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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Arvidsson, Y; Johanson, V; Pfragner, R; Wängberg, B; Nilsson, O.
Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells.
Neuroendocrinology. 2016; 103(5):578-591 Doi: 10.1159/000441849
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Pfragner Roswitha

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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. 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. 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. 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. © 2015 S. Karger AG, Basel.
Find related publications in this database (using NLM MeSH Indexing)
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 -

Find related publications in this database (Keywords)
Neuroendocrine tumour
Histone deacetylase inhibitor
Valproic acid
Cell cycle
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