Inhibition of tumor specific angiogenesis by amentoflavone.
The formation of new capillaries from existing blood vessels is critical for tumor growth and metastasis. In this study we report that amentoflavone, a biflavonoid from Biophytum sensitivum, could inhibit the process of angiogenesis. Amentoflavone at nontoxic concentrations (0.05-0.2 microg/ml) showed significant inhibition in the proliferation, migration, and tube formation of endothelial cells, which are key events in the process of angiogenesis. In vivo studies in C57BL/6 mice using amentoflavone showed remarkable inhibition (52.9%) of tumor directed capillary formation. Amentoflavone showed inhibitory effect on the production of various endogenous factors such as IL-1beta, IL-6, TNF-alpha, GM-CSF, and VEGF that control the process of angiogenesis. Amentoflavone treatment could increase the production of IL-2 and TIMP-1, which could successfully shift the equilibrium towards an angiostatic condition. The antiangiogenic activity of amentoflavone was supported by its remarkable suppression in sprouting of microvessels from rat aorta. Our results also show that amentoflavone could inhibit the production of VEGF mRNA in B16-F10 cells. These findings indicate that amentoflavone inhibits angiogenesis by disrupting the integrity of endothelial cells and by altering the endogenous factors that are required for the process of neovascularization.
Guruvayoorappan
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Department of Immunology, Amala Cancer Research Centre, Amala Nagar, Thrissur, Kerala State, India. amalaresearch@rediffmail.com
Kuttan
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G
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D044946:Biflavonoids / Q000737:chemistry / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D020533:Angiogenesis Inhibitors; D044946:Biflavonoids; D016207:Cytokines; D009573:Nitrites; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; C011164:amentoflavone