title: Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling.
abstract: Interaction between vascular endothelial growth factor (VEGF) and its cognate receptors, KDR/Flk-1 and Flt-1, of vascular endothelial cells is expected to induce an angiogenesis "switch" in tumors and other angiogenesis-associated diseases. SU5416, a selective inhibitor of the KDR/Flk-1 tyrosine kinase, is known to be a potent inhibitor of tumor angiogenesis. In this study, we first observed that SU5416 inhibited Flt-1 tyrosine kinase activity at similar doses, in addition to inhibiting KDR/Flk-1 tyrosine kinase activity in response to VEGF. SU5416 inhibited cell migration of human vascular endothelial cells expressing both Flt-1 and KDR in response to VEGF and also inhibited the cell migration in response to placenta growth factor (PIGF), a specific ligand for Flt-1. Chemotaxis of monocytes expressing only Flt-1 was also inhibited by SU5416 in a dose-dependent manner. Moreover, SU5416 was found to inhibit tyrosine kinase of Flt-1 in response to PIGF in vitro. And angiogenesis induced by PIGF in a Matrigel plug assay was inhibited by administration of SU5416. The antiangiogenic effects by this VEGF receptor-targeting compound appeared to be mediated through interference not only with KDR/Flk-1 but also with Flt-1. Cell migration of vascular endothelial cells and monocytic cells through Flt-1, thus, might play a key role in VEGF-induced tumor angiogenesis in concert with KDR/Flk-1.
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Itokawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nokihara
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamada
authors.forename: Julie
authors.initials: J
authors.lastname: Cherrington
authors.forename: Gerald
authors.initials: G
authors.lastname: McMahon
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
mesh_terms: D016475:3T3 Cells; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis; D003094:Collagen / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology*; D007797:Laminin / Q000494:pharmacology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D018995:Myosin Heavy Chains; D009389:Neovascularization, Pathologic; D024501:Nonmuscle Myosin Type IIB; D010766:Phosphorylation; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011509:Proteoglycans / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D014162:Transfection; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D018076:DNA, Complementary; D004338:Drug Combinations; D016326:Extracellular Matrix Proteins; D007211:Indoles; D007797:Laminin; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011509:Proteoglycans; D011758:Pyrroles; C059485:matrigel; D000072483:Placenta Growth Factor; C116890:Semaxinib; D003094:Collagen; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D011505:Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains