The histone deacetylase inhibitor vorinostat prevents TNFα-induced necroptosis by regulating multiple signaling pathways

Apoptosis. 2013 Nov;18(11):1348-1362. doi: 10.1007/s10495-013-0866-y.

Abstract

Histone deacetylase (HDAC) inhibitors are novel anticancer reagents that have recently been reported to have anti-inflammatory and neuroprotective effects; however, the mechanisms underlying their activities are largely undefined. The data from this study show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can protect L929 cells from TNFα-induced necroptosis. This effect involves multiple mechanisms, including the upregulation of cFLIPL expression, the enhanced activation of NFκB and p38 MAPK, and the inactivation of JNK. In addition, SAHA could initiate cell autophagy by inhibiting Akt and mTOR, which also play important roles in protecting cells from necroptosis. Because cell necroptosis is important for inflammation-related deterioration and neurodegenerative disease, our results indicate that preventing cell necrosis may be an important mechanism through which HDAC inhibitor compounds exert their anti-inflammatory or neuroprotective effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Autophagy / drug effects
  • CASP8 and FADD-Like Apoptosis Regulating Protein / agonists
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Cell Line, Tumor
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation
  • Histone Deacetylase Inhibitors / pharmacology*
  • Hydroxamic Acids / pharmacology*
  • MAP Kinase Kinase 4 / antagonists & inhibitors
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • NF-kappa B / agonists
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Necrosis / prevention & control*
  • Neuroprotective Agents / pharmacology*
  • Oncogene Protein v-akt / antagonists & inhibitors
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Vorinostat
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • NF-kappa B
  • Neuroprotective Agents
  • Tumor Necrosis Factor-alpha
  • Vorinostat
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Oncogene Protein v-akt
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4