Antitumoral actions of natural stilbenes derived from Vitis Vinifera.

Abstract

Grapes and red wine are the main sources of resveratrol, a polyphenol widely known for its beneficial effects on various diseases. However, other parts of the vine (wood, canes and roots) are important and cheap sources of other bioactive stilbenes. The main objective of this thesis was 1) to carry out a preliminary screening of a series of novel stilbenes (including glucosides and oligomers of resveratrol) from Vitis vinifera vine for their cytotoxic and anti¿inflammatory potential, and 2) to select the most potent one to establish its mechanism of action. We tested cytotoxicity in human hepatocarcinoma HepG2 (wild-type p53) and Hep3B (p53-null), and inflammation in the murine macrophage RAW 264.7 cell line. Several glucosides, which had never before been extracted from the woody part of the vine, showed moderate cytotoxic activity. Piceatannol and the oligomers, ¿-viniferin, hopeaphenol and isohopeaphenol, inhibited the inflammatory response decreasing the levels of nitric oxide, reactive oxygen species, and cytokines. Of the oligomers tested, R2¿viniferin (tetramer) was the most potent in inducing cell death in HepG2, not affecting human non¿transformed hepatocyes. R2¿viniferin exerted its toxic action by a p53¿dependent mechanism, that involved DNA damage, increased H2O2, upregulation of mitochondrial SOD, and apoptosis. We conclude that Vitis vinifera cane is a source of R2¿viniferin, a promising natural compound in the development of chemotherapies against p53¿positive human hepatocellular carcinomas.