Estrogen metabolite 2-methoxyestradiol induces apoptosis and inhibits cell proliferation and collagen production in rat and human leiomyoma cells: a potential medicinal treatment for uterine fibroids.
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OBJECTIVE
The current study sought to investigate the effect of the estrogen metabolite 2-methoxyestradiol (2-MeOHE(2)) on apoptosis, cell proliferation, and collagen synthesis in human and rat leiomyoma cells.
METHODS
[(3)H] thymidine and [(3)H] proline incorporation studies were conducted. The expression of vascular endothelial growth factor (VEGF), cyclin D1, Bcl-2, and Bax were evaluated by Western blot. Flow cytometry analysis was used to study the effect of 2-MeOHE(2) on apoptosis and the cell cycle.
RESULTS
Compared with untreated controls, treatment of rat leiomyoma (ELT3) cells with 2-MeOHE(2) (0.1, 1, 2, 5, or 10 muM) reduced cell proliferation by 17%, 52%, 61%, 73%, and 79%, respectively (P <.05). Similarly, in human uterine leiomyoma cell line (huLM) cells, proliferation was reduced by 4%, 18%, 37%, 41%, and 51%, respectively. 2-MeOHE(2) also caused a concentration-dependent inhibition of collagen synthesis by 4%, 16%, 23%, 51%, and 70%, respectively, in huLM cells (P <.05). Cell cycle analysis indicated that 2-MeOHE(2) treatment (1 to 5 muM) in huLM cells resulted in G(2)/M cell cycle arrest and a 45% increase in apoptosis compared with untreated control (P <.05). Western immunoblotting analysis indicated that 2-MeOHE(2) induces a concentration-dependent reduction in the expression of cyclin D1, Bcl-2, and VEGF proteins in both rat and human leiomyoma cell lines.
CONCLUSIONS
This study provides the first evidence that 2-MeOHE(2) is a potent antiproliferative/apoptotic and collagen synthesis inhibiting agent in human and rat leiomyoma cells. To the best of our knowledge, this is the first report showing the potential use of 2-methoxyestradiol as a nonsurgical alternative therapy for uterine leiomyomas.
