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Resveratrol (Res) has been reported to possess cancer chemopreventive activity on the basis of itsin vitroeffects on tumor cells andin vivoexperimental models of rodents transplanted with parental tumors or treated with carcinogens. We investigated the effects of Res on the development of mammary tumors appearing spontaneously in HER-2/neutransgenic mice at an early age. The mechanisms involved in the Res antitumor effect were evaluated by studying the immune effectiveness, tumor apoptosis and expression of mRNA and protein for HER-2/neuin tumoral mammary glands from Res-treated mice and in tumor cell lines. Res supplementation delayed the development of spontaneous mammary tumors (p< 0.001), reduced the mean number and size of mammary tumors (p< 0.0001) and diminished the number of lung metastases in HER-2/neutransgenic mice. The effects of Res were associated with downregulation ofHER-2/neugene expression and increased apoptosis both in tumoral mammary glands and in murine (N202) and human (SKBr3) tumor cell lines. Neither the basal, the IL-2-induced NK activity nor the lymphocyte number and proliferation was modified in Res-supplemented compared to control mice. Our results demonstrate that Res supplementation delays the development and reduces the metastasizing capacity of spontaneous mammary tumors in HER-2/neutransgenic mice. The antitumor effect of Res might be related to the downregulation of HER-2/neuexpression and the induction of apoptosis in tumor cells. © 2005 Wiley-Liss, Inc.