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Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells.

DC Field Value Language
dc.contributor.authorSung, ES-
dc.contributor.authorKim, A-
dc.contributor.authorPark, JS-
dc.contributor.authorChung, J-
dc.contributor.authorKwon, MH-
dc.contributor.authorKim, YS-
dc.date.accessioned2011-05-17-
dc.date.available2011-05-17-
dc.date.issued2010-
dc.identifier.issn1360-8185-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/2612-
dc.description.abstractCell-death signaling through the pro-apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, death receptor 4 (DR4) and DR5, has shown tumor-selective apoptotic activity. Here, we examine susceptibility of various leukemia cell lines (HL-60, U937, K562, CCRF-CEM, CEM-CM3, and THP-1) to an anti-DR4 agonistic monoclonal antibody (mAb), AY4, in comparison with TRAIL. While most of the leukemia cell lines were intrinsically resistant to AY4 or TRAIL alone, the two T-cell acute lymphoblastic leukemia (T-ALL) lines, CEM-CM3 and CCRF-CEM cells, underwent synergistic caspase-dependent apoptotic cell death by combination of AY4 or TRAIL with a histone deacetylase inhibitor (HDACI), either suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). All of the combined treatments synergistically downregulated several anti-apoptotic proteins (c-FLIP, Bcl-2, Bcl-X(L), XIAP, and survivin) without significant changing the expression levels of pro-apoptotic proteins (Bax and Bak) or the receptors (DR4 and DR5). Downregulation of c-FLIP to activate caspase-8 was a critical step for the synergistic apoptosis through both extrinsic and intrinsic apoptotic pathways. Our results demonstrate that the HDACIs have synergistic effects on DR4-specific mAb AY4-mediated cell death in the T-ALL cells with comparable competence to those exerted by TRAIL, providing a new strategy for the targeted treatment of human T-ALL cells.-
dc.language.isoen-
dc.subject.MESHAntibodies, Monoclonal/pharmacology-
dc.subject.MESHAntineoplastic Agents/pharmacology-
dc.subject.MESHApoptosis/*drug effects-
dc.subject.MESHBlotting, Western-
dc.subject.MESHCaspases/metabolism-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHDown-Regulation-
dc.subject.MESHDrug Synergism-
dc.subject.MESHFlow Cytometry-
dc.subject.MESHHistone Deacetylase Inhibitors/*pharmacology-
dc.subject.MESHHistone Deacetylases/metabolism-
dc.subject.MESHHumans-
dc.subject.MESHHydroxamic Acids/*pharmacology-
dc.subject.MESHInhibitor of Apoptosis Proteins/metabolism-
dc.subject.MESHMitochondria/drug effects/metabolism-
dc.subject.MESHPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism/*pathology-
dc.subject.MESHRNA, Small Interfering-
dc.subject.MESHReceptors, Tumor Necrosis Factor/*immunology/*metabolism-
dc.subject.MESHSignal Transduction/drug effects-
dc.subject.MESHTNF-Related Apoptosis-Inducing Ligand/metabolism/pharmacology-
dc.subject.MESHValproic Acid/*pharmacology-
dc.titleHistone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells.-
dc.typeArticle-
dc.identifier.pmid20582477-
dc.contributor.affiliatedAuthor박, 준성-
dc.contributor.affiliatedAuthor권, 명희-
dc.type.localJournal Papers-
dc.identifier.doi10.1007/s10495-010-0521-9-
dc.citation.titleApoptosis : an international journal on programmed cell death-
dc.citation.volume15-
dc.citation.number10-
dc.citation.date2010-
dc.citation.startPage1256-
dc.citation.endPage1269-
dc.identifier.bibliographicCitationApoptosis : an international journal on programmed cell death, 15(10):1256-1269, 2010-
dc.identifier.eissn1573-675X-
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Hematology-Oncology
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology

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