Phosphodiesterase (PDE) inhibitors reduce in vitro proliferation of prostate primary cells but do not interfere with growth of prostate carcinoma cell lines

Abstract

14604 Background: PDE 5 is highly expressed in cavernosal and prostatic tissue. The mechanism of PDE-5 inhibitors on cavernosal tissue is well established but the effects of PDE-5 inhibitors on prostatic cells are unknown. The aim of this study was to analyze in vitro effects of PDE-5 inhibitors on prostate primary cells, fibroblasts (PrSC), basal epithelial cells (PrEC) and prostate cancer cell lines. Methods: Cultivated PrEC and PrSC, immortalized BPH cells (BPH 1), androgen dependent (LNCaP) and androgen independent (PC3) prostate carcinoma cell lines were exposed to increasing concentrations of commercially available PDE 5 inhibitors Sildenafil (Sil), Tadalafil (Tad), Vardenafil (Var). After incubation for 3 days cell viability was determined by a WST-1 assay (Roche-Biochemicals). Cells were evaluated morphologically by invert-light microscopy. PDE-5 protein concentrations were determined by western blot analyses and tissue distribution of PDE-5 by immunohistochemistry (IHC) with a polyclonal antiserum. Results: None of the PDE-5 inhibitors induced cell proliferation. Significant decreases in proliferation and viability were observed at high concentrations (1 mg/ml) of all substances in PrSC and PrEC. In PrSC, proliferation rate decreased to 37.7% in Sil, to 16.9% in Tad and to 63.7% for Var as compared to controls. In PrEC, proliferation decreased to 72.7%, 21.6% and 84.4% for Sil, Tad and Var, respectively. At 0.1 mg/ml only Tad reduced proliferation significantly to 57.4%. Moreover, Tad induced neuroendocrine-like morphology in some PrEC. High protein concentrations of PDE 5 were observed in PrEC, low concentrations in PrSC but none in cancer cells. Conclusions: Sil, Tad and Var inhibit proliferation of prostate primary cells in vitro. Tad showed highest inhibition. Tumor cells were insensitive to PDE-5 inhibitors, due to the lack of PDE-5 protein. It seems unlikely that any of these substances increases proliferation of prostate carcinoma. Tad induced neuroendocrine-like morphology in some basal PrEC indicating effects on cellular differentiation. No significant financial relationships to disclose.