The DDAH/NOS pathway in human prostatic cancer cell lines: Antiangiogenic effect of L-NAME

Abstract

Abstract. Benign prostate hypertrophy (BPH) and prostate cancer (PC) are prostate chronic diseases that require a long period for development from a small lesion to clinical manifestation. PC is the most common cancer in men in Europe and the Americas. Tumor growth and metastasis depend upon the development of neovasculature around the tumor. This process, called angiogenesis, may be regulated by NO, and thus modulation of NO production could play an important role in tumor progression. Recent studies report the involvement of DDAH, an enzyme which metabolizes the endogenous NOS inhibitor ADMA, in the development of tumor vasculature. The aim of the present study was to verify the involvement of the DDAH/ NOS pathway in the progression of prostate cancer. The effect of the NOS inhibitor L-NAME was evaluated in the human prostate cancer cell line LnCap and in BPH-1 cells which represent benign prostatic hypertrophy. Higher DDAH-2, eNOS, iNOS and VEGF expression was found in LnCap cells compared to BPH-1 cells. L-NAME treatment of LnCap cells resulted in a reduction in VEGF, iNOS and eNOS expression. VEGF, iNOS and eNOS inhibition is a promising approach for targeting tumor vasculature and certain NOS inhibitors could potentially serve as experimental agents for treatment of certain chemoresistant tumors, including prostate tumors. Moreover, since in our experimental conditions L-NAME was unable to reduce DDAH activity and expression, it is plausible to hypothesize the development of a targeted polypharmacological approach by developing dual and specific inhibitors of DDAH and NOS to better control NO biosynthesis. IntroductionBenign prostate hypertrophy (BPH) and prostate cancer (PC) are prostate chronic diseases that require a long period for development from a small lesion to clinical manifestation. PC is the second leading cause of death in men of Western world (1) Despite significant improvements in local and systemic therapies, most deaths from prostate cancer are due to metastasis which resist conventional therapies (2-4). Therefore, novel therapeutic strategies targeting specific molecular markers are being pursued to allow early detection and cure.Tumor growth and metastasis depend upon the development of a neovasculature around the tumor (5-9). This process, called angiogenesis, is critical to tumorigenicity and metastasis (10). Similarly to carcinogenesis, angiogenesis is a multistep process, regulated by a balance between stimulatory and inhibitory factors released by the tumor and its microenvironment (7,(11)(12)(13)(14)(15)(16)(17).Angiogenesis facilitates tumor growth through a series of steps including dissociation of endothelial cells (EC) from adjacent perycites, remodelling of extracellular matrix, proliferation and migration of EC and capillary differentiation.Nitric oxide (NO) is a signalling molecule produced by three isoforms of nitric oxide synthases (neuronal NOS, endothelial NOS and inducible NOS); it mediates a variety of actions such as vasodilatation, neurotransmission, host defence a...

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