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

SIMPLE SUMMARY: Nitric oxide and arginine metabolism in colorectal cancer (CRC) holds potential for therapeutic intervention. We hypothesized that it can be modulated by oxicams, a class of non-steroidal anti-inflammatory drugs with documented chemopreventive and antineoplastic activity. The aim of this study was to determine the transcriptional patterns of pathway enzymes in CRC and evaluate the impact of classic and new oxicam analogues. Arginine metabolic pathways were altered not only in tumors but also in non-transformed mucosa from tumor vicinity, contributing to the phenomenon of tumor molecular margin. Classic oxicams, piroxicam and meloxicam, had negligible impact but their new analogues downregulated expression of dimethylarginine dimethylaminohydrolases and protein methyltransferases and upregulated asymmetric dimethylarginine. Those beneficial effects were accompanied by upregulation of arginase-2 and the potentially disadvantageous accumulation of arginine and symmetric dimethylarginine. Our findings provide novel insight into metabolic reprogramming in CRC and demonstrate that oxicam analogues are worth further consideration as novel anticancer agents. ABSTRACT: L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine’s and piperazine’s nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.