The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species

Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10833-8. doi: 10.1073/pnas.191208598. Epub 2001 Sep 4.


Many chemotherapeutic agents induce mitochondrial-membrane disruption to initiate apoptosis. However, the upstream events leading to drug-induced mitochondrial perturbation have remained poorly defined. We have used a variety of physiological and pharmacological inhibitors of distinct apoptotic pathways to analyze the manner by which suberoylanilide hydroxamic acid (SAHA), a chemotherapeutic agent and histone deacetylase inhibitor, induces cell death. We demonstrate that SAHA initiates cell death by inducing mitochondria-mediated death pathways characterized by cytochrome c release and the production of reactive oxygen species, and does not require the activation of key caspases such as caspase-8 or -3. We provide evidence that mitochondrial disruption is achieved by means of the cleavage of the BH3-only proapoptotic Bcl-2 family member Bid. SAHA-induced Bid cleavage was not blocked by caspase inhibitors or the overexpression of Bcl-2 but did require the transcriptional regulatory activity of SAHA. These data provide evidence of a mechanism of cell death mediated by transcriptional events that result in the cleavage of Bid, disruption of the mitochondrial membrane, and production of reactive oxygen species to induce cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 10
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Cytochrome c Group / metabolism
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / metabolism*
  • Hydroxamic Acids / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • Vorinostat


  • Antineoplastic Agents
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Carrier Proteins
  • Cytochrome c Group
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Vorinostat
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 10
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases
  • CASP10 protein, human