Abstract
Bastadin 6, a macrocyclic tetramer of a brominated tyrosine derivative, was isolated from a marine sponge and its anti-angiogenic activity was evaluated. Bastadin 6 was found to inhibit vascular endothelial growth factor (VEGF)- or basic fibroblast growth factor (bFGF)-dependent proliferation (IC50=0.052 micromol/l) of human umbilical vein endothelial cells (HUVECs) 20- to 100-fold selectively in comparison with normal fibroblast (3Y1) or several tumor cells (KB3-1, K562 and Neuro2A). Bastadin 6 also inhibited VEGF- or bFGF-induced tubular formation (0.1 micromol/l, 6 h treatment) and VEGF-induced migration (1 micromol/l, 4 h treatment) of HUVECs. Moreover, bastadin 6 almost completely blocked VEGF- or bFGF-induced in vivo neovascularization in the mice corneal assay and suppressed growth of s.c. inoculated A431 solid tumor in nude mice (100 mg/kg, i.p.). Bastadin 6 induced cell death of HUVECs with an apoptotic phenotype, whereas it showed no effect on the VEGF-induced auto-phosphorylation of VEGF receptors Flt-1 and KDR/Flk-1. These results suggest that the anti-angiogenic effect of bastadin 6 is closely related to selective induction activity of apoptosis against endothelial cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Apoptosis / drug effects*
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Carcinoma, Squamous Cell / blood supply*
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Carcinoma, Squamous Cell / drug therapy*
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Cell Growth Processes / drug effects
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Cornea / blood supply
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Endothelial Cells / cytology
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Endothelial Cells / drug effects*
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Fibroblast Growth Factor 2 / antagonists & inhibitors
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Fibroblast Growth Factor 2 / pharmacology
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Halogenated Diphenyl Ethers
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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NIH 3T3 Cells
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / pathology
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Neovascularization, Physiologic / drug effects
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Porifera / chemistry
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Rats
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Tyrosine / analogs & derivatives*
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Tyrosine / pharmacology
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / blood
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Halogenated Diphenyl Ethers
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Vascular Endothelial Growth Factor A
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bastadin 6
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Fibroblast Growth Factor 2
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Tyrosine
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2