title: Prevention of colitis-associated colorectal cancer with 8-hydroxydeoxyguanosine.
abstract: 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 antioxidative agent offers the chance of cancer prevention. Supported with the facts that Rac1 binds and activates STAT3, which are significantly upregulated in inflammatory bowel disease (IBD) as well as CAC, but 8-hydroxydeoxyguanosine (8-oxo-7,8-dihydrodeoxyguanosine or 8-OHdG) paradoxically can block Rac1 activation and subsequent NADPH oxidase (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 interleukin (IL)-10 knockout 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. 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-containing diets were given for 20 weeks. As results, mice that consumed 8-OHdG-containing diet significantly reduced both tumor incidence and multiplicity. Rac1 activity and phosphorylated STAT3 level were significantly attenuated in the 8-OHdG-treated group. Significantly decreased levels of malondialdehyde, monocyte chemotactic protein-1, matrix metalloproteinasess, 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.
authors: Laboratory of Translational Medicine, Gachon University Lee Gil Ya Cancer and Diabetes Institute, Republic of Korea. hahmkb@gachon.ac.kr
authors: Chan Young
authors: CY
authors: Ock
authors: Eun-Hee
authors: EH
authors: Kim
authors: Hua
authors: H
authors: Hong
authors: Kyung Sook
authors: KS
authors: Hong
authors: Young-Min
authors: YM
authors: Han
authors: Ki-Seok
authors: KS
authors: Choi
authors: Ki-Baik
authors: KB
authors: Hahm
authors: Myung-Hee
authors: MH
authors: Chung
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane / Q000494:pharmacology; D003092:Colitis / Q000150:complications*; D015179:Colorectal Neoplasms / Q000150:complications* / Q000517:prevention & control*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003911:Dextrans / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007249:Inflammation; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013431:Sulfates / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; D003911:Dextrans; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013431:Sulfates; C012036:sodium sulfate; D016753:Interleukin-10; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D001397:Azoxymethane