Abstract
Inflammatory bowel disease (IBD) patients have an increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Several studies have shown that IBD patients have signs of increased oxidative damage, which could be a result of genetic and environmental factors such as an excess in oxidant molecules released during chronic inflammation, mitochondrial dysfunction, a failure in antioxidant capacity, or oxidant promoting diets. It has been suggested that chronic oxidative environment in the intestine leads to the DNA lesions that precipitate colon carcinogenesis in IBD patients. Indeed, several preclinical and clinical studies show that different endogenous and exogenous antioxidant molecules are effective at reducing oxidation in the intestine. However, most clinical studies have focused on the short-term effects of antioxidants in IBD patients but not in CAC. This review article examines the role of oxidative DNA damage as a possible precipitating event in CAC in the context of chronic intestinal inflammation and the potential role of exogenous antioxidants to prevent these cancers.
Highlights
NAC as combination therapy with mesalamine resulted in clinical improvement in ulcerative colitis (UC) patients
Intake of Vitamin C (vitC) was negatively associated to UC risk
Positive response only in nonsmoker subjects; an antioxidant micronutrient cocktail decreased the level of oxidants and inflammation only in nonsmokers
Summary
Preclinical studies suggest a role for oxidative molecules in the pathophysiology of colitis-associated cancer. Ectopic expression of GSTTT1 1 in DSS-treated mice attenuated colitis severity via interleukin 22–dependent restoration of epithelial cell functions.[17] Similar to glutathione, supplementing another thiol-containing endogenous antioxidant alpha-lipoic acid reduced colitis and ileitis in animal models.[66,67] Melatonin is another nonenzymatic compound recognized to have enteroprotective activity through its antioxidant and anti-inflammatory action.[68] Exogenous administration of melatonin in experimental colitis models improved the disease pathology by reducing inflammation and epithelial damage.[69,70,71] Melatonin reduced the levels of oxidative DNA damage in colonic mucosa of IBD patients[72]; the effects on CAC were not evaluated These studies suggest the therapeutic potential of endogenous antioxidants in IBD.
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