Effect of resveratrol on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.
Resveratrol (Res) has been reported to possess cancer chemopreventive activity on the basis of its in vitro effects on tumor cells and in vivo experimental 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/neu transgenic 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/neu in 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/neu transgenic mice. The effects of Res were associated with downregulation of HER-2/neu gene 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/neu transgenic mice. The antitumor effect of Res might be related to the downregulation of HER-2/neu expression and the induction of apoptosis in tumor cells.
Provinciali
Mauro
M
Laboratory of Tumor Immunology, Immunology Center, Research Department, Italian National Research Centers on Aging (INRCA), Ancona, Italy. m.provinciali@inrca.it
Re
Francesca
F
Donnini
Alessia
A
Orlando
Fiorenza
F
Bartozzi
Beatrice
B
Di Stasio
Grazia
G
Smorlesi
Arianna
A
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D012313:RNA; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077185:Resveratrol; D013267:Stilbenes