Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in Lewis lung carcinoma-bearing mice.
Resveratrol is a naturally occurring phytoalexine found in medicinal plants. We found that resveratrol, at doses of 2.5 and 10 mg/kg, significantly reduced the tumor volume (42%), tumor weight (44%) and metastasis to the lung (56%) in mice bearing highly metastatic Lewis lung carcinoma (LLC) tumors, but not at a dose of 0.6 mg/kg. Resveratrol did not affect the number of CD4(+), CD8(+) and natural killer (NK)1.1.(+) T cells in the spleen. Therefore, the inhibitory effects of resveratrol on tumor growth and lung metastasis could not be explained by natural killer or cytotoxic T-lymphocyte activation. In addition, resveratrol inhibited DNA synthesis most strongly in LLC cells; its 50% inhibitory concentration (IC(50)) was 6.8 micromol/L. Resveratrol at 100 micromol/L increased apoptosis to 20.6 +/- 1.35% from 12.1 +/- 0.36% (P < 0.05) in LLC cells, and decreased the S phase population to 22.1 +/- 1.03% and 29.2 +/- 0.27% from 35.2 +/- 1.72% (P < 0.05) at concentrations of 50 and 100 micromol/L, respectively. Resveratrol inhibited tumor-induced neovascularization at doses of 2.5 and 10 mg/kg in an in vivo model. Moreover, resveratrol significantly inhibited the formation of capillary-like tube formation from human umbilical vein endothelial cells (HUVEC) at concentrations of 10-100 micromol/L; the degree of the inhibition of capillary-like tube formation by resveratrol was 45.5% at 10 micromol/L, 50.2% at 50 micromol/L and 52.6% at 100 micromol/L. Resveratrol inhibited the binding of vascular endothelial growth factor (VEGF) to HUVEC at concentrations of 10-100 micromol/L, but not at concentrations of 1 and 5 micromol/L. The degree of inhibition of VEGF binding to HUVEC by resveratrol was 16.9% at 10 micromol/L, 53.2% at 50 micromol/L and 47.8% at 100 micromol/L. We suggest that the antitumor and antimetastatic activities of resveratrol might be due to the inhibition of DNA synthesis in LLC cells and the inhibition of LLC-induced neovascularization and tube formation (angiogensis) of HUVEC by resveratrol
Kimura
Y
Y
Second Department of Medical Biochemistry, School of Medicine, Ehime University, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan. yokim@m.ehime-u.ac.jp
Okuda
H
H
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001835:Body Weight; D016516:CD4-CD8 Ratio; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009929:Organ Size; D019664:Polygonaceae / Q000737:chemistry*; D000077185:Resveratrol; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013267:Stilbenes / Q000302:isolation & purification / Q000494:pharmacology*; D013950:Thymus Gland / Q000473:pathology; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D016588:Anticarcinogenic Agents; D013267:Stilbenes; D004247:DNA; D000077185:Resveratrol