Grape antioxidant dietary fiber inhibits intestinal polyposis in Apc Min/+ mice: relation to cell cycle and immune response

Abstract

Epidemiological and experimental studies suggest that fiber and phenolic compounds might have a protective effect on the development of colon cancer in humans. Accordingly, we assessed the chemopreventive efficacy and associated mechanisms of action of a lyophilized red grape pomace containing proanthocyanidin (PA)-rich dietary fiber [grape antioxidant dietary fiber (GADF)] on spontaneous intestinal tumorigenesis in the Apc(Min/+) mouse model. Mice were fed a standard diet (control group) or a 1% (w/w) GADF-supplemented diet (GADF group) for 6 weeks. GADF supplementation greatly reduced intestinal tumorigenesis, significantly decreasing the total number of polyps by 76%. Moreover, size distribution analysis showed a considerable reduction in all polyp size categories [diameter <1mm (65%), 1-2mm (67%) and >2mm (87%)]. In terms of polyp formation in the proximal, middle and distal portions of the small intestine, a decrease of 76, 81 and 73% was observed, respectively. Putative molecular mechanisms underlying the inhibition of intestinal tumorigenesis were investigated by comparison of microarray expression profiles of GADF-treated and non-treated mice. We observed that the effects of GADF are mainly associated with the induction of a G1 cell cycle arrest and the downregulation of genes related to the immune response and inflammation. Our findings show for the first time the efficacy and associated mechanisms of action of GADF against intestinal tumorigenesis in Apc(Min/+) mice, suggesting its potential for the prevention of colorectal cancer.

Non-extractable polyphenols, a major dietary antioxidant: occurrence, metabolic fate and health effects

“…(5) A reduction of intestinal tumorigenesis in APC Min/þ mice, an animal model of colorectal cancer, including significant reductions in the number (276 %) and size (265 to 2 87 %) of polyps (88) . (6) Modifications in gene expression in healthy mice and in APC Min/þ mice, in particular, down-regulation of genes associated with tumour development and proto-oncogenes (for example, genes belonging to the RAS family, such as RASSF4, RAP2C and RAP2B), and up-regulation of tumour-suppressor genes (for instance, NLB1 or TGFb3, related to cell cycle and cell proliferation, respectively) (87,88) .…”

“…Wistar rats, n 10 Reduction of lipid oxidation in distal colonic mucosa (2 25 %) (86) Grape antioxidant dietary fibre 0·1 g/kg bw, 2 weeks C57BL/6J mice, n 8 Overexpression of enzymes pertaining to the xenobiotic detoxifying system and endogenous antioxidant cell defences (þ100 to þ 200 %) (87) Grape antioxidant dietary fibre 0·1 g/kg bw, 2 weeks C57BL/6J mice, n 8 Down-regulation in colon mucosa of genes associated with tumour development and proto-oncogenes (2 100 to 2 200 %), up-regulation of tumour-suppressor genes (þ 100 %) (87) Grape antioxidant dietary fibre 1 % of the diet, 16 weeks APC Minþ/2 mice, n 12 Reduction in the number (2 76 %) and size (2 65 to 2 87 %) of polyps (88) Grape antioxidant dietary fibre 5 -7 % of the diet, 4 weeks…”

Prevention and treatment of cancers by immune modulating nutrients

“…A grape anti‐oxidant dietary fiber treatment, consisting of soluble phenolics, insoluble phenolic acids, and other components of the dietary fiber fraction, including polysaccharides and lignins, prevented polyp formation by ∼81% in Apc Min/+ mice by modifying cell cycle genes. DNA microarray analysis of colonic mucosa revealed downregulation of immune response genes (CXCR4 signaling via second messenger, T‐cell receptor, and CD28 costimulation in activation of nuclear factor‐κB, inducible T‐cell co‐stimulator pathway in T‐helper cells, T‐cell receptor signaling pathway, nuclear factor of activated T cells in immune response) in the colonic mucosa of treated animals compared with untreated animals . Several dietary fiber studies conducted by our group suggest that a high‐fiber diet protects against colon and other cancers; the lipid fraction of wheat bran fiber in particular provides maximal protection against AOM‐induced colon cancer in rats .…”

An immunological perspective for preventing cancer with berries

“…One group treated Apc Min/ + mice either a control diet (Teklad Global 18% Protein rodent diet), or the control diet supplemented with 1% grape antioxidant dietary fiber (GADF), a lyophilized red grape pomace containing proanthocyanidins-rich dietary fiber, for 6 weeks [48]. This study found that GADF suppressed the intestinal tumor development, and downregulated several genes associated with the immune response, such as CXCR4 signaling, which has been reported to be involved in the tumorigenesis and lymph node metastasis.…”