Simvastatin, at clinically relevant concentrations, affects human uterine leiomyoma growth and extracellular matrix production

Objective: To observe the antifibroid effects of therapeutic concentrations of simvastatin, which interferes with cholesterol biosynthesis, a known precursor of five major classes of steroid hormones, including progesterone and estrogen, which play a major role in the development and growth of uterine leiomyomas. Design: Two-dimensional and three-dimensional cell culture study of immortalized human leiomyoma and patient-matched myometrium cells treated with simvastatin. Setting: University laboratory. Patient(s): None. Interventions(s): None. Main Outcome Measure(s): Cell proliferation, alteration in apoptotic signaling pathways, and extracellular matrix (ECM) protein production. Result(s): Simvastatin demonstrated a concentration-dependent antiproliferative effect on both the leiomyoma cells and the patient-matched myometrium cells, but a higher inhibitory effect at lower concentrations of simvastatin was observed in leiomyoma cells. Simvastatin also regulated leiomyoma cell apoptosis through a concentration-dependent increase in activity of caspase-3. Simvastatin significantly inhibited expression of major ECM proteins collagen I, collagen III, fibronectin, versican, and brevican in leiomyoma cells at concentrations as low as 10 ⁻⁹ mol/L within 48 hours of exposure. Conclusion(s): Simvastatin induces apoptosis in uterine leiomyoma cells at low concentrations, as evidenced by increased active caspase levels. Furthermore, inhibited production of the ECM proteins may lead to reduction in tumor size. Simvastatin may represent a novel therapeutic treatment strategy for uterine leiomyomas.