Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy

Oncol Rep. 2006 Jan;15(1):227-30. doi: 10.3892/or.15.1.227.


Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy, leading to a poor prognosis of advanced disease. Inhibitors of histone deacetylase (HDACi) induce re-differentiation in tumor cells and thereby re-establish sensitivity towards apoptotic stimuli. HDACi are entering the clinical stage of tumor treatment, and several substances are currently being tested in clinical trials to prove their efficacy in the treatment of leukemias and solid tumors. In this study, we investigated the impact of the HDACi valproic acid (VA) on TRAIL- and CD95-mediated apoptosis in hepatoma cells, as well as its sensitizing effect on a chemotherapeutic agent. Treatment of HepG2 cells with VA increased sensitivity to CD95-mediated apoptosis (4% apoptosis vs. 42%), and treatment with epirubicin (74% vs. 90% viability). Caspase-3 activity was significantly enhanced in cells treated with VA plus anti-CD95 antibodies compared to cells treated with antibodies alone. In parallel, VA strongly augmented the effect of TNF-related apoptosis-inducing ligand (TRAIL or Apo2 ligand) on HepG2 cells (10% vs. 58% apoptosis). VA induced down-regulation of cellular FLICE-inhibitory protein (c-FLIP/CASH, also known as Casper/iFLICE/FLAME-1/CLARP/MRIT/usurpin), providing a possible molecular mechanism underlying the increased sensitivity towards cell death-mediated apoptosis. HDAC inhibitors are a promising class for the treatment of leukemias. In addition, among other class members, VA deserves further evaluation as a treatment option for patients with advanced HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis Regulatory Proteins / therapeutic use
  • Apoptosis*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / enzymology
  • Caspase 3
  • Caspases / metabolism
  • Down-Regulation
  • Drug Resistance, Neoplasm / drug effects
  • Epirubicin / administration & dosage
  • Epirubicin / therapeutic use
  • Histone Deacetylase Inhibitors*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / enzymology
  • Membrane Glycoproteins / therapeutic use
  • Receptors, Tumor Necrosis Factor / agonists
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / therapeutic use
  • Valproic Acid / administration & dosage
  • Valproic Acid / therapeutic use*
  • fas Receptor / metabolism


  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Histone Deacetylase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Epirubicin
  • Valproic Acid
  • CASP3 protein, human
  • Caspase 3
  • Caspases