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CELLULAR AND MOLECULAR

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

Departments of Pharmacology (K.Y.K., K.W.H.) and Internal Medicine (Y.W.S.), College of Medicine, and Research Institute of Genetic Engineering (K.W.H.), Pusan National University, Busan, Korea; Dongbu Hannong Chemical Co. (S.O.K., H.L.), Daejon, Korea; and Research Institute of Chemical Technology (S.-E.Y.), Daejon, Korea

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 VEGF₁₆₅. 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.

Address correspondence to: Dr. Ki Whan Hong, Department of Pharmacology, College of Medicine, Pusan National University, 10 Ami-Dong, 1-Ga, Seo-Gu Busan 602-739, Korea. E-mail: kwhong{at}pusan.ac.kr