DA-6034, a derivative of flavonoid, prevents and ameliorates dextran sulfate sodium-induced colitis and inhibits colon carcinogenesis.
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.
Nam
Su Youn
SY
Center for Cancer Prevention and Detection, National Cancer Center, Goyang, Korea.
Kim
Joo Sung
JS
Kim
Jung Mogg
JM
Lee
Jong Yeul
JY
Kim
Nayoung
N
Jung
Hyun Chae
HC
Song
In Sung
IS
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
D005419:Flavonoids; D019394:Ki-67 Antigen; D016264:Dextran Sulfate; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; C121889:recoflavone