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

Abstract

ObjectivesTo assess the effect of simvastatin on uterine leiomyoma growth and extracellular matrix (ECM) deposition. DesignLaboratory analysis of human leiomyoma cell culture, xenograft in a mouse model, and patient tissue from a clinical trial. SettingAcademic 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. ResultsMice 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 serum from mice injected at the highest dose. Xenograft volumes were significantly smaller (mean 53% smaller at the highest concentration, p < 0.05). There was dissolution of compact ECM, decreased ECM formation, and lower collagen protein expression in xenografts. Membrane type 1 matrix metalloproteinase (MT1-MMP) was increased in vitro and in vivo. Matrix metalloproteinase 2 (MMP2) and low density lipoprotein receptor related protein 1 (LRP1) were increased in vitro. ConclusionsSimvastatin exhibited antitumoral activity, with extracellular matrix degradation and decreased leiomyoma tumor volume in vivo. Activation of the MMP2/MT1-MMP/LRP1 pathway may explain these findings.