Chemoprevetive Effects Of Natural Compound Riccardin D And AKBA On Intestinal Adenoma Formation In APC^Min+Mice

Part I Chemopreventive effects of natural compound Riccardin D on intestinal adenoma formation in APCMin+miceBackgroundsMutation of tumor suppressor gene, adenomatous polyposis coli (APC), is the primary molecular event in the development of most intestinal carcinomas. Animal model with APC gene mutation is an effective tool for study of preventive approaches against intestinal carcinomas. We aimed to evaluate the effect of Riccardin D, a macrocyclic bisbibenzyl compound, as a chemopreventive agent against intestinal adenoma formation in APCMin+mice.METHODSAPCMin+mice were given Riccardin D by p.o. gavage for7weeks. Mice were sacrificed, and the number, size and histopathology of intestinal polyps were examined under a microscope. We performed immunohistochemical staining, Western blotting, reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) in intestinal polyps to investigate the mechanism of chemopreventive effect of Riccardin D.RESULTSRiccardin D treatment resulted in a significant inhibition of intestinal adenoma formation, showing a reduction of polyp number by41.7%,31.1%and44.4%, respectively, in proximal, middle and distal portions of small intestine. The activity of Riccardin D against polyp formation was more profound in colon, wherein Riccardin D decreased polyp number by79.3%. Size distribution analysis revealed a significant reduction in large-size polyps (2-3mm) by40.0%,42.5%and33.3%, respectively, in proximal, middle and distal portions of small intestine, and77.8%in colon. Histopathological analysis of the intestinal polyps revealed mostly hyperplastic morphology without obvious dysplasia in Riccardin D-treated mice. Molecular analyses of the polyps suggested that the inhibitory effect of Riccardin D on intestinal adenoma formation was associated with its abilities of reduction in cell proliferation, induction of apoptosis, antiangiogenesis, inhibition of the Wnt signaling pathway and suppression of inflammatory mediators in polyps.CONCLUSIONSOur results suggested that Riccardin D exerts its chemopreventive effect against intestinal adenoma formation through a collective mechanism including anti-proliferative, apoptotic, anti-angiogenic and anti-inflammatory processes.Part II Chemopreventive effects of Acetyl-11-keto-beta-boswellicacid (AKBA) on intestinal adenoma formation in APCMin+miceBackgroundsAcetyl-11-keto-beta-boswellicacid (AKBA) is the derivative of boswellic acids that are the effective components of gum resin of Boswellia serrata. AKBA has been used as an adjuvant medicine for treatment of inflammatory diseases. We aimed to evaluate the efficacy of AKBA as a chemopreventive agent against intestinal adenoma in APCMin+mouse model.METHODSAPCMin+mice were given AKBA by p.o. gavage for8weeks. Mice were sacrificed, and the number, size and histopathology of intestinal polyps were examined under a microscope. We performed immunohistochemical staining, Western blotting and enzyme-linked immunosorbent assay (ELISA) in intestinal polyps to investigate the mechanism of chemoprevention of AKBA.RESULTSAKBA treatment resulted in inhibition of intestinal adenomas, showing a reduction of polyp number, size and appearance. The number of polyps were significantly decreased by48.9%(p<0.001) and60.4%(p=0.005), respectively, in small intestine and colon in AKBA-treated mice The inhibitory effect of AKBA was more profound in colonic polyps’ number and appearance, wherein it obviously arrested the growth to larger-size polyps. The molecular analysis of polyps suggested that these effects of AKBA were associated with the inhibition in cell proliferation, apoptosis, angiogenesis and Wnt signaling pathway in intestinal adenoma. AKBA strongly reduced polyps with potent inhibition of inflammatory mediators, suggesting that AKBA might exert its chemopreventive activity through the mechanism of anti-inflammation.CONCLUSIONSTogether, our results indicated that this naturally occurring food component is a safer and effective chemopreventive agent against intestinal cancers derived from APC gene mutation.