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

Sung, ES; Kim, A; Park, JS; Chung, J; Kwon, MH; Kim, YS
Apoptosis : an international journal on programmed cell death, 15(10):1256-1269, 2010
Journal Title
Apoptosis : an international journal on programmed cell death
Cell-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.
MeSH terms
Antibodies, Monoclonal/pharmacologyAntineoplastic Agents/pharmacologyApoptosis/*drug effectsBlotting, WesternCaspases/metabolismCell Line, TumorDown-RegulationDrug SynergismFlow CytometryHistone Deacetylase Inhibitors/*pharmacologyHistone Deacetylases/metabolismHumansHydroxamic Acids/*pharmacologyInhibitor of Apoptosis Proteins/metabolismMitochondria/drug effects/metabolismPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism/*pathologyRNA, Small InterferingReceptors, Tumor Necrosis Factor/*immunology/*metabolismSignal Transduction/drug effectsTNF-Related Apoptosis-Inducing Ligand/metabolism/pharmacologyValproic Acid/*pharmacology
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Hematology-Oncology
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
AJOU Authors
박, 준성권, 명희
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