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Effects of Genetic and Pharmacologic Inhibition of COX-2 on Colitis-associated Carcinogenesis in Mice

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Authors
Lee, Jeong-Sang; Kim, Hyun Soo; Hahm, Ki Baik; Surh, Young-Joon
Issue Date
2020-03
Citation
대한암예방학회지, Vol.25 No.1, pp.27-37
Keywords
ChemopreventionCelecoxibColitisColon cancerCOX-2
Abstract
COX-2 has been inappropriately overexpressed in various human malignancies, and is considered as one of the representative targets for the chemoprevention of inflammation-associated cancer. In order to assess the role of COX-2 in colitis-induced carcinogenesis, the selective COX-2 inhibitor celecoxib and COX-2 null mice were exploited in an azoxymethane (AOM)-initiated and dextran sulfate sodium (DSS)-promoted murine colon carcinogenesis model. The administration of 2% DSS in drinking water for 1 week after a single intraperitoneal injection of AOM produced colorectal adenomas in 83% of mice, whereas only 27% of mice given AOM alone developed tumors. Oral administration of celecoxib significantly lowered the incidence as well as the multiplicity of colon tumors. The expression of COX-2 and inducible nitric oxide synthase (iNOS) was upregulated in the colon tissues of mice treated with AOM and DSS, and this was inhibited by celecoxib administration. Likewise, celecoxib treatment abrogated the DNA binding of NF-kappa B, a key transcription factor responsible for regulating expression of aforementioned pro-inflammatory enzymes, which was associated with suppression of I kappa B alpha degradation. In the COX-2 null (COX-2(-/-)) mice, there was about 30% reduction in the incidence of colon tumors, and the tumor multiplicity was also markedly reduced (7.7 +/- 2.5 vs. 2.43 +/- 1.4, P < 0.01). As both pharmacologic inhibition and genetic ablation of COX- 2 gene could not completely suppress colon tumor formation following treatment with AOM and DSS, it is speculated that other pro-inflammatory mediators, including COX-1 and iNOS, should be additionally targeted to prevent inflammation-associated colon carcinogenesis.
ISSN
2288-3649
URI
https://hdl.handle.net/10371/172925
DOI
https://doi.org/10.15430/JCP.2020.25.1.27
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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