Cilostazol prevents tumor necrosis factor-alpha-induced cell death by suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and activation of Akt/cyclic AMP response element-binding protein phosphorylation.
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| Abstract |
This study examines the signaling mechanism by which cilostazol prevents neuronal cell death. Cilostazol ( approximately 0.1-100 microM) prevented tumor necrosis factor-alpha (TNF-alpha)-induced decrease in viability of SK-N-SH and HCN-1A cells, which was antagonized by 1 microM iberiotoxin, a maxi-K channel blocker. TNF-alpha did not suppress the viability of the U87-MG cell, a phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-null glioblastoma cell, but it did decrease viability of U87-MG cells transfected with expression vectors for the sense PTEN, and this decrease was also prevented by cilostazol. Cilostazol as well as 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619) and (3S)(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one (BMS 204352), maxi-K channel openers, prevented increased DNA fragmentation evoked by TNF-alpha, which were antagonizable by iberiotoxin. TNF-alpha-induced increased PTEN phosphorylation and decreased Akt/cyclic AMP response element-binding protein (CREB) phosphorylation were significantly prevented by cilostazol, those of which were antagonized by both iberiotoxin and paxilline, maxi-K channel blockers. The same results were evident in U87-MG cells transfected with expression vectors for sense PTEN. Cilostazol increases the K+ current in SK-N-SH cells by activating maxi-K channels without affecting the ATP-sensitive K+ channel. Thus, our results for the first time provide evidence that cilostazol prevents TNF-alpha-induced cell death by suppression of PTEN phosphorylation and activation of Akt/CREB phosphorylation via mediation of the maxi-K channel opening.
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| Authors | Ki Whan Hong, Ki Young Kim, Hwa Kyoung Shin, Jeong Hyun Lee, Jae Moon Choi, Yong-Geun Kwak, Chi Dae Kim, Won Suk Lee, Byung Yong Rhim |
| Journal | The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 306 Issue 3 Pg. 1182-90 (Sep 2003) ISSN: 0022-3565 [Print] United States |
| PMID | 12807996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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