Dietary Resveratrol Does Not Affect Intestinal Tumorigenesis in Apc/+ Mice

Ziegler, Carol; Rainwater, Leah; Whelan, Jay; McEntee, Michael F.

doi:10.1093/jn/134.1.5

Cited by 70 publications

(49 citation statements)

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“…In Min mice, a strain predisposed to develop intestinal tumours, resveratrol administered in the drinking water strongly reduced the formation of colon and small intestinal tumours (Schneider et al, 2001). However, the doses used in this study have been questioned by Ziegler et al (2004), who found no effect of resveratrol in the diet on either COX-2 expression or the number of tumours. In the negative studies, including the present, resveratrol given in the diet may not have reached the target tissue in sufficient concentrations or biological active form.…”

Section: Discussionmentioning

confidence: 81%

Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene

et al. 2004

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Resveratrol inhibits PAH bioactivation through reduced expression of the CYP1A1 and CYP1B1 genes in human bronchial epithelial cells. Ad libitum access to a diet containing resveratrol showed no effect on benzo [a]pyrene-induced lung tumorigenesis in A/J mice. Also, resveratrol did not change CYP1A1 and CYP1B1 gene expression or benzo [a] Lung cancer is the major cause of cancer-related mortality worldwide and tobacco smoke is established as the primary aetiologic factor for the disease. Other risk factors are occupational exposure and urban air pollution (Twombly, 2003). Today, 25 -30% of adults in western populations are active smokers, while the number is increasing in developing countries (Peto et al, 1996). The cancer has proven difficult to control with conventional therapeutic and surgical approaches, and the prognosis is poor with an overall 5-year survival rate of 10 -14% in the USA (Jemal et al, 2004). The use of naturally occurring or synthetic agents to prevent, inhibit or reverse lung carcinogenesis would therefore greatly benefit public health. Resveratrol (trans-3,4 0 ,5-trihydroxystilbene) is a phenolic phytoalexin present in wines, berries and nuts, which has shown chemopreventive potential (Jang et al, 1997).Benzo [a]pyrene (B[a]P) is a major carcinogenic constituent in tobacco smoke (Hecht, 2003). It is metabolically activated by the cytochrome P450 (CYP) system to reactive diolepoxides which are capable of interacting with DNA or proteins to form adducts. In the lung, CYP1A1 and CYP1B1 are important in the biotransformation of B[a]P, and their expression is inhibited by resveratrol in vitro (Ciolino and Yeh, 1999;Mollerup et al, 2001;Berge et al, 2004b). Accordingly, in human bronchial epithelial cells, inhibition of CYP1A1 and CYP1B1 was accompanied by reduced formation of the ultimate carcinogen BPDE-I and BPDE -DNA adducts (Mollerup et al, 2001;Berge et al, 2004b).The anticancer effect of resveratrol has previously been studied with conflicting results in vivo. In this study, we addressed the effect of resveratrol on initiation of lung tumorigenesis in A/J mice. Mice with free access to a diet containing resveratrol were repeatedly exposed to B[a]P by gavage. The effect of resveratrol on the expression level of CYP1A1 and CYP1B1 in the lung tissue was determined by quantitative real-time RT -PCR, and hydrolysed B[a]P -protein adducts were measured by HPLC. Furthermore, the development of lung tumours in response to resveratrol was investigated. MATERIALS AND METHODS Animal handling and treatmentA total of 150 female A/JOlaHsd mice (Harlan, UK) were housed in an animal facility with a 12-h light/dark cycle at 211C and 55% RH. The mice had ad libitum access to tap water and diet throughout the study. Diet was prepared daily by dispensing EtOH only (solvent control) or resveratrol/EtOH to a pulverised standard diet (RM1)(SDS, UK) (0.4% w w À1 ), and the solvent was evaporated overnight in the dark. Food dishes were replaced each morning and were shaded by metal plates over the cages. The stab...

