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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

Departments of Obstetrics & Gynecology and Microbiology, University of Texas Medical Branch, Galveston, Texas; and the Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Abdelhakim Ben Nasr, PhD

Raghvendra K. Dubey, PhD

Ayman Al-Hendy, MD, PhD

Departments of Obstetrics & Gynecology and Microbiology, University of Texas Medical Branch, Galveston, Texas; and the Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania ayalhend{at}utmb.edu

Objective: The current study sought to investigate the effect of the estrogen metabolite 2-methoxyestradiol (2-MeOHE₂) on apoptosis, cell proliferation, and collagen synthesis in human and rat leiomyoma cells.

Methods: [³H] thymidine and [³H] 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-MeOHE₂ on apoptosis and the cell cycle.

Results: Compared with untreated controls, treatment of rat leiomyoma (ELT3) cells with 2-MeOHE₂ (0.1, 1, 2, 5, or 10 µM) 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-MeOHE₂ 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-MeOHE₂ treatment (1 to 5 µM) in huLM cells resulted in G₂/M cell cycle arrest and a 45% increase in apoptosis compared with untreated control (P <.05). Western immunoblotting analysis indicated that 2-MeOHE₂ 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-MeOHE₂ 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.

Key Words: 2-Methoxyestradiol • uterine leiomyoma • apoptosis • collagen synthesis • cell cycle

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