title: Novel effects of simvastatin on uterine fibroid tumors: in vitro and patient-derived xenograft mouse model study.
abstract: OBJECTIVE
  Uterine leiomyomas represent a common gynecologic problem with no satisfactory long-term medical treatment. The purpose of this study is to examine the effects of simvastatin on uterine leiomyoma, both in vitro and in vivo.
  
  
  METHODS
  This is a laboratory-based experimental study. For in vitro studies, we used human and rat leiomyoma cells. For in vivo studies, we used immunodeficient mice supplemented with estrogen/progesterone pellets xenografted with human leiomyoma tissue explant.
  
  
  RESULTS
  For in vitro studies, cells were treated with different concentrations of simvastatin for 48 hours. Simvastatin induced dose-dependent apoptosis in leiomyoma cells as measured by a fluorometric caspase-3 activity assay, and inhibited proliferation as demonstrated by an (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay (both were significant at 5 and 10 μM). In addition, simvastatin decreased Akt signaling pathway phosphorylation as examined using Western blot analysis. For in vivo studies, animals were treated for 28 days with simvastatin (20 μg/gm body weight/day) vs vehicle control. The treatment inhibited tumor growth as measured weekly using calipers and/ or ultrasound (P < .01). Finally, simvastatin decreased expression of the proliferation marker Ki67 in xenograft tumor tissue as examined by immunohistochemistry (P = .02).
  
  
  CONCLUSIONS
  Simvastatin can be a promising treatment for uterine leiomyoma. Further studies, including pharmacokinetic and drug delivery studies, are required.
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX; Department of Biochemistry and Molecular Biology, University of Texas Health Sciences Center at Houston, Houston, TX. Electronic address: maboraha@utmb.edu.
authors.forename: Mostafa A
authors.initials: MA
authors.lastname: Borahay
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX; Biomedical Engineering Center, University of Texas Medical Branch, Galveston, TX.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Vincent
authors.affiliation: Biomedical Engineering Center, University of Texas Medical Branch, Galveston, TX.
authors.forename: Massoud
authors.initials: M
authors.lastname: Motamedi
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX.
authors.forename: Elena
authors.initials: E
authors.lastname: Sbrana
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors.forename: Gokhan S
authors.initials: GS
authors.lastname: Kilic
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA.
authors.forename: Ayman
authors.initials: A
authors.lastname: Al-Hendy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Sciences Center at Houston, Houston, TX.
authors.forename: Darren
authors.initials: D
authors.lastname: Boehning
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D019394:Ki-67 Antigen / Q000187:drug effects / Q000378:metabolism; D007889:Leiomyoma / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D014594:Uterine Neoplasms / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004967:Estrogens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019394:Ki-67 Antigen; D011372:Progestins; D011374:Progesterone; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt
keywords: leiomyoma; patient-derived xenograft model; simvastatin; treatment; tumor
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