Resveratrol in human cancer chemoprevention--choosing the 'right' dose.
ABSTRACT There is now robust preclinical evidence to suggest that resveratrol possesses cancer chemopreventive properties. A series of clinical pilot studies has provided insights into its pharmacokinetics, and data on its human antineoplastic pharmacodynamics start to emerge. It is likely that resveratrol will be developed further in the clinic as a putative cancer chemopreventive agent. The question that remains unresolved is: What is the most suitable dose of resveratrol for effective cancer preventive intervention? Mechanistic studies in cells in vitro have almost invariably used concentrations of resveratrol in the 10(-5) to 10(-4) M range, which is much higher than those which can be achieved in the human biophase after consumption of doses up to 1 g. Many of the preclinical efficacy studies in rodent models of carcinogenesis have employed doses which are dramatically above those which can be ingested with the diet. New experimental paradigms need to be used to obtain information on pharmacological changes elicited by resveratrol when present at very low concentrations or when administered at dietary-relevant doses.
[show abstract] [hide abstract]
ABSTRACT: Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of foodstuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the attention worldwide of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol-based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increase the number of 'potential' benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called 'Resveratrol Paradox', i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. To date, it is becoming evident that RES exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, especially in medicated people. This review will focus on the current available evidence regarding resveratrol's effects on humans through randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.Current pharmaceutical design 02/2013; · 4.41 Impact Factor
Article: Hydrogenosome metabolism is the key target for antiparasitic activity of resveratrol against Trichomonas vaginalis.[show abstract] [hide abstract]
ABSTRACT: Metronidazole (MDZ) and related 5-nitroimidazoles are the recommended drugs for treatment of trichomoniasis; a sexually transmitted disease caused by the protozoan parasite Trichomonas vaginalis. However, novel treatment options are needed, as recent reports claim resistance to these drugs in T. vaginalis isolates. In this study, we analyzed for the first time the in vitro effects of the natural polyphenol resveratrol (RESV) on T. vaginalis. At concentrations between 25-100 μM, RESV inhibited the in vitro growth of T. vaginalis trophozoites; doses of 25 μM exerted a cytostatic effect and higher doses exerted a cytotoxic effect. At these concentrations, RESV caused inhibition of the specific activity of a 120 kD [Fe]-hydrogenase (Tvhyd). RESV did not affect Tvhyd gene expression and only upregulated pyruvate ferredoxin oxidoreductase (a hydrogesomal enzyme) gene expression at a high dose (100 μM). At doses of 50-100 μM, RESV also caused overexpression of heat shock protein 70 (Hsp70), a protective protein found in the hydrogenosome of T. vaginalis. The results demonstrate the potential of RESV as an antiparasitic treatment for trichomoniasis and suggest that the mechanism of action involves induction of hydrogenosomal dysfunction. In view of the results, we propose the hydrogenosomal metabolism as a key target in the design of novel antiparasitic drugs.Antimicrobial Agents and Chemotherapy 03/2013; · 4.84 Impact Factor