title: DA-6034, a derivative of flavonoid, prevents and ameliorates dextran sulfate sodium-induced colitis and inhibits colon carcinogenesis.
abstract: Previously, we have shown that DA-6034, a synthetic derivative of flavonoid eupatilin, inhibited NF-kappaB 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-kappaB kinase alpha (IKKalpha), 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-IKKalpha 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.
authors.affiliation: Center for Cancer Prevention and Detection, National Cancer Center, Goyang, Korea.
authors.forename: Su Youn
authors.initials: SY
authors.lastname: Nam
authors.forename: Joo Sung
authors.initials: JS
authors.lastname: Kim
authors.forename: Jung Mogg
authors.initials: JM
authors.lastname: Kim
authors.forename: Jong Yeul
authors.initials: JY
authors.lastname: Lee
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.forename: Hyun Chae
authors.initials: HC
authors.lastname: Jung
authors.forename: In Sung
authors.initials: IS
authors.lastname: Song
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D003092:Colitis / Q000139:chemically induced* / Q000150:complications / Q000201:enzymology / Q000517:prevention & control*; D003110:Colonic Neoplasms / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology*; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D005419:Flavonoids; D019394:Ki-67 Antigen; D016264:Dextran Sulfate; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; C121889:recoflavone