Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

Abstract

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.

Methotrexate and Valproic Acid Affect Early Neurogenesis of Human Amniotic Fluid Stem Cells from Myelomeningocele

“…These data suggested that MTX and VPA severely affected neural and RG commitment. In addition, as expected [ 39 , 40 ], both drugs negatively impacted cell proliferation, as shown by a decrease on the amount of Ki67 + cells.…”

Repurposing the anti-epileptic drug sodium valproate as an adjuvant treatment for diffuse intrinsic pontine glioma

“…These findings are consistent with other in vitro cancer studies, which have demonstrated IC 50 ranging from 3–10 mM for ovarian and uterine sarcoma cells, and 4.5–8 mM for thoracic (oesophageal and non-small cell lung) cancer cells [29, 30]. Much lower cytotoxic IC 50 of 0.89–1.92 mM have been noted in neuroendocrine tumours, but this required drug exposure times of up to seven days [31]. …”

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

“…DNA methylases inhibitor and HDAC inhibitor have been extensively used in vitro in both PanNET and small intestine cell lines showing results in terms of reducing cell viability and increasing gene expression (Baradari et al 2006, Habbe et al 2007, Alexander et al 2010, Arvidsson et al 2016. Interestingly, Decitabine increased the expression of SSTR2 and the Ga-DOTATOC uptake in BON1 tumour-bearing mice, indicating a possible therapy implication in re-expression the target for somatostatin receptor-based radiotherapy (Taelman et al 2016).…”