Reduction of prostate cancer incidence by naftopidil, an α1-adrenoceptor antagonist and transforming growth factor-β signaling inhibitor

ObjectivesQuinazoline-based (1)-adrenoceptor antagonists are known to inhibit prostate tumor growth through induction of apoptosis. We investigated the effect of a naphthalene-based (1)-adrenoceptor antagonist, naftopidil, on prostate cancer incidence, apoptosis of prostatic cell and transforming growth factor- signaling. MethodsPrescription records were linked to pathological data for men who continued naftopidil (n=766) or tamsulosin (n=1015) for 3months or longer between 2003 and 2010. Prostate cancer incidence was analyzed by log-rank test and the Cox proportional hazards model. Apoptosis and cell cycle arrest in human tissues were assessed by immunohistochemical detection of Bcl2 and p21, respectively. Growth inhibition and apoptosis treatment with naftopidil and tamsulosin were assessed in cancer cell lines. Interference with transforming growth factor- signaling was examined by western blot analysis. ResultsProstate cancer incidence was significantly lower in men who received naftopidil for 3months or longer compared with tamsulosin (P=0.035). Multivariate analysis confirmed a decreased hazard ratio, 0.46, for naftopidil use (P=0.013), which was more evident with longer treatment. Immunohistochemical positivity for Bcl2, a marker for resistance to apoptosis, was less frequently detected in prostate cancer cells of men who received naftopidil compared with tamsulosin (P<0.05). Naftopidil inhibited cancer cell growth, induced apoptosis and blocked Smad2 phosphorylation activated by transforming growth factor- in cell lines, with a half maximal inhibitory concentration of 1.1 mu mol/L. ConclusionsNaftopidil seems to reduce prostate cancer incidence, possibly by inducing apoptosis, preferentially in cancer cells, and blocking transforming growth factor- signaling.