Prevention of colitis‐associated carcinogenesis in a mouse model by diet supplementation with ursodeoxycholic acid

Abstract

Bile acids in the intestinal lumen contribute to the homeostatic regulation of proliferation and death of the colonic epithelial cells: Deoxycholic acid (DCA) appears to enhance and ursodeoxycholic acid (UDCA) to attenuate the process of chemically induced carcinogenesis. We studied the effects of UDCA on colitis-related colorectal carcinogenesis. Three groups of 25 mice were given 0.7% dextran sulphate in drinking water for 7 days and pure water for 10 days and were fed a standard diet containing double iron concentration. In 2 groups, the diet was supplemented with 0.2% cholic acid (CA), the precursor of DCA, or with 0.4% UDCA. After 15 cycles, the histology, the expression of MUC2, b-catenin, p27 and p16 and the fecal water concentration of DCA and UDCA were investigated. All animals showed colitis with similar severity and histologic as well as immunophenotypic alterations, resembling those of human colitis. Among the animals fed the nonsupplemented diet, 46% developed colorectal adenocarcinomas and 54% anal-rectal squamous cell carcinomas. The prevalence of dysplasia and carcinomas did not change significantly in the animals given CA. Among the mice fed with UDCA, none developed adenocarcinomas and 20% squamous carcinomas. Dysplastic lesions were found in 88%, 67% and 40% of each group, respectively. The prevalence of dysplasia as well as of carcinoma showed an inverse relationship to the UDCA concentration in the fecal water. These data indicate that UDCA suppresses colitis-associated carcinogenesis. This model is suitable for investigation of the mechanism of the anticarcinogenic effect of UDCA in vivo. ' 2005 Wiley-Liss, Inc.Key words: murine colitis; colon carcinogenesis; DSS colitis; ursodeoxycholic acid Ulcerative colitis (UC) in patients and in experimental animals is associated with a high risk of intraepithelial neoplasia and colonic carcinoma. The cumulative risk for colorectal cancer in a patient with UC is 2% at 10 years, 8% at 20 years and 18% at 30 years of disease duration. 1 Since the occurrence of dysplasia can be a strong indication for prophylactic proctocolectomy, 2 the inhibition or slowing down of the colitis-associated carcinogenesis would essentially reduce the number of necessary operations.Factors contributing to colon carcinogenesis are high epithelial proliferation rate in the inflamed region and the resulting increased accumulation of mutations as well as the disturbed regulation of cell death and proliferation. Intestinal bile acids contribute to the homeostatic regulation of proliferation and apoptosis of the colonic epithelium. Deoxycholic acid (DCA), whose fecal water concentration in patients with colitis is increased, 3 stimulates the proliferation of the colonic epithelial cells 4 and promotes colon carcinogenesis in an azoxymethane (AOM) rat model. 5 The addition of ursodeoxycholic acid (UDCA) to the diet decreases the prevalence of AOM-induced rat colonic tumors 6 as well as the prevalence of tumors in MIN mice. 7 These data indicate that DCA enhances the chemical colo...

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

“…24,25 In addition, UDCA reduces carcinogenesis in several pre-malignant conditions of liver and colon in a rodent model. [26][27][28][29] Furthermore, recurrence of colorectal adenomas with highgrade dysplasia in a phase III trial was shown to be decreased after treatment with UDCA. 30 Although the tumor suppressive activity of UDCA is believed to be linked to the induction of apoptosis and cell cycle arrest, and the inhibition of oncogenic factors including Ras and COX-2, in human cancer cell lines, [31][32][33] these mechanisms are not yet fully understood.…”

A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-κB-dependent manner

“…Separately, it is well established that inflammatory disorders, such as ulcerative colitis, may also lead to colon cancer in the long run (18). Interestingly, the chronic model of DSS-induced colitis can eventually result in colon carcinogenesis, with animals exhibiting intestinal neoplasia similar to that seen in human disease (38). Thus it is not surprising that this preclinical model of colitis has been extensively utilized for studying the pathophysiological mechanisms of disease and assessing the efficacy of potential treatments for ulcerative colitis (16,57).…”

Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells

“…UDCA feeding resulted in a highly significant inhibition of colorectal cancer and adenoma formation in the azoxymethane rat model (Earnest et al, 1994). UDCA supplementation suppressed colitisassociated carcinogenesis in a dextran sulphate sodium mouse model (Loddenkemper et al, 2006). In a rodent model of cholestasis, the administration of 24-norUrsodeoxycholic acid (norUDCA) to Mdr2 knockout mice improved sclerosing cholangitis (Fickert et al, 2006).…”