| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Angiogenesis, the formation of new capillary blood vessels for supplying oxygen and nutrients, is essential for their continuous growth and metastasis of solid tumors. The inhibition of tumor angiogenesis by potent angiogenic inhibitors may be a useful approach for cancer therapy. Recently, cyclooxygenase (COX), particularly COX-2, was postulated to be involved in tumor growth, metastasis and angiogenesis. To find a new potent angiogenic inhibitor, we focused our previous finding that humulone, a bitter acid from beer hop (Humulus lupulus L.) was a potent inhibitor of bone resorption and inhibited catalytic activity of cyclooxygenase-2 and more potently the transcription of COX-2 gene.
We first examined the effect of humulone on angiogenesis, using chick embryo chorioallantoic membranes (CAM) and vascular endothelial and tumor cells. Humulone significantly prevented in vivo angiogenesis in CAM in a dose dependent manner. Humulone potently inhibited the proliferation of endothelial cells stimulated by bFGF, VEGF and serum. It also suppressed in vitro angiogenesis of vascular endothelial tube formation and production of angiogenic factor (VEGF) in endothelial and tumor cells. We next examined the effects of the synthesized or purified compounds derived from humulone on angiogenesis in CAM. Among the compounds tested, humulone was the most potent angiogenesis inhibitor. Therefore, we synthesized large volume of humulone and examined in vivo assays in mice. Humulone inhibited tumor-induced angiogenesis in mouse dorsal air sac assay and also suppressed spontaneous lung metastasis of tumor cells by intraperitoneal administration. On the bases of these results, humulone is a potent angiogenesis inhibitor, and may be a novel powerful tool for the therapy in various angiogenic diseases involving solid tumor, rheumatoid arthritis and diabetic retinopathy.
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