Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

Neuroendocrinology. 2016;103(5):578-91. doi: 10.1159/000441849. Epub 2015 Oct 28.


Background/aims: Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class I and class IIa HDACs, on neuroendocrine tumour (NET) cell growth.

Methods: Three NET cell lines, GOT1 (small intestinal), KRJ-I (small intestinal), and BON (pancreatic), were treated with VPA and examined with respect to cell viability, cell cycle arrest, apoptosis, and global transcriptional response.

Results: We found that VPA induced a dose-dependent growth inhibition of NET cells in vitro, which was mainly due to activation of extrinsic and intrinsic apoptotic pathways. VPA induced a major transcriptional response by altering the expression of 16-19% of the protein-coding genes in NET cell lines. Pathway analysis allowed the prediction of alterations in key regulatory pathways, e.g. activation of TGF-β1, FOXO3, p53 signalling, and inhibition of MYC signalling. Analysis of GOT1 xenografts showed reduced growth and reduced Ki-67 index, as well as an increase in apoptosis and necrosis after VPA treatment.

Conclusions: We found that VPA treatment has a cytotoxic effect on NET cells of intestinal and pancreatic origin. There are several mechanisms by which VPA kills NET cells, which suggests the possibility of combination therapy. We propose that epigenetic therapy with HDAC inhibitors should be evaluated further in patients with NET disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / toxicity
  • Forkhead Box Protein O3 / genetics
  • Forkhead Box Protein O3 / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Mice, Nude
  • Neuroendocrine Tumors / drug therapy*
  • Neuroendocrine Tumors / pathology*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Valproic Acid / toxicity*
  • Xenograft Model Antitumor Assays


  • Enzyme Inhibitors
  • Forkhead Box Protein O3
  • Proto-Oncogene Proteins c-myc
  • Transforming Growth Factor beta1
  • Tumor Suppressor Protein p53
  • Valproic Acid
  • Histone Deacetylases