KR-31372 inhibits KDR/Flk-1 tyrosine phosphorylation via K+(ATP) channel opening in its antiangiogenic effect.
The aim of this study was to identify the signaling pathway of the antiangiogenesis by (2R,3R,4S)-N-cyano-N-(6-nitro-3,4-dihydro-hydroxy-2-methyl-2-dimethoxymethyl 2H-1-benzopyran-4yl)-N'-benzylguanidine (KR-31372). KR-31372 inhibited the in vitro basal tube formation using Matrigel-coated plate and in vivo neovascularizations in mice induced by Matrigel containing vascular endothelial growth factor (VEGF(165), 5 ng/ml). VEGF(165) markedly increased cell proliferation using 5-bromo-2'-deoxyuridine incorporation and chemotactic migration using transwell chamber in human umbilical vein endothelial cells, those of which were significantly suppressed by pretreatment with KR-31372 and levcromakalim concentration dependently. The suppression of all these variables were strongly antagonized by glibenclamide, ATP-sensitive K(+) channel blocker. KR-31372 (10(-6)-10(-4) M) and levcromakalim (10(-5) M) concentration-dependently suppressed the VEGF(165)-induced increases in KDR/Flk-1 tyrosine phosphorylation as well as the extracellular signal-related kinase 1/2 (ERK1/2), p38 MAK and p125(FAK) tyrosine phosphorylation. These variables were significantly antagonized by glibenclamide. In conclusion, KR-31372 significantly inhibited the KDR/Flk-1 tyrosine phosphorylation-linked ERK1/2, p38 MAPK and p125(FAK) tyrosine phosphorylation via mediation of K(+)(ATP) channel opening, thereby resulting in antiangiogenesis.
Kim
Ki Young
KY
Department of Pharmacology, College of Medicine, Research Institute of Genetic Engineering, Pusan National University, 10 Ami-Dong 1 Ga, Seo-Gu, Busan 602-739, South Korea.
Kim
Sun-Ok
SO
Lim
Hong
H
Yoo
Sung-Eun
SE
Hong
Ki Whan
KW
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002478:Cells, Cultured; D002633:Chemotaxis; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000648:ultrastructure; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D015640:Ion Channel Gating; D007797:Laminin; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011509:Proteoglycans; D014443:Tyrosine / Q000378:metabolism*; D014471:Umbilical Veins; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000502:physiology*; D042442:Vascular Endothelial Growth Factors / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases
D001578:Benzopyrans; D004338:Drug Combinations; C419651:KR 31372; D007797:Laminin; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D011509:Proteoglycans; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; D014443:Tyrosine; D000255:Adenosine Triphosphate; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases