Effect of doxazosin on oxidative stress-related proteins in benign prostatic hyperplasia

Oxidative stress can induce cell mutations or proliferation which then can progress to carcinogenesis or remodeling. The same oxidative stress-mediated mechanism could participate in prostate cell proliferation and remodeling present in benign prostatic hyperplasia (BPH). Doxazosin induces prostate epithelial and stromal cell apoptosis through production of transforming growth factor-beta (TGF-beta), but cellular mechanisms are not completely clarified. In 10 prostate samples from BPH untreated patients who underwent TUR, we have assessed the gene and protein expression of: p22(phox) (subunit of NAD(P)H oxidase essential for O(2)(-) production); heme oxygenase-1 (HO-1) (induced by oxidative stress and antiapoptotic); TGF-beta (inhibitor of prostatic epithelial and stromal cell growth); the in vitro effect of doxazosin on expression of these markers.

RT-PCR and Western blot with specific primers and antibodies. p22(phox), HO-1 and TGF-beta were quantified by the ratio between their PCR and Western blot products and GAPDH.

Doxazosin significantly reduced p22(phox) gene and protein expression (0.61 +/- 0.04 vs. 0.36 +/- 0.04 d.u., p < 0.0002; 0.85 +/- 0.03 vs. 0.47 +/- 0.03, p < 0.0001, respectively). Doxazosin concentration dependently reduced HO-1 gene and protein expression (0.57 +/- 0.07 vs. 0.49 +/- 0.06 d.u. (1 microM) p < 0.04, vs. 0.22 +/- 0.08 (10 microM) p < 0.0001; 0.78 +/- 0.04 vs. 0.44 +/- 0.1 (10 microM) p < 0.003 respectively) and increased TGF-beta protein expression (0.58 +/- 0.05 vs. 0.74 +/- 0.16 (1 microM) n.s. vs. 0.81 +/- 0.07 (10 microM) p < 0.01).

Induction of oxidative stress-related proteins seems to be involved in the prostate cell proliferation and remodeling present in BPH. Doxazosin may reduce oxidative stress through reduction of p22(phox). Surprisingly, HO-1, which is induced and protected by oxidative stress, is also reduced by doxazosin. HO-1 is a potent antiapoptotic factor and downregulator of TGF-beta. From the results of this preliminary study it could be proposed that the proapoptotic effect of doxazosin could be mediated, at least in part, through the contemporary inhibition of HO-1.