title: Antiangiogenic activity of 11,11'-dideoxyverticillin, a natural product isolated from the fungus Shiraia bambusicola.
abstract: The fungus Shiraia bambusicola yields the phytochemical 11,11'-dideoxyverticillin, which has been shown to possess potent anticancer activity both in vitro and in vivo. In this study, we reveal that 11,11'-dideoxyverticillin has anti-angiogenic activities and explore the potential mechanisms for this effect. Treatment with 11,11'-dideoxyverticillin inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) with IC(50) values of 0.17+/-0.05muM for VEGF-stimulated cells and 0.39+/-0.08muM for serum-stimulated cells. 11,11'-Dideoxyverticillin also antagonized the antiapoptotic effects of VEGF on serum-deprived HUVECs, inhibited VEGF-induced HUVEC migration in vitro, and blocked serum-induced HUVEC tube formation. Moreover, 11,11'-dideoxyverticillin completely blocked VEGF-induced microvessel sprouting from Matrigel-embedded rat aortic rings and vessel growth in Matrigel plugs in mice. In addition, 11,11'-dideoxyverticillin decreased VEGF secretion by MDA-MB-468 breast cancer cells, and significantly suppressed VEGF-induced tyrosine phosphorylation of Flt-1 and KDR/Flk-1. This inhibition of receptor phosphorylation was correlated with a marked decrease in VEGF-triggered pERK activation and a dramatic increase in pP38 MAPK, but no apparent change in pAkt. Together, these findings strongly suggest that 11,11'-dideoxyverticillin is a structurally novel angiogenesis inhibitor.
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Science, Chinese Academy of Sciences, Shanghai, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Yi-Xiang
authors.initials: YX
authors.lastname: Zhang
authors.forename: Mei-Hong
authors.initials: MH
authors.lastname: Li
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Zhao
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Shi
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Zhang
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D001203:Ascomycota / Q000737:chemistry*; D001685:Biological Factors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification* / Q000493:pharmacokinetics*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D011509:Proteoglycans / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology
chemical_list: C490191:11,11'-dideoxyverticilin; D020533:Angiogenesis Inhibitors; D001685:Biological Factors; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen