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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

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Abstract

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.

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Authors and Affiliations

  1. Division of Gynecology, Department of Obstetrics & Gynecology, University of Texas Medical Branch, 301 University Blvd., Galveston, Texas, 77555-0587, USA

    Salama A. Salama PhD, Abdelhakim Ben Nasr PhD, Raghvendra K. Dubey PhD & Ayman Al-Hendy MD, PhD

  2. Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

    Salama A. Salama PhD, Abdelhakim Ben Nasr PhD, Raghvendra K. Dubey PhD & Ayman Al-Hendy MD, PhD

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  1. Salama A. Salama PhD
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  2. Abdelhakim Ben Nasr PhD
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  3. Raghvendra K. Dubey PhD
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  4. Ayman Al-Hendy MD, PhD
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Corresponding author

Correspondence to Ayman Al-Hendy MD, PhD.

Additional information

Supported by National Institute of Child Health and Human Development Grant No. R01 HD046228 to A.A.-H., Swiss National Science Foundation (grant 32-64040-00) and Oncosuisse (grant OCS-01551 -08-2004).

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Salama, S.A., Nasr, A.B., Dubey, R.K. et al. 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. Reprod. Sci. 13, 542–550 (2006). https://doi.org/10.1016/j.jsgi.2006.09.003

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