Apoptosis

, Volume 15, Issue 10, pp 1256–1269

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

  • Eun-Sil Sung
  • Aeyung Kim
  • Joon Seong Park
  • Junho Chung
  • Myung-Hee Kwon
  • Yong-Sung Kim
Original Paper

DOI: 10.1007/s10495-010-0521-9

Cite this article as:
Sung, ES., Kim, A., Park, J.S. et al. Apoptosis (2010) 15: 1256. doi:10.1007/s10495-010-0521-9
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Abstract

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-XL, 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.

Keywords

Death receptor 4 Agonistic antibody TRAIL Histone deacetylase inhibitor Apoptosis 

Supplementary material

10495_2010_521_MOESM1_ESM.pdf (220 kb)
Supplementary material 1 (PDF 220 kb)

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Eun-Sil Sung
    • 1
  • Aeyung Kim
    • 1
  • Joon Seong Park
    • 2
  • Junho Chung
    • 3
  • Myung-Hee Kwon
    • 4
  • Yong-Sung Kim
    • 1
  1. 1.Department of Molecular Science and TechnologyAjou UniversitySuwonKorea
  2. 2.Department of Hematology-OncologyAjou University School of MedicineSuwonKorea
  3. 3.Department of Biochemistry and Molecular Biology and Cancer Research InstituteSeoul National University College of MedicineSeoulKorea
  4. 4.Department of MicrobiologyAjou University School of MedicineSuwonKorea

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