Novel Effects of Simvastatin on Uterine Fibroids

Uterine fibroids (also known as leiomyomas) represent a common gynecologic problem with a significant medical and economic burden. Unfortunately, no satisfactory long-term medical treatment is currently available. Statins are drugs commonly used for the treatment of high plasma cholesterol levels. Beyond these well-known lipid-lowering properties, they possess broad reaching effects in vivo which include anti-tumor effects. Statins inhibit the growth of multiple tumors; however the mechanisms remain incompletely understood. The purpose of this study was to examine the effects of simvastatin on uterine fibroid, both in vitro and using an animal model. For the in vitro studies, we used primary and immortalized human fibroid cells. For the in vivo studies, we used immunodeficient mice supplemented with estrogen/progesterone pellets xenografted with human fibroid tissue explant. We found that simvastatin inhibits the proliferation of human fibroid cells. This was associated with decreased mitogen-activated protein kinase signaling and multiple changes in cell cycle progression. Simvastatin potently induced fibroid cell apoptosis in a manner mechanistically dependent upon apoptotic calcium release from L-type voltage-gated calcium channels. Thus, simvastatin possesses anti-tumor effects which are dependent upon the apoptotic calcium release machinery. For the in vivo studies, animals were treated with simvastatin vs vehicle control. The treatment inhibited tumor growth as measured weekly using calipers and/ or ultrasound. Finally, simvastatin decreased the expression of the proliferation marker Ki67 in xenograft tumor tissue as examined by immunohistochemistry. In conclusion, simvastatin can be a promising treatment for uterine fibroid. Further studies, including pharmacokinetic and drug delivery studies, are required.

Name thesis:degree_name

Cell Biology (Doctoral)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Obstetrics and Gynecology

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Borahay, Mostafa A.

Advisor dc:contributor.advisor

• Barral, Jose

Committee members dc:contributor.committeemember

• Boehning, Darren
• Elferink, Lisa
• Cheng, Xiaodong
• Ozpolat, Bulent

• Uterine fibroids
• leiomyoma
• simvastatin
• statins
• calcium
• apoptosis
• mouse model

Handle dc:identifier.uri

http://hdl.handle.net/2152.3/729

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/729