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Articles

Resveratrol Isolated from Polygonum cuspidatum Root Prevents Tumor Growth and Metastasis to Lung and Tumor-Induced Neovascularization in Lewis Lung Carcinoma-Bearing Mice

Second Department of Medical Biochemistry, School of Medicine, Ehime University, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan

¹To whom correspondence should be addressed. E-mail: yokim{at}m.ehime-u.ac.jp.

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 (IC₅₀) was 6.8 µmol/L. Resveratrol at 100 µmol/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 µmol/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 µmol/L; the degree of the inhibition of capillary-like tube formation by resveratrol was 45.5% at 10 µmol/L, 50.2% at 50 µmol/L and 52.6% at 100 µmol/L. Resveratrol inhibited the binding of vascular endothelial growth factor (VEGF) to HUVEC at concentrations of 10–100 µmol/L, but not at concentrations of 1 and 5 µmol/L. The degree of inhibition of VEGF binding to HUVEC by resveratrol was 16.9% at 10 µmol/L, 53.2% at 50 µmol/L and 47.8% at 100 µmol/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

KEY WORDS: • resveratrol • antitumor activity • antimetastaic activity • angiogenesis • mice