Novel effects of simvastatin on uterine fibroid tumors: In vitro and patient-derived xenograft mouse model study

Mostafa A. Borahay, Kathleen Vincent, Massoud Motamedi, Elena Sbrana, Gokhan S. Kilic, Ayman Al-Hendy, Darren Boehning

Research output: Contribution to journalArticle

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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. Study Design 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). Conclusion Simvastatin can be a promising treatment for uterine leiomyoma. Further studies, including pharmacokinetic and drug delivery studies, are required.

Original languageEnglish (US)
Pages (from-to)196.e1-196.e8
JournalAmerican Journal of Obstetrics and Gynecology
Volume213
Issue number2
DOIs
StatePublished - Aug 1 2015

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Simvastatin
Leiomyoma
Heterografts
In Vitro Techniques
Caspase 3
Progesterone
Neoplasms
Estrogens
Therapeutics
Pharmacokinetics
Western Blotting
Immunohistochemistry
Body Weight
Phosphorylation
Apoptosis
Growth
Pharmaceutical Preparations

Keywords

  • leiomyoma
  • patient-derived xenograft model
  • simvastatin
  • treatment
  • tumor

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Borahay, M. A., Vincent, K., Motamedi, M., Sbrana, E., Kilic, G. S., Al-Hendy, A., & Boehning, D. (2015). Novel effects of simvastatin on uterine fibroid tumors: In vitro and patient-derived xenograft mouse model study. American Journal of Obstetrics and Gynecology, 213(2), 196.e1-196.e8. https://doi.org/10.1016/j.ajog.2015.03.055

Novel effects of simvastatin on uterine fibroid tumors : In vitro and patient-derived xenograft mouse model study. / Borahay, Mostafa A.; Vincent, Kathleen; Motamedi, Massoud; Sbrana, Elena; Kilic, Gokhan S.; Al-Hendy, Ayman; Boehning, Darren.

In: American Journal of Obstetrics and Gynecology, Vol. 213, No. 2, 01.08.2015, p. 196.e1-196.e8.

Research output: Contribution to journalArticle

Borahay, MA, Vincent, K, Motamedi, M, Sbrana, E, Kilic, GS, Al-Hendy, A & Boehning, D 2015, 'Novel effects of simvastatin on uterine fibroid tumors: In vitro and patient-derived xenograft mouse model study', American Journal of Obstetrics and Gynecology, vol. 213, no. 2, pp. 196.e1-196.e8. https://doi.org/10.1016/j.ajog.2015.03.055
Borahay, Mostafa A. ; Vincent, Kathleen ; Motamedi, Massoud ; Sbrana, Elena ; Kilic, Gokhan S. ; Al-Hendy, Ayman ; Boehning, Darren. / Novel effects of simvastatin on uterine fibroid tumors : In vitro and patient-derived xenograft mouse model study. In: American Journal of Obstetrics and Gynecology. 2015 ; Vol. 213, No. 2. pp. 196.e1-196.e8.
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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. Study Design 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). Conclusion Simvastatin can be a promising treatment for uterine leiomyoma. Further studies, including pharmacokinetic and drug delivery studies, are required.",
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N2 - 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. Study Design 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). Conclusion Simvastatin can be a promising treatment for uterine leiomyoma. Further studies, including pharmacokinetic and drug delivery studies, are required.

AB - 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. Study Design 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). Conclusion Simvastatin can be a promising treatment for uterine leiomyoma. Further studies, including pharmacokinetic and drug delivery studies, are required.

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