Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice
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 dietarydose 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.
El resveratrol es considerado como un potencial agente protector contra el cáncer, pero aún se necesita más información sobre la dosis optima para obtener este efecto. Este estudio observó el efecto entre una dosis obtenida de la dieta a una ingesta 200 veces mayor. Se observó que una dosis más baja fue más eficaz que la dosis alta, concluyendo que las estrategia de desarrollo deben ser revisada con el fin de lograr el efecto deseado.
Resveratrol is considered a potential protective agent against cancer, but we still need more information about the optimal dose for this effect. This study observed the different doses, comparing the dose obtained from the diet to an intake 200 times higher. It was seen that a lower dose was more effective than a higher dose, concluding that the developmental strategies should be revised in order to achieve cancer prevention.