N21 Comparative effects of rosuvastatin and simvastatin on growth of normal prostatic epithelial cells at clinically relevant concentrations

      Introduction and Objectives

      3-hydroxy-3-methylglutaryl CoA reductase inhibitors, statins, have been shown to inhibit the growth of normal and cancerous prostate cells, indicating their chemotherapeutic and -preventive potential to prostate cancer. Although several studies with prostate cancer cell lines have revealed inhibitory effects of supratherapeutic doses of statins to involve enhanced apoptosis and cell cycle arrest, corresponding studies with noncancerous cells have not been done. In this study we compared two different statins’ (rosuvastatin and simvastatin) potency to inhibit the growth of normal epithelial prostate cells at clinically relevant drug doses and further analyzed the underlying mechanisms.

      Material and Methods

      A prostatic epithelial cell line of noncancerous tissue origin (P96E), an in vitro transformed prostate epithelial cell line (RWPE-1) and an advanced cancer cell line (LNCaP) were used in the study. Cells were treated with vehicle, rosuvastatin or simvastatin at concentrations of 10 and 100 nM. Changes in cellular growth rate were measured after 7 days with crystal violet staining. Other analyses involved quantitation of histone-complexed DNA fragments for apoptosis and Ki-67 index for proliferation. Also changes in the expression of HMG-CoA reductase (HMGCR) and various cell cycle proteins were measured using immunoblotting and quantitative RTPCR.


      Of the two statins tested, simvastatin was found 10-fold more potent than rosuvastatin to inhibit cellular growth of normal cells. The strongest inhibition in growth was seen with P96E cells (about 77% with 100 nM simvastatin) whereas the growth of LNCaP cells was not inhibited. Following statin treatment, a feedback upregulation of HMGCR mRNA was seen in normal epithelial cells but not in LNCaP. Simvastatin was a more potent inducer of feedback upregulation. Both statins at 100 nM induced apoptosis only slightly (<2-fold) with no major differences between cell lines. A clear decrease in Ki-67 index (≈31%) was noted in P96E after 5 days of simvastatin treatment while in RWPE-1 the decrease was only about 11%. No major differences in the expression of cyclin D1 and D3 or cyclin dependent kinase inhibitors p15, p16, p21 or p27 in P96E cells were seen after 24–96 h exposure to 100nM simvastatin.


      Our results suggest simvastatin to be more potent in inhibiting normal prostate epithelial cell growth than rosuvastatin. Because rosuvastatin is known to be a more potent HMGCR inhibitor in vitro than simvastatin the reason for the difference is likely to involve differential hydrophobicity-based cellular uptake of these agents. Considering the underlying mechanisms, enhanced apoptosis seems not to be the main explanation for growth inhibition but it is likely to involve an exit of cells from active cell cycle.