lower binding affinity for ER as compared with E₂ and other E₂ metabolites and antagonists, and we demonstrate that the affinity of 2ME₂ for ERß is even lower. When assessed in the presence of galangin, a cytochrome P450 enzyme inhibitor, at concentrations at which 2ME₂ interacts with ER in an in vitro binding assay, it does not stimulate the proliferation of an estrogen-dependent breast carcinoma cell line. Similar IC₅₀ values for inhibition of proliferation and induction of apoptosis are obtained in estrogen-dependent and estrogen-independent human breast cancer cell lines, irrespective of the expression of ER and ERß. Moreover, the estrogen antagonist ICI 182,780 does not inhibit the antiproliferative activity of 2ME₂. In E₂-responsive cells such as MCF-7 and human umbilical vascular endothelial cells, high levels of E₂ inhibit the antiproliferative activity of ICI 182,780 but not of 2ME₂. Collectively, these results suggest that 2ME₂ is distinct among estradiol metabolites because of its inability to engage ERs as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of ER and ERß.

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