Abstract
Histamine and histamine receptors (Hrhs) have been identified as critical molecules during inflammation and carcinogenesis. This study was conducted to determine the effects of Hrh1-Hrh3 antagonists on inflammation-associated colorectal carcinogenesis. Male ICR mice were treated with azoxymethane (AOM, 10 mg/kg bw, i.p.) and 1.5% dextran sodium sulfate (DSS, drinking water for 7 days) to induce colorectal carcinogenesis. The mice were then fed diets containing test chemical (500 ppm terfenadine, 500 ppm cimetidine or 10 ppm clobenpropit) for 15 weeks. At week 18, feeding with the diets containing cimetidine (Hrh2 antagonist) and clobenpropit (Hrh3 antagonist/inverse agonist) significantly lowered the multiplicity of colonic adenocarcinoma. Terfenadine (Hrh1 antagonist) did not affect AOM-DSS-induced colorectal carcinogenesis. Adenocarcinoma cells immunohistochemically expressed Hrh1, Hrh2, Hrh3 and Hrh4 with varied intensities. Because clobenpropit is also known to be a Hrh4 receptor agonist, Hrh2, Hrh3 and Hrh4 may be involved in inflammation-related colorectal carcinogenesis. Additional data, including the mRNA expression of pro-inflammatory cytokines and inducible inflammatory enzymes in the colonic mucosa, are also presented.
Highlights
A strong association between inflammation and cancer in several tissues has been suggested [1,2].Patients with inflammatory bowel disease (IBD), especially ulcerative colitis (UC) and Crohn’s disease (CD), have a significantly increased risk of developing premalignant lesions and malignancy in the colorectum [3]
We have developed a novel animal model, azoxymethane (AOM)/dextran sodium sulfate (DSS) murine model of colitis-related colorectal carcinogenesis [9]
We investigated the effects of three antagonists of Hrh1, Hrh2 and Hrh3 on the derivatives of reactive oxygen metabolites (d-ROMs) [35], as an index of products of reactive oxygen species (ROS), and biological antioxidant potential (BAP) [36], as a biomarker of antioxidant potential
Summary
A strong association between inflammation and cancer in several tissues has been suggested [1,2].Patients with inflammatory bowel disease (IBD), especially ulcerative colitis (UC) and Crohn’s disease (CD), have a significantly increased risk of developing premalignant lesions (dysplasia) and malignancy (adenocarcinoma, ADC) in the colorectum [3]. It is necessary to investigate the precise mechanisms of CRC development in the inflamed colon to establish preventive strategies, such as chemoprevention [8]. For this purpose, we have developed a novel animal model, azoxymethane (AOM)/dextran sodium sulfate (DSS) murine model of colitis-related colorectal carcinogenesis [9]. We have developed a novel animal model, azoxymethane (AOM)/dextran sodium sulfate (DSS) murine model of colitis-related colorectal carcinogenesis [9] Using this model [9], we previously demonstrated that the chemopreventive efficacy of ursodeoxycholic acid (UDCA) is superior to that of 5-ASA [10]
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