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Section: Discussionmentioning

confidence: 81%

Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene

et al. 2004

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“…This finding is consistent with a recent report according to which dietary administration of doses of resveratrol (up to 90 mg/kg) failed to affect adenoma number in this model. 14 In contrast, it has been previously suggested that resveratrol at 0.01% in the drinking water (a dose of approximately 12 mg/kg per day) decreased adenoma number by 70%. 13 When this experimental design was repeated in our laboratory, significant reduction in adenoma number was not detected (data not shown).…”

Section: Discussionmentioning

confidence: 92%

“…14 Apc Minþ mice harbor a germline mutation in the adenomatous polyposis coli (Apc) gene and are characterized by inactivation of Apc, nuclear accumulation of bcatenin and enhanced expression of specific genes activated by T-cell factor (TCF)/b-catenin signaling. They are therefore a model of human intestinal carcinogenesis that is related to inactivated Apc.…”

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confidence: 99%

Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′‐tetramethoxystilbene (DMU‐212) on adenoma development in the Apc^Min+ mouse and cyclooxygenase‐2 in human‐derived colon cancer cells

Sale

Tunstall

Ruparelia

et al. 2005

Intl Journal of Cancer

163

127

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Naturally occurring molecules with putative cancer chemopreventive properties such as the phytoalexin resveratrol (3,5,4 0 -trihydroxystilbene) are lead molecules that guide the design of novel agents with improved pharmacologic properties. The synthetic resveratrol analog 3,4,5,4 0 -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 ApcMinþ mouse, a model of human intestinal carcinogenesis. Apc Minþ 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 µM) 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 Minþ mice or to interfere with PGE-2 generation in cells. ' 2005 Wiley-Liss, Inc.

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“…We have confirmed the effects of resveratrol on cell cycling in colon-derived cells in vitro in our study. Other reports suggest that resveratrol dosages as high as 90 mg/kg [42] are ineffective or that only extremely high dosages up to 500 mg/kg show activity [43]. Sale [44] utilized dosages of 60 mg/kg and 240 mg/kg, and found the former ineffective but the latter effective in inducing a more modest reduction in intestinal tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

Hope

Planutis

Planutiene

et al. 2008

Mol. Nutr. Food Res.

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Resveratrol is a bioflavonoid which is known to inhibit cell proliferation and induce apoptosis in cancer cell lines at concentrations above 50uM. It also has colon cancer prevention activity in mouse models and possibly in humans. We have examined the effects of low concentrations of resveratrol on a specific signaling pathway, the Wnt pathway, which is activated in over 85% of sporadic colon cancers. Two colon cancer (HT29 and RKO) and one normal mucosa-derived (NCM460) cell lines were utilized. Cell proliferation was not affected by resveratrol at ≤40uM for HT29 and NCM460 and <20uM for RKO though Wnt signal throughput, as measured by a reporter construct, was reduced in RKO and NCM460 at concentrations as low as 10uM (p<0.001). This effect was most easily appreciated following Wnt pathway stimulation with Wnt3a conditioned medium and LEF1 or LEF1/ β-catenin transfection. Resveratrol did not inhibit Wnt throughput in mutationally activated HT29. Low concentrations of resveratrol significantly decreased the amount and proportion of β-catenin in the nucleus in RKO (p=0.002) and reduced the expression of lgs and pygoI, regulators of β-catenin localization in all cells lines. Thus, at low concentrations, in the absence of effects on cell proliferation, resveratrol significantly inhibits Wnt signaling in colon-derived cells which do not have a basally activated Wnt pathway. This inhibitory effect may be due in part to regulation of intracellular β-catenin localization.

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Dietary Resveratrol Does Not Affect Intestinal Tumorigenesis in Apc/+ Mice

Cited by 70 publications

References 50 publications

Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene

Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene

Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′‐tetramethoxystilbene (DMU‐212) on adenoma development in the Apc^Min+ mouse and cyclooxygenase‐2 in human‐derived colon cancer cells

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

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Dietary Resveratrol Does Not Affect Intestinal Tumorigenesis in Apc/+ Mice

Cited by 70 publications

References 50 publications

Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene

Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene

Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′‐tetramethoxystilbene (DMU‐212) on adenoma development in the ApcMin+ mouse and cyclooxygenase‐2 in human‐derived colon cancer cells

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

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Product

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Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′‐tetramethoxystilbene (DMU‐212) on adenoma development in the Apc^Min+ mouse and cyclooxygenase‐2 in human‐derived colon cancer cells