Ulcerative colitis is a dynamic, idiopathic, chronic inflammatory condition that carries a high colon cancer risk. We previously showed that Cl-amidine, a small molecule inhibitor of the protein arginine deiminases (PADs), suppresses colitis in mice. Since colitis is defined as inflammation of the colon associated with infiltration of white blood cells that release free radicals, and citrullination is an inflammation-dependent process, we asked whether Cl-amidine has anti-oxidant properties. Here, we show that colitis, induced with azoxymethane (AOM) via intraperitoneal injection + 2% dextran sulfate sodium (DSS) in the drinking water, is suppressed by Cl-amidine (also given in the drinking water). iNOS, an inflammatory marker, was also down-regulated in macrophages by Cl-amidine. Since epithelial cell DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes, we tested the hypothesis that Cl-amidine can inhibit leukocyte activation, as well as subsequent target epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis, and since DNA damage is a pro-cancerous mechanism, our data predicts that Cl-amidine will not only suppress colitis, but we hypothesize that it may prevent colon cancer associated with colitis.
- The American Society for Pharmacology and Experimental Therapeutics