Simvastatin induces degradation of the extracellular matrix in human leiomyomata: novel in vitro, in vivo, and patient level evidence of matrix metalloproteinase involvement.

OBJECTIVES: To assess the effect of simvastatin on uterine leiomyoma growth and extracellular matrix (ECM) deposition. DESIGN: Laboratory analysis of human leiomyoma cell culture, xenograft in a mouse model, and patient tissue from a clinical trial. SETTING: Academic research center. PATIENT(S): Tissue culture from human leiomyoma tissue and surgical leiomyoma tissue sections from a placebo-controlled randomized clinical trial. INTERVENTION(S): Simvastatin treatment. MAIN OUTCOME MEASURE(S): Serum concentrations, xenograft volumes, and protein expression. RESULTS: Mice xenografted with 3-dimensional human leiomyoma cultures were divided as follows: 7 untreated controls; 12 treated with activated simvastatin at 10 mg/kg body weight; and 15 at 20 mg/kg body weight. Simvastatin was detected in the serum of mice injected at the highest dose. Xenograft volumes were significantly smaller (mean 53% smaller at the highest concentration). There was dissolution of compact ECM, decreased ECM formation, and lower collagen protein expression in xenografts. Membrane type 1 matrix metalloproteinase was increased in vitro and in vivo. Matrix metalloproteinase 2 and low-density lipoprotein receptor-related protein 1 were increased in vitro. CONCLUSIONS: Simvastatin exhibited antitumoral activity with ECM degradation and decreased leiomyoma tumor volume in vivo. Activation of the matrix metalloproteinase 2, membrane type 1 matrix metalloproteinase, and low-density lipoprotein receptor-related protein 1 pathway may explain these findings.

Curcumin inhibits human leiomyoma xenograft tumor growth and induces dissolution of the extracellular matrix.

OBJECTIVE: To determine whether a curcumin-supplemented diet would prevent and/or treat uterine leiomyoma growth in our mouse xenograft model. DESIGN: Animal study. SETTING: Laboratory study. PATIENT(S): N/A. INTERVENTION(S): Curcumin-supplemented diet. MAIN OUTCOME MEASURE(S): Dietary intake, blood concentrations, tumor size, extracellular matrix protein concentrations, apoptosis markers. RESULT(S): We found that curcumin was well tolerated as a dietary supplement, free curcumin and its metabolites were detected in the serum, and exposure resulted in approximately 60% less leiomyoma xenograft growth as well as dissolution of the peripheral extracellular matrix architecture of the xenografts. The production of matrix proteins, including collagens, decreased, whereas the number of apoptotic cells in the xenografts increased. Additionally, when xenografts were placed in a uterine intramural location, we found a significantly increased apoptotic response to curcumin in the diet. CONCLUSION(S): Mice on a diet supplemented with curcumin could achieve serum concentrations sufficient to regulate human leiomyoma xenograft growth, and curcumin could play both preventive and curative roles in the treatment of uterine leiomyoma as an oral nutritional supplement.