J Cancer Prev.  2020 Mar;25(1):27-37. 10.15430/JCP.2020.25.1.27.

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

Affiliations
  • 1Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Korea
  • 2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
  • 3CHA Cancer Prevention Research Center, CHA Bio Complex, Korea
  • 4Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Korea

Abstract

COX-2 has been inappropriately overexpressed in various human malignancies, and is considered as one of the representative targetsfor 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 dextransulfate sodium (DSS)-promoted murine colon carcinogenesis model. The administration of 2% DSS in drinking water for 1 week aftera single intraperitoneal injection of AOM produced colorectal adenomas in 83% of mice, whereas only 27% of mice given AOM alonedeveloped tumors. Oral administration of celecoxib significantly lowered the incidence as well as the multiplicity of colon tumors. Theexpression of COX-2 and inducible nitric oxide synthase (iNOS) was upregulated in the colon tissues of mice treated with AOM andDSS, and this was inhibited by celecoxib administration. Likewise, celecoxib treatment abrogated the DNA binding of NF-κB, a keytranscription factor responsible for regulating expression of aforementioned pro-inflammatory enzymes, which was associated withsuppression of IκBα 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 andgenetic ablation of COX-2 gene could not completely suppress colon tumor formation following treatment with AOM and DSS, it isspeculated that other pro-inflammatory mediators, including COX-1 and iNOS, should be additionally targeted to prevent inflammation-associated colon carcinogenesis.

Keyword

Chemoprevention; Celecoxib; Colitis; Colon cancer; COX-2
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