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ORIGINAL RESEARCH ARTICLE

DA-6034, a Derivative of Flavonoid, Prevents and Ameliorates Dextran Sulfate Sodium–Induced Colitis and Inhibits Colon Carcinogenesis

Su Youn Nam^*, Joo Sung Kim^,1, Jung Mogg Kim, Jong Yeul Lee^*, Nayoung Kim, Hyun Chae Jung and In Sung Song

^* Center for Cancer Prevention and Detection, National Cancer Center, Goyang, Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; and Department of Microbiology and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Korea

To whom requests for reprints should be addressed at ¹ Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110–744, Korea. E-mail: jooskim{at}snu.ac.kr

Previously, we have shown that DA-6034, a synthetic derivative of flavonoid eupatilin, inhibited NF-B activation in colon epithelial cells and prevented trinitrobenzene sulfonic acid–induced rat colitis. The aim of this study was to investigate the preventive and therapeutic effect of DA-6034 on dextran sulfate sodium (DSS)–induced colitis and on inflammation-related cancer. C57BL/6 mice were given 4% DSS for 5 days with and without DA-6034 in the acute preventive model. In the acute therapeutic model, mice were given 4% DSS for 5 days followed by rectal administration of DA-6034. Colitis was quantified by body weight, disease activity index (DAI), colon length, and histology. In the inflammation-related cancer model, mice were given a single intraperitoneal injection of azoxymethane, then three cycles of 2% DSS for 5 days, then 2 weeks of free water consumption. Apoptosis was determined by in situ terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay, and the expression of Ki-67, phospho-B kinase (IKK), and COX-2 were evaluated by immunohistochemistry. In both the acute preventive and acute therapeutic models, DA-6034 significantly attenuated DSS-induced weight loss, an increase in DAI, and a shortening of colon length. DA-6034–treated mice maintained crypt architecture and revealed a scanty infiltration of inflammatory cells in both the preventive and therapeutic models. In the inflammation-related cancer model, DA-6034 reduced the number of colon tumors and ameliorated weight loss and shortening of colon length. DA-6034 strongly enhanced apoptosis and inhibited the expression of COX-2 and phospho-IKK in inflammation-related colon cancer models. Our results suggest that DA-6034 prevents acute murine colitis and inhibits inflammation-related colon carcinogenesis. DA-6034 could be a potential therapeutic agent for inflammatory bowel disease.

Key Words: DA-6034 • inflammatory bowel disease • colon cancer