KR-31372 inhibits KDR/Flk-1 tyrosine phosphorylation via K+(ATP) channel opening in its antiangiogenic effect

Ki Young Kim; Sun-Ok Kim; Hong Lim; Sung-Eun Yoo; Ki Whan Hong

doi:10.1016/s0014-2999(03)01493-6

KR-31372 inhibits KDR/Flk-1 tyrosine phosphorylation via K+(ATP) channel opening in its antiangiogenic effect

Eur J Pharmacol. 2003 Apr 4;465(3):219-28. doi: 10.1016/s0014-2999(03)01493-6.

Authors

Ki Young Kim¹, Sun-Ok Kim, Hong Lim, Sung-Eun Yoo, Ki Whan Hong

Affiliation

¹ 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.

PMID: 12681433
DOI: 10.1016/s0014-2999(03)01493-6

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism*
Animals
Benzopyrans / pharmacology*
Cells, Cultured
Chemotaxis
Collagen
Drug Combinations
Endothelium, Vascular / drug effects
Endothelium, Vascular / ultrastructure
Focal Adhesion Kinase 1
Focal Adhesion Protein-Tyrosine Kinases
Humans
Ion Channel Gating
Laminin
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases / metabolism
Neovascularization, Physiologic / drug effects*
Peptide Fragments / chemistry
Peptide Fragments / pharmacology
Phosphorylation
Potassium Channel Blockers / pharmacology*
Protein-Tyrosine Kinases / metabolism
Proteoglycans
Tyrosine / metabolism*
Umbilical Veins
Vascular Endothelial Growth Factor Receptor-2 / drug effects
Vascular Endothelial Growth Factor Receptor-2 / physiology*
Vascular Endothelial Growth Factors / chemistry
p38 Mitogen-Activated Protein Kinases

Substances

Benzopyrans
Drug Combinations
KR 31372
Laminin
Peptide Fragments
Potassium Channel Blockers
Proteoglycans
Vascular Endothelial Growth Factors
matrigel
Tyrosine
Adenosine Triphosphate
Collagen
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor Receptor-2
Focal Adhesion Kinase 1
Focal Adhesion Protein-Tyrosine Kinases
PTK2 protein, human
Ptk2 protein, mouse
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases