Sodium valproate potentiates staurosporine-induced apoptosis in neuroblastoma cells via Akt/survivin independently of HDAC inhibition

J Cell Biochem. 2013 Apr;114(4):854-63. doi: 10.1002/jcb.24422.


Sodium valproate (VPA) has been recently identified as a selective class I histone deacetylase (HDAC) inhibitor and explored for its potential as an anti-cancer agent. The anti-cancer properties of VPA are generally attributed to its HDAC inhibitory activity indicating a clear overlap of these two actions, but the underlying mechanisms of its anti-tumor effects are not clearly elucidated. The present study aimed to delineate the molecular mechanism of VPA in potentiating cytotoxic effects of anti-cancer drugs with focus on inhibition of HDAC activity. Using human neuroblastoma cell lines, SK-N-MC, SH-SY5Y, and SK-N-SH, we show that non-toxic dose (2 mM) of VPA enhanced staurosporine (STS)-induced cell death as assessed by MTT assay, PARP cleavage, hypodiploidy, and caspase 3 activity. Mechanistically, the effect of VPA was mediated by down regulation of survivin, an anti-apoptotic protein crucial in resistance to STS-mediated cytotoxicity, through Akt pathway. Knock down of class I HDAC isoforms remarkably inhibited HDAC activity comparable with that of VPA but had no effect on STS-induced apoptosis. Moreover, MS-275, a structurally distinct class I HDAC inhibitor did not affect STS-mediated apoptosis, nor decrease the levels of survivin and Akt. Valpromide (VPM), an amide analog of VPA that does not inhibit HDAC also potentiated cell death in NB cells associated with decreased survivin and Akt levels suggesting that HDAC inhibition might not be crucial for STS-induced apoptosis. The study provides new information on the possible molecular mechanism of VPA in apoptosis that can be explored in combination therapy in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Benzamides / pharmacology
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Drug Synergism
  • Enzyme Activation
  • G2 Phase Cell Cycle Checkpoints
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyridines / pharmacology
  • Staurosporine / pharmacology*
  • Survivin
  • Valproic Acid / analogs & derivatives
  • Valproic Acid / pharmacology*


  • Antineoplastic Agents
  • BIRC5 protein, human
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Inhibitor of Apoptosis Proteins
  • Isoenzymes
  • Pyridines
  • Survivin
  • entinostat
  • Valproic Acid
  • AKT1 protein, human
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt
  • CASP3 protein, human
  • Caspase 3
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Staurosporine
  • dipropylacetamide