| Backgrounds:Colorectal cancer (CRC) is one of the most common forms of cancer and forth most common cause of cancer mortality worldwide with an increase rate of fatality. The initiation and development of CRC include many stages, namely aberrant crypt foci, polyps, adenomas, and carcinomas. The epidemiology of adenomas closely resembles that of colorectal cancer itself, so prevention of adenomas will most likely also prevent colorectal cancer. Accumulation of mutations in oncogenes and tumor suppressor genes typically occur during these stages. Mutation of Adenomatous Polyposis Coli (APC) usually occurs early during the progression of colorectal cancer. The role of the APC protein in the initiation and progression of colon cancer has been extensively studied. The APCMin/+mice remains one of the most promising genetically engineered mouse model for the study of familial adenomatous polyposis (FAP).This kind of mice, with an average lifespan of120days, develops approximately30intestinal polyps in its lifespan, and thus mimics the rapid development of adenomatous polyps. Large body of epidemiological evidence shows that treatment with nonsteroidal anti-inflammatory drugs (NSAID) reduces the risk of developing colorectal cancer. The most commonly used NSAID has been aspirin, which has been reported to reduce the risk of colon cancer by up to40%. However, long-term use of aspirin can lead to some side-effects, which cannot be ignored. The most common side-effect is gastrointestinal bleeding. Besides, data on the risk-benefit profile for cancer prevention are insufficient to recommend definitive dosage and time. AKBA (acetyl-11-keto-β-BA) is one of the active ingredients derived from Boswellia serrata. AKBA has been used for centuries for a wide variety of inflammatory diseases, including inflammatory bowel disease. The anti cancer activity of AKBA has attracted general attention in recent years. In this study, we aimed to evaluate AKBA and aspirin in the prevention of intestinal adenomatous polyposis in APCMin/+mice. Methods:APCMin/+mice were given aspirin or AKAB by p.o. gavage for7weeks. Mice were sacrificed, and the number, size and of intestinal polyps were examined and compared among three groups. In vivo experiments, the TUNEL assay was used to evaluate the efficacy of apoptosis induction in adenomatous polyps of aspirin and AKBA. Immunohistochemical staining assay was performed to examine the expression levels of β-catenin, cyclinD1, COX-2and5-Lox in intestinal polyps. Western blotting analysis was employed to determine the regulation of proliferation and apoptosis related proteins, Wnt signaling pathway and inflammatory mediators in polyps.Results:Both AKBA and aspirin can inhibit the initiation and development of adenomatous polyps of APCMin/+mice. Compared with control group, the numbers of polyps were strongly decreased by45.7%in small intestines and78.7%in colons in AKBA treated group. Aspirin reduced the polyp numbers by27.6%in small intestines and20.4%in colons in contrast. Size analysis revealed that AKBA significantly reduced the numbers of large polyps (2-3mm in small intestine and>3mm in colon) by52.5%in small intestines and84.5%in colons. Molecular analysis of polyps suggested that AKBA and aspirin are of the abilities of antiproliferation, induction of apoptosis and suppression of inflammatory mediators. Besides, AKBA significantly modulates the Wnt signaling pathway.Conclusion:Our results suggested that both AKBA and aspirin can prevent the formation of polyps in APCMin/+mice, but AKBA exerted much better preventive effects than aspirin and it is statistically significant. This may attributed to its more prominent abilities of antiproliferation, induction of apoptosis and suppression of inflammatory mediators. Besides, AKBA can dramatically suppress the aberrant activity of Wnt signaling pathway. |
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