Antiangiogenic activity of 11,11'-dideoxyverticillin, a natural product isolated from the fungus Shiraia bambusicola.
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.
Chen
Yi
Y
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.
Zhang
Yi-Xiang
YX
Li
Mei-Hong
MH
Zhao
Wei-Min
WM
Shi
Yu-Hua
YH
Miao
Ze-Hong
ZH
Zhang
Xiong-Wen
XW
Lin
Li-Ping
LP
Ding
Jian
J
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
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