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Published on: April 2, 2020
KR-31372 inhibits KDR/Flk-1 tyrosine phosphorylation via K+(ATP) channel opening in its antiangiogenic effect
Ki Young Kim1, Sun-Ok Kim, Hong Lim
1Department 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.
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.
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