Abstract
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.
Highlights
Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials assessing efficacy
Our results show that low dietary exposures elicit biological changes in mouse and human tissues relevant to colorectal cancer chemoprevention, but they have superior efficacy compared to high doses, and should be included in future preclinical testing strategies
Resveratrol plasma pharmacokinetics are reasonably well characterised at high doses, but it is unlikely that quantities exceeding 1g can be taken chronically by healthy populations due to potential gastrointestinal symptoms[17]
Summary
Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials assessing efficacy. Despite extensive preclinical data indicating that phytochemicals and micronutrients can protect against cancer, these findings have failed to translate into successful outcomes in randomised controlled trials, and in some cases cancer incidence has increased in the intervention group[6,7] These unexpected results have been partly attributed to a failure to identify the optimal preventive dose for clinical evaluation before embarking on large costly trials[8,9]. Resveratrol has been widely promoted as an agent worthy of clinical evaluation, current knowledge gaps, identification of the optimal dose and key molecular targets in humans, prohibit the rational design of trials assessing chemopreventive efficacy To address these deficiencies we compared the target tissue distribution and activity of a low dietary relevant dose, equivalent to the amount contained in a large glass of certain red wines[14] with an intake 200-times higher that has previously been used in phase I clinical trials[15,16]. Our results show that low dietary exposures elicit biological changes in mouse and human tissues relevant to colorectal cancer chemoprevention, but they have superior efficacy compared to high doses, and should be included in future preclinical testing strategies
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