title: 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.
abstract: 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.
authors.affiliation: Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Salama A
authors.initials: SA
authors.lastname: Salama
authors.forename: Abdelhakim Ben
authors.initials: AB
authors.lastname: Nasr
authors.forename: Raghvendra K
authors.initials: RK
authors.lastname: Dubey
authors.forename: Ayman
authors.initials: A
authors.lastname: Al-Hendy
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy*; D051381:Rats; D014594:Uterine Neoplasms / Q000188:drug therapy*
chemical_list: D050256:Antimitotic Agents; D004967:Estrogens; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003094:Collagen