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

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, , and were overexpressed in both tumor and tumor-adjacent tissue and solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of , , and and lower than patients-matched tumors. The 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 and and upregulating 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 and expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of expression. Metabolic reprogramming in CRC includes overexpression of and in addition to and and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.