Antiangiogenic effect of KR-31372 by apoptosis via mediation of mitochondrial K-ATP channel opening and the phosphatase and tensin homolog deleted from chromosome 10 phosphorylation

作者：Kim KY; Shin YW; Kim SO; Lim H; Yoo SE; Hong KW^*

来源：Journal of Pharmacology and Experimental Therapeutics, 2003, 305(3): 1142-1149.

DOI：10.1124/jpet.103.048819

Antiangiogenic action of (2R, 3R, 4S)- N"-cyano-N-(6-nitro- 3,4-dihydro- hydroxy-2-methyl-2-dimethoxymethyl-2H-1-benzopyran-4yl)- N'-benzyl guanidine (KR-31372) was examined with its proapoptotic action in human umbilical vein endothelial cells (HUVECs) compared with diazoxide. KR-31372 as well as diazoxide significantly suppressed the neovascularization in mice induced by the Matrigel-containing recombinant human vascular endothelial growth factor (VEGF)(165) in vivo and the basal tube formation of HUVECs in vitro with suppression of proliferation of HUVECs stimulated by VEGF(165). KR-31372 and diazoxide enhanced DNA fragmentation associated with increase in phosphatase and tensin homolog deleted from chromosome 10 ( PTEN) and decrease in serine/threonine kinase phosphorylation, which were accompanied by augmented Bax and cytochrome c release, and suppressed Bcl-2 in HUVECs. In the U87-MG cells, when transfected with expression vectors for sense PTEN, KR-31372 enhanced DNA fragmentation, but not in naive U87-MG cells. The suppression by KR-31372 and diazoxide of these variables was significantly antagonized by 5-hydroxydecanoic acid, a mitochondrial K-ATP channel blocker. Taken together, KR-31372 strongly inhibited angiogenesis in HUVECs by proapoptotic mechanism via mediation of 5-hydroxydecanoic acid-inhibitable mitochondrial K-ATP channel opening and PTEN phosphorylation.

• 出版日期2003-6