| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
It has been reported that the antitumor and antimetastatic actions of resveratrol (3,4',5-trihydroxystilbene) might be due to the inhibition of tumor-induced angiogenesis. To search for anticancer agents with stronger activity than resveratrol, this study was examined the effects of 21 syntehtic and/or natural stilbenes through the inhibition of angiogenic factors (e.g. VEGF production, VEGFR-2 expression or phosphorylation, MMP expression, COX-2 expression, HIF-lα expression and tumor-associated macrophage activation). The summary of research results were described as follows;
(1) Effects of various diet an tumor growth and metastasis through the activation of vascular endothelia growth factor (VEGF), hypo〓 inducible factor (HIF) -1α and monocyte che〓-1 (MCP I) expressions in tumor-bearing mice
Angiogenic factors such as plasma leptin and MCP-1 were increased after the implantation of tumors, wheras conversely, an anti-angiogenic factor, adiponectiin, was reduced after the implantation
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of tumors. Furthermore, it was found that VEGF, HIF-lα and MCP-1 expression levels in tumors of mice fad the high-fat, the high-sucrose, or the high-cholesterol diets were increased compared to those of mice fed the low-fat/low-sucrose diet. These findings suggest that the acceleration of tumor growth and metastasis may be due to the increase of angiogenic factors through the macrophage accumulation and activation of tumors.
(2) Antitumor and antimetastatic actions of natural products through the activation of immune function of small intestine The intraperitoneal and oral administration of low-molecular weight water-soluble β-glucan inhibited the tumor growth and liver metastasis in mice intraslenically implanted with colon 26 cells. The number of natural killer (NK)- and interferon (IFN)-γ-positive cells in the small intestine of colon 26-bearing mice were lower than those in nor mal mice. The intraperitoneally and orally administered low-molecular-weight water-soluble 3-glucan prevented the reduction of the number of NK- and IFN-γ-positive cells induced by the tumor.
(3) Anti-tumor activities of synthetic and natural stlbenes through anti-angiogenic action Among synthetic and natural 21 stilbenes, 2,3-, 3,4- and 4,4'-dihydroxystilbenes inhibited the matrix metalloproteinase (MMP)-9 production in colon 26 cells, vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) migration and VEGF-induced angiogenesis at 1 or 5 μM. Resveratrol (3,4',5-trihydroxystilbene) inhibited the MMP-9 production in colon 26 cells and VEGF-induced HUVEC migration at 25 or 50 μM. Thus, the inhibition of MMP-9 production in colon 26 cells and VEGF-induced HUVEC migration by three dihydroxystilbenes were greater than those of resveratrol. The three dihydroxystilbenes (8 mg/kg, ip) inhibited the tumor-induced neovascularization in colon 26-packed chamber-bearing mice and the tumor growth in colon 26-baering mice. Further, studies are in progress to examine the effects of dihydroxystilbenes on tumor growth and metastasis in tumor-bearing TLR-4 mutant mice. Less
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