Bastadin 6, a spongean brominated tyrosine derivative, inhibits tumor angiogenesis by inducing selective apoptosis to endothelial cells.

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.

• Authors: Shunji Aoki, Seok-hwan Cho, Mayumi Ono, Takashi Kuwano, Shintaro Nakao, Michihiko Kuwano, Shinsaku Nakagawa, Jian-Qing Gao, Tadanori Mayumi, Masabumi Shibuya, Motomasa Kobayashi
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 17 Issue 3 Pg. 269-78 (Mar 2006) ISSN: 0959-4973 [Print] England
• PMID: 16520655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Halogenated Diphenyl Ethers
• Vascular Endothelial Growth Factor A
• bastadin 6
• Fibroblast Growth Factor 2
• Tyrosine
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Apoptosis (drug effects)
• Carcinoma, Squamous Cell (blood supply, drug therapy)
• Cell Growth Processes (drug effects)
• Cornea (blood supply)
• Endothelial Cells (cytology, drug effects)
• Fibroblast Growth Factor 2 (antagonists & inhibitors, pharmacology)
• Halogenated Diphenyl Ethers
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NIH 3T3 Cells
• Neovascularization, Pathologic (drug therapy, pathology)
• Neovascularization, Physiologic (drug effects)
• Porifera (chemistry)
• Rats
• Tyrosine (analogs & derivatives, pharmacology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, blood, pharmacology)
• Vascular Endothelial Growth Factor Receptor-1 (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Xenograft Model Antitumor Assays