HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma

Oncogene. 2005 Jul 7;24(29):4609-23. doi: 10.1038/sj.onc.1208585.


Histone deacetylase (HDAC) inhibitors induce differentiation and/or apoptosis in a variety of cell types by activating transcription of target genes. Activation of the death receptor (DR) pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis preferentially in cancer cells. Here, we investigated the intracellular mechanisms by which HDAC inhibitors (suberoylanilide hydroxamic acid, m-carboxycinnamic acid bis-hydroxamide, MS-275 and trichostatin A) enhance the apoptosis-inducing potential of TRAIL in breast cancer cells in vitro. A synergism in apoptosis was observed in both TRAIL-sensitive and -resistant cells upon sequential treatments with HDAC inhibitors followed by TRAIL. HDAC inhibitors synergized with TRAIL by inducing DRs DR4/TRAIL-R1 and DR5/TRAIL-R2 through NFkappaB activation and some of the proapoptotic members of the Bcl-2 family, and engaging the mitochondrial pathway. The ability of HDAC inhibitors to sensitize TRAIL-resistant cells suggests that HDAC inhibitors may induce fundamental alterations in cell signaling pathways. Thus, the sequential treatments with HDAC inhibitors followed by TRAIL may be used as a new therapeutic approach for the treatment of human cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Enzyme Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors*
  • Humans
  • Membrane Glycoproteins / physiology*
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / physiology*


  • Apoptosis Regulatory Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Membrane Glycoproteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha