Colitis-associated cancer (CAC) is one of clear examples of inflammation-carcinogenesis sequence, by which the strict control of colitis with potent anti-inflammatory or anti-oxidative agent offers the chance of cancer prevention. Supported with the facts that Rac1 binds and activates STAT3 which are significantly up-regulated in inflammatory bowel disease (IBD) as well as CAC, but 8-hydroxydeoxyguanosine (8-OHdG) paradoxically can block Rac1 activation and subsequent NOX inactivation in various inflammation models, we hypothesized that attenuated Rac1-STAT3 and COX-NF-κB pathway by exogenous 8-OHdG administration may ameliorate inflammatory signaling in dextran sodium sulfate (DSS) induced colitis and can prevent CAC. Before commencing carcinogenesis model, we checked whether exogenous 8-OHdG can alleviate IBD, for which IL-10 knock-out mice were designed to ingest 5% DSS for 1 week, and 8-OHdG is given through intraperitoneal route daily. 8-OHdG treatment groups significantly reduced pathologic grade of DSS-induced colitis as well as various inflammatory mediators such as TNF-α, IL-6, COX-2 and iNOS in a dose-dependent manner. In order to document the cancer prevention effects of 8-OHdG, mice were injected azoxymethane followed by drinking 2.5% DSS for 1 week, after which 8-OHdG-contained diets were given for 20 weeks. As results, mice which consumed 8-OHdG-contained-diet significantly reduced both tumor incidence and multiplicity. Rac1 activity and phosphorylated STAT3 level were significantly attenuated in 8-OHdG treated group. Significantly decreased levels of MDA, MCP-1, MMPs, COX-2, NOX4, and β-catenin nuclear accumulation were responsible for cancer prevention effects of exogenous 8-OHdG. In conclusion, we clearly showed cancer preventive effect of exogenous 8-OHdG against CAC.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B49.