Background and Objectives: 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-β (TGF-β), 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: p22phox (subunit of NAD(P)H oxidase essential for O2– production); heme oxygenase-1 (HO-1) (induced by oxidative stress and antiapoptotic); TGF-β (inhibitor of prostatic epithelial and stromal cell growth); the in vitro effect of doxazosin on expression of these markers. Methods: RT-PCR and Western blot with specific primers and antibodies. p22phox, HO-1 and TGF-β were quantified by the ratio between their PCR and Western blot products and GAPDH. Results: Doxazosin significantly reduced p22phox 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 µM) p < 0.04, vs. 0.22 ± 0.08 (10 µM) p < 0.0001; 0.78 ± 0.04 vs. 0.44 ± 0.1 (10 µM) p < 0.003 respectively) and increased TGF-β protein expression (0.58 ± 0.05 vs. 0.74 ± 0.16 (1 µM) n.s. vs. 0.81 ± 0.07 (10 µM) p < 0.01). Conclusions: 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 p22phox. 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-β. 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.

Keywords:
Benign prostatic hyperplasia, Doxazosin, Heme oxygenase-1, Oxidative stress, Transforming growth factor-β
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© 2006 S. Karger AG, Basel
2006
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