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Updated: Mar 31, 2026
Viability Assays for Cells in Culture
Published on: January 20, 2014
Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells
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.
Insights
Valproic acid (VPA) inhibits neuroendocrine tumour (NET) cell growth by inducing apoptosis and altering gene expression. This study suggests VPA as a potential epigenetic therapy for NET patients.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Histone deacetylases (HDACs) are frequently deregulated in cancer.
- HDAC inhibitors show potent anti-tumour effects and are in clinical trials.
- Valproic acid (VPA) is a class I and IIa HDAC inhibitor.
Purpose of the Study:
- To investigate the effects of VPA on neuroendocrine tumour (NET) cell growth.
- To explore the mechanisms of VPA's anti-tumour activity in NET cells.
Main Methods:
- Three NET cell lines (GOT1, KRJ-I, BON) were treated with VPA.
- Assessed cell viability, cell cycle arrest, apoptosis, and global transcriptional response.
- Analyzed GOT1 xenografts for tumor growth, proliferation (Ki-67), apoptosis, and necrosis.
Main Results:
- VPA induced dose-dependent growth inhibition of NET cells via apoptosis.
- VPA significantly altered the expression of 16-19% of protein-coding genes.
- VPA treatment reduced tumor growth and proliferation, increasing apoptosis and necrosis in xenografts.
Conclusions:
- VPA exhibits cytotoxic effects on intestinal and pancreatic NET cells.
- VPA-induced cell death involves multiple mechanisms, suggesting combination therapy potential.
- Epigenetic therapy with HDAC inhibitors warrants further evaluation in NET patients.
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