Induction of mammalian cell transformation and genotoxicity by 2-methoxyestradiol, an endogenous metabolite of estrogen

Abstract

2-methoxyestradiol (2-MeOE(2)) is an endogenous metabolite of 17beta-estradiol and a proposed inhibitor of tumor growth and angiogenesis. However, 2-MeOE(2) is also an inhibitor of microtubule assembly and other microtubule inhibitors, e.g. colcemid and diethylstilbestrol, induce aneuploidy and cell transformation in cultured mammalian cells. To assess the in vitro carcinogenicity and related activity of 2-MeOE(2), the abilities of this metabolite to induce cell transformation and genetic effects were studied simultaneously using Syrian hamster embryo (SHE) fibroblasts. Growth of these cells was reduced by treatment with 2-MeOE(2) at 0.1-1.0 microg/ml in a concentration-dependent manner. Treatment of SHE cells with 2-MeOE(2) at 0.3 or 1.0 microg/ml for 2-48 h also resulted in a concentration- and treatment time-related increase in the mitotic index and the percentage of multinucleated cells. Treatment with 2-MeOE(2) at 0.1-1.0 microg/ml for 48 h induced a statistically significant increase in the frequencies of morphological transformation of SHE cells in a concentration-dependent manner. A statistically significant increase in the frequencies of somatic mutations at the Na(+)/K(+) ATPase or hprt locus was also observed in cells treated with 2-MeOE(2) for 48 h at 0.1 or 0.3 microg/ml, respectively. Treatment of SHE cells with 2-MeOE(2) at 0.3 or 1.0 microg/ml for 24 h induced chromosome aberrations, mainly breaks, exchanges and chromosome pulverization. The incidence of chromosome aberrations was not affected by co-treatment with alpha-naphthoflavone, an inhibitor of 2-hydroxylase that inhibits oxidative conversion of 2-MeOE(2) to 2-hydroxyestradiol, but the incidence was slightly increased by co-treatment with L-ascorbic acid. Numerical chromosomal changes in the near diploid range and in the tetraploid and near tetraploid ranges were also detected in 2-MeOE(2)-treated cells. These findings indicate that 2-MeOE(2) has cell transforming and genotoxic activities in cultured mammalian cells and potential carcinogenic activity.

Mitochondrial Superoxide Dismutase: A Promising Target for New Anticancer Therapies

“…Moreover, a raise of intracellular superoxide not confined to mitochondria may easily lead to genotoxic stress, as it is the case for some traditional anticancer drugs. In keeping with this possibility, a recent paper by Tsutsui and colleagues has reported induction of mammalian cell transformation and genotoxicity by 2-methoxyestradiol [102].…”

Dual roles of estrogen metabolism in mammary carcinogenesis

“…It is thought that either ER or growth factor-mediated signaling pathway is converged on activation of MAPK pathways that play a critical role in regulation of apoptosis, cell proliferation, and cell-cycle control, thereby, leading to growth of tissue and/or tumor (67,72) (23,77). It is of our special interest that O-methoxylated catechol estrogens also displayed the proliferative effects via genomic ER signaling pathways and enhanced tumor growth in animal models (26,27). These findings would contradict the notion that O-methoxylation represents a favorable biotransformation, since 2-MeOE2 possess antitumor activity in ER-independent mechanisms and it is generally accepted that O-methoxylation prevents cells from genetoxic effects by the reactive intermediates through catechol estrogen formation.…”

“…Conjugation metabolic pathways are thought to protect cells from mitogenic and genotoxic effects by the parent estrogen as well as the catechol estrogen metabolites (24). O-Methoxylated conjugates are known to have very low binding affinity to the ER but to activate both genomic and non-genomic ER-signaling pathways (25)(26)(27). These findings imply that methoxylation may not be a deactivation pathway and make the hypothesis plausible that various types of estrogen metabolites as well as the parent estrogen may play a critical role in breast tumor promotion via the ER-mediated pathway.…”

Steroid hormone progesterone induces cell proliferation and abnormal mitotic processes in rat liver

“…In the case of the steroid hormone PR, its mechanism of action could be similar to that exerted by other natural or synthetic steroid hormones, such as diethylstilbestrol, which exhibits transforming and genotoxic activities and acts as a microtubule-disrupting agent inducing c-mitosis (Ochi 1999), and the endogenous metabolite of estrogens, 2-methoxyestradiol (Tsutsui et al 2000) and ethinylestradiol (our unpub- lished data). The precise mechanism by which PR induces spindle disturbances requires further study.…”