title: 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.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, Pusan National University, Busan, Korea. kwhong@pusan.ac.kr
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Jae Moon
authors.initials: JM
authors.lastname: Choi
authors.forename: Yong-Geun
authors.initials: YG
authors.lastname: Kwak
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
authors.forename: Byung Yong
authors.initials: BY
authors.lastname: Rhim
mesh_terms: D016923:Cell Death; D002879:Chromosomes, Human, Pair 10; D000077407:Cilostazol; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004347:Drug Interactions; D017353:Gene Deletion; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000070876:Tensins; D013777:Tetrazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000070876:Tensins; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077407:Cilostazol