title: Inhibition of intestinal adenoma formation in APC(Min/+) mice by Riccardin D, a natural product derived from liverwort plant Dumortiera hirsuta.
abstract: BACKGROUND
  Mutation 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 APC(Min/+) mice.
  
  
  METHODS
  APC(Min/+) mice were given Riccardin D by p.o. gavage for 7 weeks. 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.
  
  
  RESULTS
  Riccardin D treatment resulted in a significant inhibition of intestinal adenoma formation, showing a reduction of polyp number by 41.7%, 31.1% and 44.4%, 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 by 79.3%. Size distribution analysis revealed a significant reduction in large-size polyps (2-3 mm) by 40.0%, 42.5% and 33.3%, respectively, in proximal, middle and distal portions of small intestine, and 77.8% 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.
  
  
  CONCLUSIONS
  Our results suggested that Riccardin D exerts its chemopreventive effect against intestinal adenoma formation through multiple mechanisms including anti-proliferative, apoptotic, anti-angiogenic and anti-inflammatory activity.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Liu
authors.forename: Zu-Hua
authors.initials: ZH
authors.lastname: Gao
authors.forename: Shu-Xiang
authors.initials: SX
authors.lastname: Cui
authors.forename: De-Fu
authors.initials: DF
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Cui-Rong
authors.initials: CR
authors.lastname: Zhao
authors.forename: Hong-Xiang
authors.initials: HX
authors.lastname: Lou
authors.forename: Xian-Jun
authors.initials: XJ
authors.lastname: Qu
mesh_terms: D000236:Adenoma / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D035926:Hepatophyta / Q000737:chemistry*; D007249:Inflammation / Q000473:pathology; D007414:Intestinal Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D007417:Intestinal Polyps / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011230:Precancerous Conditions / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D001688:Biological Products; D016328:NF-kappa B; D010647:Phenyl Ethers; D013267:Stilbenes; D051176:beta Catenin; C547185:riccardin D; D019938:Cyclin D1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020169:Caspases