Inhibition of Dimethylarginine Dimethylaminohydrolase (DDAH) Enzymes as an Emerging Therapeutic Strategy to Target Angiogenesis and Vasculogenic Mimicry in Cancer

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.

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

“…However, our analysis of clinical samples showed the downregulation of DDAH1 and DDAH2 in colonic tumors. While consistent with ADMA accumulation [ 33 , 34 ], our observation contradicts the results of RNA-seq expression data analysis, indicating higher DDAH1 expression level in tumors than normal tissue in colonic and rectal adenocarcinomas [ 37 ]. Still, in line with the cancer-promoting activities attributed to DDAH1 [ 40 , 41 , 42 , 43 ] and DDAH2 [ 44 ], the expression ratio (tumor-to-adjacent) of DDAH2 tended to increase with cancer advancement, reflecting lymph node involvement.…”

“…Accordingly, local expression of NOS2 is upregulated in inflammatory bowel conditions [ 6 ] and linked with increased risk of CRC development [ 35 ]. The NO is also implicated in the promotion of angiogenesis and therefore in aiding cancer cell dissemination [ 37 ]. In this respect, targeting NOS2 may be considered beneficial in both chemopreventive and antiangiogenic capacity.…”

“…On the other hand, it interferes with vascular endothelial growth factor (VEGF)-induced angiogenesis. Consequently, targeting DDAH1, its key degrading enzyme, is viewed as an antiangiogenic strategy (reviewed in [ 37 ]). However, our analysis of clinical samples showed the downregulation of DDAH1 and DDAH2 in colonic tumors.…”

Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings

“…DDAH2, in turn, has been implicated in angiogenesis in lung adenocarcinoma [50]. Illogically, however, HIF1A displayed a weak but negative association with DDAH1 in multivariate analysis, an observation that requires further investigation, especially because targeting DDAHs has only recently been proposed as a novel antiangiogenic strategy in cancer [46]. In the present study, in multivariate analysis, FGF2 was negatively or positively associated with, respectively, DDAH1 and DDAH2 expression.…”

“…Similarly, in the colon, there was a switch from the correlation with DDAH1 in inflamed tissue to DDAH2 in quiescent one. DDAH1 is the primary enzyme in ADMA catabolism and there is some uncertainty concerning metabolic activity and the role of DDAH2 [46]. As DDAH enzymes are known mostly as ADMA-metabolizing enzymes and ADMA is primarily implicated in the pathogenesis of cardiovascular diseases [47], little, if not nothing, is known on DDAHs in IBD.…”