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Int. J. Mol. Sci. 2018, 19(10), 3128; https://doi.org/10.3390/ijms19103128

Pharmacological Inhibition of Class IIA HDACs by LMK-235 in Pancreatic Neuroendocrine Tumor Cells

1
Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
2
Biomedical Sciences, Salzburg University of Applied Sciences, 5412 Puch/Salzburg, Austria
3
Department of Biosciences, Research Division of Regeneration, Stem Cell Biology and Gerontology, University of Salzburg, 5020 Salzburg, Austria
4
Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria
5
Department for Radon Therapy Research, Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria
6
Gastein Research Institute, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria
7
Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
8
Cancer Cluster Salzburg, 5020 Salzburg, Austria
9
Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
10
Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
11
Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, 35033 Marburg, Germany
*
Author to whom correspondence should be addressed.
Received: 14 August 2018 / Revised: 18 September 2018 / Accepted: 29 September 2018 / Published: 12 October 2018
(This article belongs to the Special Issue Roles of HDACs and HDAC Inhibitors in Human Cancers)
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Abstract

Histone deacetylases (HDACs) play a key role in epigenetic mechanisms in health and disease and their dysfunction is implied in several cancer entities. Analysis of expression patterns in pancreatic neuroendocrine tumors (pNETs) indicated HDAC5 to be a potential target for future therapies. As a first step towards a possible treatment, the aim of this study was to evaluate the in vitro cellular and molecular effects of HDAC5 inhibition in pNET cells. Two pNET cell lines, BON-1 and QGP-1, were incubated with different concentrations of the selective class IIA HDAC inhibitor, LMK-235. Effects on cell viability were determined using the resazurin-assay, the caspase-assay, and Annexin-V staining. Western Blot and immunofluorescence microscopy were performed to assess the effects on HDAC5 functionality. LMK-235 lowered overall cell viability by inducing apoptosis in a dose- and time-dependent manner. Furthermore, acetylation of histone-H3 increased with higher LMK-235 concentrations, indicating functional inhibition of HDAC4/5. Immunocytochemical analysis showed that proliferative activity (phosphohistone H3 and Ki-67) decreased at highest concentrations of LMK-235 while chromogranin and somatostatin receptor 2 (SSTR2) expression increased in a dose-dependent manner. HDAC5 expression was found to be largely unaffected by LMK-235. These findings indicate LMK-235 to be a potential therapeutic approach for the development of an effective and selective pNET treatment. View Full-Text
Keywords: pancreatic neuroendocrine tumors; histone deacetylases; LMK-235; cytotoxicity; apoptosis pancreatic neuroendocrine tumors; histone deacetylases; LMK-235; cytotoxicity; apoptosis
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Wanek, J.; Gaisberger, M.; Beyreis, M.; Mayr, C.; Helm, K.; Primavesi, F.; Jäger, T.; Di Fazio, P.; Jakab, M.; Wagner, A.; Neureiter, D.; Kiesslich, T. Pharmacological Inhibition of Class IIA HDACs by LMK-235 in Pancreatic Neuroendocrine Tumor Cells. Int. J. Mol. Sci. 2018, 19, 3128.

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