Abstract 2274: Effect of myeloperoxidase inhibitor resorcinol on colon tumorigenesis in APCmin/+ mice

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Beneficial actions of non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer progression are well accepted. Nevertheless, NSAIDs have had only a minor impact in primary or secondary prevention - even in high risk populations - for at least two reasons. First, NSAIDs are contra-indicated in some high risk conditions, such as colitis-associated colorectal cancer, because of their corrosive actions in the gut. Second, publicity about the cardiovascular safety of NSAIDs has thwarted their potential in primary or secondary prevention of sporadic polyps. Thus, we sought to identify molecular targets and agents that might work in these situations. Myeloperoxidase (MPOx) from neutrophils is distantly related to the cyclooxygenase (COX) enzymes. MPOx and its relative, eosinophil peroxidase (EPOx) constitute part of the innate immune process in the normal gut, and the pathology of colitis. Hypochlorite generated by MPOx oxidizes amino acids (serine, threonine) and polyunsaturated fatty acids (arachidonic acid). Several of these oxidative by-products generated by MPOx - hypochlorite are non-prostaglandin E2 (PGE2) mediators that enhance β-catenin signaling. Thus, we hypothesized that MPOx and its by-products may promote intestinal malignancy, comparable to the actions of COX and PGE2. Using APCmin/+ mice we tested the effect of resorcinol, an irreversible MPOx inhibitor, under two experimental conditions: 1) colorectal and intestinal tumor promotion accompanying inflammation induced with dextran sodium sulfate (DSS); and 2) tumor formation in the normal intestine, without colitis, but with basal “inflammation” (para-inflamation) due to commensal bacteria in the gut. For APCmin/+ mice with DSS induced inflammation, 1.25mg/kg intraperitoneal (IP) resorcinol caused a 30% reduction in colorectal adenoma numbers, and a 40% reduction in average adenoma size (p<0.05). Small intestinal polyp numbers were also reduced by 20%. Surprisingly, in APCmin/+ mice without DSS-induced colitis, but with basal “inflammation” of the normal gut, resorcinol 1.25mg/kg IP caused a modest, but detectable increase in adenoma formation. To reconcile these results we hypothesize that anti-inflammatory effects dominate the high intensity inflammation in the DSS colitis-APCmin/+ mouse, and manifest as reduced colitis-associated tumor formation. Conversely, we hypothesize that anti-inflammatory action in the lesser basal “inflammation” of normal APCmin/+ mice suppresses innate immune surveillance and elimination processes, which spares aberrant crypt foci. Alternatively, oxidation of resorcinol in the gut of normal APCmin/+ mice may be generating tumor promoting quinine metabolites. We are breeding an MPOx null-APCmin/+ mouse to help distinguish between these two alternatives. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2274.