stilbenes and Adenoma

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

In Apc(Min) mice (an animal model of colorectal carcinogenesis) fed a high-fat diet, low doses of resveratrol suppress intestinal adenoma development more potently than high doses do; however, these findings appear affected by multiple confounding factors, as resveratrol alone added to a standard diet has opposite outcomes.

Topics: Adenoma; Animals; Chemoprevention; Diet, High-Fat; Humans; Mice; Mice, Inbred C57BL; Resveratrol; Stilbenes

Low-dose resveratrol did not have the opposite effect on intestinal adenoma development when given in a standard diet instead of a high-fat diet, although we agree on the need for more information on the interaction of diet-derived compounds such as resveratrol and other lifestyle, metabolic and hormonal factors.

Topics: Adenoma; Animals; Antioxidants; Carcinogenesis; Chemoprevention; Colorectal Neoplasms; Diet, High-Fat; Female; Humans; Male; Mice; Resveratrol; Stilbenes

Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess efficacy. To challenge the assumption that "more is better," we compared the pharmacokinetics and activity of a dietary dose with an intake 200 times higher. The dose-response relationship for concentrations generated and the metabolite profile of [(14)C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels. In Apc(Min) mice (a model of colorectal carcinogenesis) that received a high-fat diet, the low resveratrol dose suppressed intestinal adenoma development more potently than did the higher dose. Efficacy correlated with activation of adenosine monophosphate-activated protein kinase (AMPK) and increased expression of the senescence marker p21. Nonlinear dose responses were observed for AMPK and mechanistic target of rapamycin (mTOR) signaling in mouse adenoma cells, culminating in autophagy and senescence. In human colorectal tissues exposed to low dietary concentrations of resveratrol ex vivo, we measured enhanced AMPK phosphorylation and autophagy. The expression of the cytoprotective NAD(P)H dehydrogenase, quinone 1 (NQO1) enzyme was also increased in tissues from cancer patients participating in our [(14)C]-resveratrol trial. These findings warrant a revision of developmental strategies for diet-derived agents designed to achieve cancer chemoprevention.

Topics: Adenoma; AMP-Activated Protein Kinases; Animals; Antineoplastic Agents, Phytogenic; Autophagy; Colorectal Neoplasms; Diet, High-Fat; Dose-Response Relationship, Drug; Humans; Mice; Resveratrol; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases

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

Tissue-like cultures of LT97 human colonic adenoma cells were produced by plating on reconstructed connective tissue supports (CTR) containing colon-associated fibroblasts to form mucosal monolayers and polyp-like structures closely resembling the in vivo situation. Tight cell-cell contacts and a high density of desmosomes were observed in 93.8+/-3.5% of the section area for CTR cultures, but only in 17.8+/-10.0% of the area for cultures on collagen gels (CG) without fibroblasts. While LT97 cultures on plastic shed apoptotic bodies into the medium, they collected at the basal pole of the cell layer in the CTR cultures as is also observed in adenoma tissue. Only a small proportion was released into the medium as shown by the detection of apoptosis specific keratin fragments, which could be increased by 100microM of quercetin and resveratrol. In addition, tissue-like structures altered the relative effectivity of test compounds. As the tissue-like conditions closely resemble the situation in vivo tissue-like cultures are an important step towards the establishment of tissue reconstructs that can replace animal models in the analysis of basic mechanisms of growth control and the testing of tumor promoting and chemopreventive compounds and may even be superior in terms of predictivity as they use human cells.

Topics: Adenoma; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Culture Techniques; Collagen; Colorectal Neoplasms; Drug Evaluation, Preclinical; Models, Biological; Quercetin; Resveratrol; Stilbenes; Tumor Cells, Cultured

Naturally occurring molecules with putative cancer chemopreventive properties such as the phytoalexin resveratrol (3,5,4'-trihydroxystilbene) are lead molecules that guide the design of novel agents with improved pharmacologic properties. The synthetic resveratrol analog 3,4,5,4'-tetramethoxystilbene (DMU-212) has been shown to possess stronger antiproliferative properties in human colon cancer cells than resveratrol. We tested the hypothesis that DMU-212 is also a more potent inhibitor of adenoma development in the Apc(Min+) mouse, a model of human intestinal carcinogenesis. Apc(Min+) mice received either stilbene derivative with the diet (0.2%), and adenomas were counted after experiments were terminated. Resveratrol and DMU-212 decreased adenoma load by 27% and 24%, respectively, compared to untreated controls. Cyclooxygenase (COX) enzymes are important mechanistic targets of resveratrol, and we investigated whether DMU-212 interferes with the expression and activity of COX in human colon cells. Incubation of HCA-7 cancer cells for 24-96 hr with either stilbene derivative (1-50 microM) decreased prostaglandin E-2 (PGE-2) production, but only resveratrol decreased COX-2 protein expression. In mice, which received either stilbene derivative (0.2%) for 3 weeks with their diet, PGE-2 levels in the intestinal mucosa were reduced by between 45% and 62% compared to mice on control diet. While resveratrol inhibited enzyme activity in purified COX preparations, DMU-212 failed to do so. The PGE-2 decrease seen with DMU-212 in cells and in vivo is probably mediated via its metabolites. The results suggest that alteration of the resveratrol molecule to generate DMU-212 does not abrogate its ability to decrease adenoma number in Apc(Min+) mice or to interfere with PGE-2 generation in cells.

Topics: Adenoma; Animals; Antineoplastic Agents, Phytogenic; Chemoprevention; Colonic Neoplasms; Cyclooxygenase 2; Diet; Dinoprostone; Female; Genes, APC; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin-Endoperoxide Synthases; Resveratrol; Ribonucleotide Reductases; Stilbenes; Tissue Distribution

Topics: 17-Ketosteroids; Adenoma; Adrenal Cortex Hormones; Carcinoma; Estradiol; Estradiol Congeners; Estriol; Estrone; Geriatrics; Humans; Male; Prostatic Neoplasms; Stilbenes; Urine