Abstract
The small free radical gas nitric oxide (NO) plays a key role in various physiological and pathological processes through enhancement of endothelial cell survival and proliferation. In particular, NO has emerged as a molecule of interest in carcinogenesis and tumor progression due to its crucial role in various cancer-related events including cell invasion, metastasis, and angiogenesis. The dimethylarginine dimethylaminohydrolase (DDAH) family of enzymes metabolize the endogenous nitric oxide synthase (NOS) inhibitors, asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA), and are thus key for maintaining homeostatic control of NO. Dysregulation of the DDAH/ADMA/NO pathway resulting in increased local NO availability often promotes tumor growth, angiogenesis, and vasculogenic mimicry. Recent literature has demonstrated increased DDAH expression in tumors of different origins and has also suggested a potential ADMA-independent role for DDAH enzymes in addition to their well-studied ADMA-mediated influence on NO. Inhibition of DDAH expression and/or activity in cell culture models and in vivo studies has indicated the potential therapeutic benefit of this pathway through inhibition of both angiogenesis and vasculogenic mimicry, and strategies for manipulating DDAH function in cancer are currently being actively pursued by several research groups. This review will thus provide a timely discussion on the expression, regulation, and function of DDAH enzymes in regard to angiogenesis and vasculogenic mimicry, and will offer insight into the therapeutic potential of DDAH inhibition in cancer based on preclinical studies.
Highlights
Despite recent therapeutic advances, cancer remains among one of the leading causes of death worldwide, and the development of novel anti-tumor therapies is still a key priority
A comprehensive discussion on all dimethylarginine dimethylaminohydrolase (DDAH) inhibitors synthesized to date and their impact on endothelial cells falls outside the scope of this review, here we summarize a small body of evidence that identifies the therapeutic potential for pharmacological inhibition of DDAH1 in cancer
The DDAH enzymes are responsible for the metabolism of the endogenous nitric oxide synthase (NOS) inhibitors, the asymmetrically methylated arginines asymmetric dimethylarginine (ADMA) and L-NMMA, and are critical factors in both maintaining and modulating precise nitric oxide (NO) production
Summary
Cancer remains among one of the leading causes of death worldwide, and the development of novel anti-tumor therapies is still a key priority. Increased expression of DDAH enzymes in tumors of different origins has been reported by numerous research groups in recent years, and inhibition of DDAH expression and/or activity in cell culture models and in vivo studies has indicated the potential therapeutic benefit of targeting this pathway [53,54,55,56].
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