Comparison of Radiosensitization by HDAC Inhibitors CUDC-101 and SAHA in Pancreatic Cancer Cells

Pancreatic cancer has a poor prognosis. New treatment options are urgently required to improve patient outcomes. One promising new class of anticancer drugs are synthetic histone deacetylase inhibitors (HDACi) which modulate chromatin structure and gene expression by blocking histone deacetylation....

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Main Authors: Simone Moertl, Sarah Payer, Rosemarie Kell, Klaudia Winkler, Natasa Anastasov, Michael J. Atkinson
Format: Article
Language:English
Published: MDPI AG 2019-07-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/20/13/3259
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spelling doaj-aa9064628ab54a7089657d86c355da932020-11-25T01:42:51ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-07-012013325910.3390/ijms20133259ijms20133259Comparison of Radiosensitization by HDAC Inhibitors CUDC-101 and SAHA in Pancreatic Cancer CellsSimone Moertl0Sarah Payer1Rosemarie Kell2Klaudia Winkler3Natasa Anastasov4Michael J. Atkinson5Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Radiation Biology, 85764 Neuherberg, GermanyHelmholtz Center Munich, German Research Center for Environmental Health, Institute of Radiation Biology, 85764 Neuherberg, GermanyHelmholtz Center Munich, German Research Center for Environmental Health, Institute of Radiation Biology, 85764 Neuherberg, GermanyHelmholtz Center Munich, German Research Center for Environmental Health, Institute of Radiation Biology, 85764 Neuherberg, GermanyHelmholtz Center Munich, German Research Center for Environmental Health, Institute of Radiation Biology, 85764 Neuherberg, GermanyHelmholtz Center Munich, German Research Center for Environmental Health, Institute of Radiation Biology, 85764 Neuherberg, GermanyPancreatic cancer has a poor prognosis. New treatment options are urgently required to improve patient outcomes. One promising new class of anticancer drugs are synthetic histone deacetylase inhibitors (HDACi) which modulate chromatin structure and gene expression by blocking histone deacetylation. In this study, we aimed at comparing the in vitro capacities of the HDACi SAHA and CUDC-101 to increase radiosensitivity of human pancreatic tumor cell lines. Therefore, three pancreatic cancer cell lines (Su.86.86, MIA Paca-2, T3M-4) were treated with SAHA (1.5−5 µM) or CUDC-101 (0.25−3 µM) and after 24 h irradiated. Cell proliferation, clonogenic survival and apoptosis was determined. Additionally, cell lysates were investigated for the expression of apoptosis-related proteins. CUDC-101 and SAHA increased the radiation sensitivity of pancreatic tumor cell lines in a dose-dependent manner. This was evidenced by cell proliferation and clonogenic survival. Furthermore, enhanced radiation sensitivity after CUDC-101 or SAHA treatment was confirmed for Su.86.86 and T3M-4 cells in a 3-D microtissue approach. Increased amounts of subG1 cells and diminished full length PARP-1 suggest increased radiation-induced apoptosis after SAHA or CUDC-101 treatment. The comparison of both inhibitors in these assays manifested CUDC-101 as more potent radiosensitizer than SAHA. In line, western blot quantification of the apoptosis-inhibitory proteins XIAP and survivin showed a stronger down-regulation in response to CUDC-101 treatment than after SAHA application. These proteins may contribute to the synergy between HDAC inhibition and radiation response. In conclusion, these preclinical results suggest that treatment with the HDAC inhibitors CUDC-101 or SAHA can enhance radiation-induced cytotoxicity in human pancreatic cells. However, comparison of both inhibitors identified the multi target inhibitor CUDC-101 as more potent radiosensitizer than the HDAC inhibitor SAHA.https://www.mdpi.com/1422-0067/20/13/3259HDAC inhibitorpancreatic cancerionizing radiationapoptosis
collection DOAJ
language English
format Article
sources DOAJ
author Simone Moertl
Sarah Payer
Rosemarie Kell
Klaudia Winkler
Natasa Anastasov
Michael J. Atkinson
spellingShingle Simone Moertl
Sarah Payer
Rosemarie Kell
Klaudia Winkler
Natasa Anastasov
Michael J. Atkinson
Comparison of Radiosensitization by HDAC Inhibitors CUDC-101 and SAHA in Pancreatic Cancer Cells
International Journal of Molecular Sciences
HDAC inhibitor
pancreatic cancer
ionizing radiation
apoptosis
author_facet Simone Moertl
Sarah Payer
Rosemarie Kell
Klaudia Winkler
Natasa Anastasov
Michael J. Atkinson
author_sort Simone Moertl
title Comparison of Radiosensitization by HDAC Inhibitors CUDC-101 and SAHA in Pancreatic Cancer Cells
title_short Comparison of Radiosensitization by HDAC Inhibitors CUDC-101 and SAHA in Pancreatic Cancer Cells
title_full Comparison of Radiosensitization by HDAC Inhibitors CUDC-101 and SAHA in Pancreatic Cancer Cells
title_fullStr Comparison of Radiosensitization by HDAC Inhibitors CUDC-101 and SAHA in Pancreatic Cancer Cells
title_full_unstemmed Comparison of Radiosensitization by HDAC Inhibitors CUDC-101 and SAHA in Pancreatic Cancer Cells
title_sort comparison of radiosensitization by hdac inhibitors cudc-101 and saha in pancreatic cancer cells
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1422-0067
publishDate 2019-07-01
description Pancreatic cancer has a poor prognosis. New treatment options are urgently required to improve patient outcomes. One promising new class of anticancer drugs are synthetic histone deacetylase inhibitors (HDACi) which modulate chromatin structure and gene expression by blocking histone deacetylation. In this study, we aimed at comparing the in vitro capacities of the HDACi SAHA and CUDC-101 to increase radiosensitivity of human pancreatic tumor cell lines. Therefore, three pancreatic cancer cell lines (Su.86.86, MIA Paca-2, T3M-4) were treated with SAHA (1.5−5 µM) or CUDC-101 (0.25−3 µM) and after 24 h irradiated. Cell proliferation, clonogenic survival and apoptosis was determined. Additionally, cell lysates were investigated for the expression of apoptosis-related proteins. CUDC-101 and SAHA increased the radiation sensitivity of pancreatic tumor cell lines in a dose-dependent manner. This was evidenced by cell proliferation and clonogenic survival. Furthermore, enhanced radiation sensitivity after CUDC-101 or SAHA treatment was confirmed for Su.86.86 and T3M-4 cells in a 3-D microtissue approach. Increased amounts of subG1 cells and diminished full length PARP-1 suggest increased radiation-induced apoptosis after SAHA or CUDC-101 treatment. The comparison of both inhibitors in these assays manifested CUDC-101 as more potent radiosensitizer than SAHA. In line, western blot quantification of the apoptosis-inhibitory proteins XIAP and survivin showed a stronger down-regulation in response to CUDC-101 treatment than after SAHA application. These proteins may contribute to the synergy between HDAC inhibition and radiation response. In conclusion, these preclinical results suggest that treatment with the HDAC inhibitors CUDC-101 or SAHA can enhance radiation-induced cytotoxicity in human pancreatic cells. However, comparison of both inhibitors identified the multi target inhibitor CUDC-101 as more potent radiosensitizer than the HDAC inhibitor SAHA.
topic HDAC inhibitor
pancreatic cancer
ionizing radiation
apoptosis
url https://www.mdpi.com/1422-0067/20/13/3259
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