Resveratrol Inhibits Intestinal Tumorigenesis and Modulates Host-Defense-Related Gene Expression in an Animal Model of Human Familial Adenomatous Polyposis

Abstract

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.

Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene

“…In the light of the suggestion that resveratrol at 0.01% in the drinking water (constituting a dose of B15 mg kg À1 per day) decreased adenoma multiplicity in the Apc Min/ þ mouse model (Schneider et al, 2001), the results described here render a comparison of resveratrol and DMU 212 in this model appropriate, and such experiments are currently planned in this laboratory. However, it is important to add a note of caution, because the chemopreventive efficacy of resveratrol in this model is highly contentious, as borne out by two contradictory abstracts published subsequent to the paper by Schneider et al (2001).…”

“…However, it is important to add a note of caution, because the chemopreventive efficacy of resveratrol in this model is highly contentious, as borne out by two contradictory abstracts published subsequent to the paper by Schneider et al (2001). These abstracts suggest that in the same murine model, dietary doses comparable to, or much higher than, those used by Schneider et al were completely ineffective (Ziegler et al, 2001) or, in the case of a dietary daily dose of 500 mg kg À1 for 14 days, reduced adenoma load, but did so only in female mice and not at all in male mice (Gignac and Bourquin, 2001).…”

“…It inhibits the proliferation of a variety of cancer cell lines (for a review, see Gusman et al, 2001), formation of preneoplastic lesions in the 7,12-dimethylbenz(a)anthracene-(DMBA) induced mouse mammary organ culture model (Bhat et al, 2001) and benzo(a)pyrene-induced transformation of rat tracheal epithelial cells (Jang et al, 1997). In animal studies, resveratrol interfered with the formation of azoxymethane-(AOM) induced aberrant crypt foci in rat colon (Tessitore et al, 2000), attenuated oesophageal carcinoma formation in rats that received N-nitrosomethylbenzylamine (NMBA) , decreased the number of adenomas in the small intestine and suppressed tumour formation in the colon of Apc Min þ mice (Schneider et al, 2001) and reduced mammary tumour formation in N-methyl-Nnitrosourea-(NMU) treated rats (Bhat et al, 2001). Resveratrol has been reported to possess a variety of anti-inflammatory, antiplatelet and both pro-and antioestrogenic effects (Bertelli et al, 1996;Gehm et al, 1997;Jang et al, 1997;Uenobe et al, 1997).…”

Resveratrol Exerts Differential Effects in Vitro and in Vivo against Ovarian Cancer Cells

“…Resveratrol is gaining tremendous importance as it possesses cancer preventive as well as anticancer activities in various biological systems (reviewed by Bishayee, 2009). In animal studies, resveratrol prevents or delays the development of skin (Jang et al, 1997), mammary (Banerjee et al, 2002) and prostate (Harper et al, 2007) tumors as well as blocks or suppresses esophageal (Li et al, 2002), gastric (Zhou et al, 2005), small intestinal (Schneider et al, 2001), colonic (Tessitore at al., 2000;Sengottuvelan et al, 2006) pancreatic (Harikumar et al, 2010), and hepatic (Bishayee & Dhir, 2009) tumorigenesis. Resveratrol has also been shown to possess in vitro cytotoxic effects against a wide variety of human tumor cells, including lymphoid and myeloid cancer cells as well as skin, breast, ovary, cervix, prostate, stomach, colon, pancreas, liver and thyroid carcinoma cells (reviewed by Aggarwal et al, 2004;Kundu and Surh, 2008).…”

Uptake of resveratrol and role of resveratrol-targeting protein, quinone reductase 2, in normally cultured human prostate cells

“…The chemopreventive property of resveratrol is illustrated by suppression of cell proliferation and induction of apoptosis in numerous cancer cell types [7][8][9][10]. Animal studies provide support that resveratrol inhibits tumorigenesis at the stages of initiation, promotion and progression [11,12]. These results suggest that resveratrol might indeed confer chemoprotection even in humans.…”