Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells

Br J Cancer. 2005 Feb 28;92(4):751-9. doi: 10.1038/sj.bjc.6602309.


Neuroblastoma (NB), a sympathetically derived childhood tumour, shows characteristics of neuronal precursor cells, suggesting a halted differentiation process. We have previously shown that the Notch signalling cascade, a key player during normal neurogenesis, also might be involved in NB differentiation. Valproic acid (VPA), a well-tolerated antiepileptic drug, has been shown to induce differentiation and cell death of NB cells, possibly associated with its recently described HDAC inhibiting activity. Stimulation of NB cells with VPA led to increased cell death and phenotypic changes associated with differentiation, that is, neurite extension and upregulation of neuronal markers. VPA treatment also led to an activated Notch signalling cascade as shown by increased levels of intracellular Notch-1 and Hes-1, mimicking the initial phase of induced differentiation. These results reinforce that VPA potentially could be used in differentiation therapy of NB and that the effects in part could be a consequence of interference with the Notch signalling cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticonvulsants / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Northern
  • Blotting, Western
  • Cell Line, Tumor
  • DNA, Complementary / chemical synthesis
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Flow Cytometry
  • Histone Deacetylase Inhibitors*
  • Homeodomain Proteins / drug effects
  • Homeodomain Proteins / metabolism
  • Humans
  • Luciferases / analysis
  • Membrane Proteins / drug effects*
  • Membrane Proteins / metabolism*
  • Neuroblastoma / enzymology
  • Neuroblastoma / metabolism*
  • Phenotype
  • RNA, Neoplasm / isolation & purification
  • Receptor, Notch1
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / metabolism
  • Receptors, Notch
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Transcription Factor HES-1
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism
  • Valproic Acid / pharmacology*


  • ASCL1 protein, human
  • Anticonvulsants
  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA, Complementary
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Homeodomain Proteins
  • Membrane Proteins
  • NOTCH1 protein, human
  • RNA, Neoplasm
  • Receptor, Notch1
  • Receptors, Cell Surface
  • Receptors, Notch
  • Transcription Factor HES-1
  • Transcription Factors
  • HES1 protein, human
  • Valproic Acid
  • Luciferases