LOVASTATIN-INDUCED APOPTOSIS IN PROSTATE STROMAL CELLS

Benign prostatic hyperplasia (BPH) is a common disease of aging men. C urrent medical treatment for this condition is only partially effectiv e, therefore many patients must undergo surgery for symptomatic relief . BPH is caused by an increase in prostate epithelial and stromal cell s, especially the latter. Since BPH stromal cells have a long life spa n and are not very responsive to androgen withdrawal, cultured BPH str omal cells mere used to explore the feasibility of pharmacologically i nducing apoptosis in these cells. We obtained BPH tissue during surger y, and stromal cells were isolated and maintained in culture. After ce lls achieved confluence, we induced apoptosis with the HMGCoA reductas e inhibitor, lova-statin (30 pmol/L). The effects of testosterone (100 mu mol/L), dihydrotestosterone (DHT; 100 pmol/L) and finasteride (100 pmol/L) on lovastatin-induced apoptosis were studied on cells grown i n media containing charcoal stripped serum. Similarly, we examined the effect of the cholesterol pathway metabolites, mevalonic acid (30 mu mol/L), geranyl geraniol (30 mu mol/L), farnesol (10 mu mol/L), squale ne (30 mu mol/L) and 7-ketocholesterol (3 mu mol/L) on lovastatin-indu ced apoptosis. We demonstrated apoptosis by DNA laddering in agarose g els, by fluorescence microscopy following acridine orange staining, an d by now cytometry after end-labeling of DNA strand breaks with biotin -16-dUTP using deoxynucleotidyl exotransferase (TdT). Lovastatin at 30 mu mol/L, but not at lower concentrations, induced apoptosis in BPH p rostate stromal cells. This was seen (by flow cytometry) in 16.6 +/- 7 .3% (mean +/- SD) of BPH cells treated with lovastatin at 72 h vs. 2.5 +/- 1.2% of cells treated viith ethanol. Lovastatin-induced apoptosis was not increased in stripped serum or by the addition finasteride, a nd was not inhibited by testosterone or DHT. Only mevalonate and geran yl geraniol, prevented lovastatin-induced apoptosis whereas farnesol, squalene, or 7-ketocholesterol did not. We conclude that lovastatin ca n induce apoptosis in BPH stromal cells in vitro, and this is not affe cted by androgen withdrawal or stimulation. It is unlikely that lovast atin, per se, will be an effective treatment for BPH in vivo, but it d oes provide a means for inducing apoptosis in vitro. Understanding the apoptotic process in BPH stromal cells ultimately may lead to new the rapeutic strategies for BPH.