Histone deacetylase inhibitors potentiate tnf-related apoptosis-inducing ligand (Trail)-induced apoptosis in lymphoid malignancies

S. Inoue, M. Macfarlane, N. Harper, L. M.C. Wheat, M. J.S. Dyer, G. M. Cohen

Research output: Contribution to journalArticlepeer-review

149 Citations (Scopus)

Abstract

New therapies are required for chronic lymphocytic leukemia (CLL), an incurable disease characterized by failure of mature lymphocytes to undergo apoptosis. Activation of cell surface death receptors, such as via TRAIL receptor ligation, may provide a novel therapeutic target for various malignancies. However, CLL and other lymphoid malignancies are resistant to TRAIL. We report that low concentrations of histone deacetylase (HDAC) inhibitors, such as depsipeptide, which alone failed to induce apoptosis, markedly sensitize CLL cells and other primary lymphoid malignancies to TRAIL-induced apoptosis. These combinations caused little or no toxicity to normal lymphocytes. HDAC inhibitors sensitized resistant cells to TRAIL-induced apoptosis by facilitating formation of an active death-inducing signalling complex (DISC), leading to the rapid activation of caspase-8. The facilitated DISC formation also occurred in the absence of TRAIL-R2 upregulation. Thus, the combination of HDAC inhibitors and TRAIL may be valuable in the treatment of various hemopoietic malignancies.

Original languageEnglish
Pages (from-to)S193-S206
JournalCell Death and Differentiation
Volume11
DOIs
Publication statusPublished - 2004
Externally publishedYes

Keywords

  • Chronic lymphocytic leukemia
  • Depsipeptide
  • Disc
  • Histone deacetlyase inhibitors
  • Tumor necrosis factorrelated apoptosis-inducing ligand

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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