Resveratrol: A potential challenger against gastric cancer P-5

RESVERATROL ANTITUMORAL EFFECTS IN ANIMAL MODELS

The inhibitory effects of resveratrol on GC were also verified in vivo using nude mice xenograft models. Resveratrol (40 mg/kg per day) exerted inhibitory activities on GC development and significantly decreased the fractions of Ki67-positive cells in the tumor specimens from the nude mice.

Resveratrol significantly inhibited carcinoma growth when it was injected near the carcinoma in a tumor model established by transplanting human primary GC cells into subcutaneous tissue of nude mice. An inhibitory effect was observed in all groups using resveratrol at the doses of 500 mg/kg, 1000 mg/kg and 1500 mg/kg. Resveratrol induced implanted tumor cells to undergo apoptosis by down-regulation of the apoptosis-regulated gene bcl-2 and up-regulation of the apoptosis-regulated gene bax. The principal effects of resveratrol treatment on gastric cancer.

USE OF RESVERATROL AS A NUTRACEUTICAL IN HUMANS: A CHALLENGE AGAINST ITS POOR BIOAVAILABILITY

Although the use of resveratrol in cell culture models has demonstrated much potential, there has been substantial concern that the concentrations used in vitro and in animal models are not reasonably attainable in humans. There is little data regarding the bioavailability of resveratrol in humans. Early research suggested that resveratrol bioavailability was rather limited, considerably less than 1% despite a high absorption of almost 70% due to its rapid and extensive metabolism. The metabolism of resveratrol involves both glucuronidation and sulfation in the intestine and liver. One of the initial human studies of the absorption and bioavailability uses a single 25 mg oral dose, which corresponds to a moderate intake of red wine. After this dose to healthy human subjects, the compound appears in serum and urine predominantly as glucuronide and sulfate conjugates and reaches peak concentrations (10-40 nmol/L) in serum around 30 min after consumption. Sulfate conjugation occurs very rapidly and could be the primary metabolic pathway.

Numerous strategies have been developed to enhance the bioavailability of orally administered resveratrol, as recently reviewed. Most of these are based on increasing resveratrol absorption and on protecting resveratrol from its rapid metabolization in the gastrointestinal tract. Resveratrol administration combined with red wine polyphenols could be a simple approach to improving bioavailability, in accordance with the “French Paradox”. Indeed, these polyphenols could target the key enzymes that conjugate resveratrol reducing the rate of transformation of trans-resveratrol. While piperine, a polyphenol found in black pepper, enhances the pharmacokinetics of resveratrol by inhibiting its glucuronidation, quercetin, found in many fruits, vegetables, leaves and grains, inhibits the human liver sulfotransferase SULT1A1 and thereby reduces the rate of resveratrol sulfate formation. Although research into cellular and animal models has shown that these polyphenols enhance the effects of resveratrol, the co-administration in humans did not increase resveratrol bioavailability. An approach aimed at improving resveratrol absorption is to decrease the particle size of resveratrol by micronization, thus increasing its rate of dissolution and absorption. The micronized resveratrol formulation SRT501 resulted in increased plasma levels and time of maximum plasma concentrations in patients of a phase?I?trial. Prodrugs may provide another interesting solution that would allow a physiologically significant concentration without toxicity. The acetylation of three hydroxyl groups of resveratrol to obtain 3,5,4’-Tri-O-acetylresveratrol (taRES), a prodrug of resveratrol, masks its principal sites of glucoronidation and sulfation until it is deacetylated to produce resveratrol. Intragastric administration of taRES to rats resulted in a greater concentration than those obtained with the equivalent dosage of de-acetylated resveratrol. Pharmacokinetic studies of synthesized carbamate ester derivatives of resveratrol revealed a high water solubility while maintaining to some degree the ability to permeate biomembranes and confirmed absorption after oral administration in rats.  In a neuroblastoma cellular model, resveratrol lipoconjugates through phosphate bridges showed significantly more activity than unconjugated resveratrol. In addition to these strategies, recent data has revealed that resveratrol nanoformulations can improve resveratrol transport across the membranes, protect resveratrol from metabolism in animal models, as well as reduce gastrointestinal damages in rats suggesting a possible greater tolerability in humans.

Recently human pilot studies in patients with colorectal and hepatic cancers have confirmed resveratrol beneficial effects in reducing cancer cell proliferation, in modulating the expression of some genes of the WNT pathway and in increasing markers of apoptosis in the malignant tissues. Although the bioavailability is very low, rapid uptake and accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-inhibitory effects in organs like the esophagus and the stomach.