**4. Concluding comments and future perspective**

PDE-5 inhibitors including sildenafil, vardenafil and tadalafil are safe and efficacious firstline on-demand agents for the treatment of erectile dysfunction (Boolell *et al.*, 1996;Porst *et al.*, 2001). Their mechanism of action involves inhibition of the PDE-5 enzyme and resulting increase in cGMP and smooth muscle relaxation in the penis. Their target enzyme, PDE-5 is expressed in several tissues throughout the human body, including the pulmonary and systemic vasculature, hypertrophied myocardium and cancer cells. Preclinical studies have demonstrated that PDE-5 inhibitors have powerful cardioprotective effect in the setting of I/R injury, pressure overload-induced hypertrophy, heart failure and DOX-induced cardiomyopathy. The effects of PDE-5 inhibitors on the pulmonary circulation and hypertrophied right ventricle have made these agents first-line therapy for many patients with pulmonary hypertension. Several reports have indicated that PDE-5 inhibitors improve erectile function following radiation therapy or post-radical prostatectomy in prostate cancer patients. Recent research from our laboratory has reported provocative findings that **sildenafil is both a powerful sensitizer of DOX-induced killing of prostate cancer and provides concurrent cardioprotective benefit (Das** *et al.***, 2010).** Moreover, sildenafil and vardenafil have been shown to block or reverse the drug efflux function of the ABC transporters, thereby suggesting that sildenafil can be used as a modulator of ABCB1 and ABCG2 to reverse MDR in cancer cells. Considering the well-established safety profile of PDE-5 inhibitors, clinical studies are needed to fully exploit the beneficial effect of the combination treatment of anti-tumor agents such as DOX with the PDE-5 inhibitors as a therapeutic tool in prostate cancer patients. Also, further studies are needed to gain in depth understanding of the molecular mechanisms by which PDE-5 inhibitors increase the efficacy of chemotherapeutic agents.
