stilbenes and Intestinal-Neoplasms

Evidence suggests that the dietary consumption of plant extracts containing polyphenols might help prevent the onset of cancers of the gastrointestinal tract. In the present study, the chemopreventive and antiproliferative efficacy of a grapevine shoot extract (Vineatrol®30) containing resveratrol and resveratrol oligomers is investigated in vivo and in vitro.. The in vivo study is performed using Apc. Vineatrol®30 may merit further investigation as a potential dietary gastrointestinal cancer chemopreventive agent in humans.

Topics: Adenoma; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Caspases; Cell Proliferation; Female; Intestinal Neoplasms; Male; Mice, Mutant Strains; Phenols; Resveratrol; Stilbenes

Trans-resveratrol (RV) is an active polyphenol with numerous physiological properties including antitumour activity, especially in colon cancer. RV is metabolized in the intestine and then in the liver to sulphated and glucuronidated forms that are exported to target organs. After exerting their effects, they are eliminated in the urine and stools. There are few and contradictory findings on the biological effects of RV metabolites. On the basis of RV metabolism, we selected three metabolites RV 3-O-sulphate, RV 3-O-glucuronide and RV 4'-O-glucuronide, and studied their effects on cell growth inhibition, the cell cycle and apoptosis using human adenocarcinoma cell line (Caco-2 cell) cultures. Our results show that RV metabolites have an antioxidant activity similar to that RV. Moreover, all metabolites inhibited cell growth in a concentration-dependent manner as well as [(3)H] thymidine incorporation. Furthermore, we observed an increase in the percentage of cell in G0/G1 phase induced by RV metabolite treatments, as well as the induction of apoptosis. On the basis of our results we propose, for the first time, that RV metabolites remain active after their biosynthesis, contributing to the health benefits attributed previously only to RV. These metabolites are a potential target for more research into the prevention and treatment of colon cancer.

Topics: Adenocarcinoma; Antioxidants; Apoptosis; Cell Cycle; Cell Proliferation; Humans; Intestinal Neoplasms; Resveratrol; Stilbenes; Tumor Cells, Cultured

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.. 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.. 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.. 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.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Apoptosis; beta Catenin; Biological Products; Caspases; Cell Proliferation; Colon; Cyclin D1; Cyclooxygenase 2; Hepatophyta; Inflammation; Intestinal Neoplasms; Intestinal Polyps; Intestine, Small; Mice; Neovascularization, Pathologic; NF-kappa B; Phenyl Ethers; Precancerous Conditions; Signal Transduction; Stilbenes

To shed light on the association of lipid peroxidation and antioxidant status with the development of aberrant crypt foci (ACF), we studied the modulatory influence of resveratrol, supplemented in three dietary regimens (initiation, post-initiation and entire period) on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Rats were administered DMH (20 mg/kg body weight, s.c.) for 15 weeks and were supplemented with resveratrol (8 mg/kg body weight, p.o. everyday) in three dietary regimens. Intestines and colons were analyzed for the levels of diene conjugates (DC), lipid hydroperoxides (LOOHs) and thiobarbituric acid reactive substances (TBARS). Enzymic antioxidants (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPX; glutathione S-transferase, GST; and glutathione reductase, GR) and non-enzymic reserve (reduced glutathione, GSH; ascorbate; and alpha-tocopherol) were also assessed in the intestine and colon. Unsupplemented DMH exposed rats showed significantly decreased levels/activities of tissue DC, LOOHs, TBARS, SOD, CAT, GSH, GR and significantly elevated (P<0.05) GPX, GST, alpha-tocopherol and ascorbate as compared to control rats. Resveratrol supplementation during the entire period of the study resulted in significant (P<0.01) modulation of lipid peroxidation markers and antioxidants status, which were paralleled with ACF suppression, as compared to DMH-alone treated rats. These results indicate that resveratrol effectively inhibits DMH-induced ACF and colonic tumor development.

Topics: 1,2-Dimethylhydrazine; Animals; Antioxidants; Catalase; Diet; Glutathione; Intestinal Neoplasms; Lipid Peroxidation; Male; Precancerous Conditions; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase

To determine its effect on intestinal tumorigenesis and the protumorigenic COX pathway in Apc(Min/+) mice, resveratrol was administered as a powdered admixture in the diet at 0, 4, 20, or 90 mg/kg body weight for 7 wk. In two separate experiments, resveratrol did not affect intestinal tumor load. It was stable in the diet under experimental conditions, circulated in the plasma as the glucuronide-conjugated form and reached the tumors as evidenced by significant decreases in PGE2 levels. However, immunohistochemical staining of intestinal tumors revealed no changes in COX-2 expression. This study demonstrates that resveratrol consumed ad libitum in the diet, does not modify tumorigenesis in Apc(Min/+) mice.

Topics: Adenomatous Polyposis Coli; Animals; Anticarcinogenic Agents; Chromatography, High Pressure Liquid; Cyclooxygenase 2; Diet; Dinoprostone; Glucuronides; Intestinal Neoplasms; Isoenzymes; Kinetics; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Prostaglandin-Endoperoxide Synthases; Resveratrol; Stilbenes

We studied the effect of oral administration of resveratrol, a natural constituent of grapes, on tumorigenesis in Min mice. Min mice are congenic mice genetically predisposed to develop intestinal tumors as a result of a mutation of the Apc gene. Resveratrol (0.01% in the drinking water containing 0.4% ethanol) was administered for seven weeks to Min mice starting at five weeks of age. The control group was fed the same diet and received water containing 0.4% ethanol. Resveratrol prevented the formation of colon tumors and reduced the formation of small intestinal tumors by 70%. Comparison of the expression of 588 genes in the small intestinal mucosa showed that resveratrol downregulated genes that are directly involved in cell cycle progression or cell proliferation (cyclins D1 and D2, DP-1 transcription factor, and Y-box binding protein). In addition, resveratrol upregulated several genes that are involved in the recruitment and activation of immune cells (cytotoxic T lymphocyte Ag-4, leukemia inhibitory factor receptor, and monocyte chemotactic protein 3) and in the inhibition of the carcinogenic process and tumor expansion (tumor susceptibility protein TSG101, transforming growth factor-beta, inhibin-beta A subunit, and desmocollin 2). Our data highlight the complexity of the events associated with intestinal tumorigenesis and the multiplicity of the molecular targets of resveratrol. The high potency and efficacy of resveratrol support its use as a chemopreventive agent in the management of intestinal carcinogenesis.

Topics: Adenomatous Polyposis Coli; Animals; Anticarcinogenic Agents; Cell Division; Disease Models, Animal; Gene Expression Regulation; Immunity, Cellular; Intestinal Neoplasms; Male; Mice; Mice, Inbred C57BL; Resveratrol; Stilbenes; Treatment Outcome