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.
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.
Authors: Tobias Hofving; Yvonne Arvidsson; Bilal Almobarak; Linda Inge; Roswitha Pfragner; Marta Persson; Göran Stenman; Erik Kristiansson; Viktor Johanson; Ola Nilsson Journal: Endocr Relat Cancer Date: 2018-03 Impact factor: 5.678
Authors: Clare L Killick-Cole; William G B Singleton; Alison S Bienemann; Daniel J Asby; Marcella J Wyatt; Lisa J Boulter; Neil U Barua; Steven S Gill Journal: PLoS One Date: 2017-05-25 Impact factor: 3.240
Authors: Julia Wanek; Martin Gaisberger; Marlena Beyreis; Christian Mayr; Katharina Helm; Florian Primavesi; Tarkan Jäger; Pietro Di Fazio; Martin Jakab; Andrej Wagner; Daniel Neureiter; Tobias Kiesslich Journal: Int J Mol Sci Date: 2018-10-12 Impact factor: 5.923
Authors: Annamaria Colao; Filomena de Nigris; Roberta Modica; Claudio Napoli Journal: Front Endocrinol (Lausanne) Date: 2020-12-15 Impact factor: 5.555