Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines
High grade serous ovarian cancer (HGSOC) is the most common and aggressive ovarian cancer subtype with the worst clinical outcome due to intrinsic or acquired drug resistance. Standard treatment involves platinum compounds. Cancer development and chemoresistance is often associated with an increase...
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doaj-c20cdc3b305f492fbcd78a2de0f826a42020-11-25T02:01:17ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-06-012012305210.3390/ijms20123052ijms20123052Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell LinesJan J. Bandolik0Alexandra Hamacher1Christian Schrenk2Robin Weishaupt3Matthias U. Kassack4Institute for Pharmaceutical and Medicinal Chemistry, University of Duesseldorf, 40225 Duesseldorf, GermanyInstitute for Pharmaceutical and Medicinal Chemistry, University of Duesseldorf, 40225 Duesseldorf, GermanyInstitute for Pharmaceutical and Medicinal Chemistry, University of Duesseldorf, 40225 Duesseldorf, GermanyInstitute for Computer Science, Computational Complexity and Cryptology, University of Duesseldorf, 40225 Duesseldorf, GermanyInstitute for Pharmaceutical and Medicinal Chemistry, University of Duesseldorf, 40225 Duesseldorf, GermanyHigh grade serous ovarian cancer (HGSOC) is the most common and aggressive ovarian cancer subtype with the worst clinical outcome due to intrinsic or acquired drug resistance. Standard treatment involves platinum compounds. Cancer development and chemoresistance is often associated with an increase in histone deacetylase (HDAC) activity. The purpose of this study was to examine the potential of HDAC inhibitors (HDACi) to increase platinum potency in HGSOC. Four HGSOC cell lines with different cisplatin sensitivity were treated with combinations of cisplatin and entinostat (class I HDACi), panobinostat (pan-HDACi), or nexturastat A (class IIb HDACi), respectively. Inhibition of class I HDACs by entinostat turned out superior in increasing cisplatin potency than pan-HDAC inhibition in cell viability assays (MTT), apoptosis induction (subG1), and caspase 3/7 activation. Entinostat was synergistic with cisplatin in all cell lines in MTT and caspase activation assays. MTT assays gave combination indices (CI values) < 0.9 indicating synergism. The effect of HDAC inhibitors could be attributed to the upregulation of pro-apoptotic genes (<i>CDNK1A</i>, <i>APAF1</i>, <i>PUMA</i>, <i>BAK1</i>) and downregulation of <i>survivin</i>. In conclusion, the combination of entinostat and cisplatin is synergistic in HGSOC and could be an effective strategy for the treatment of aggressive ovarian cancer.https://www.mdpi.com/1422-0067/20/12/3052cisplatinhigh grade serous ovarian cancer (HGSOC)histone deacetylase inhibitorscaspase activityantitumor platinum agentscombination treatmentpanobinostatentinostatnexturastat A |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jan J. Bandolik Alexandra Hamacher Christian Schrenk Robin Weishaupt Matthias U. Kassack |
spellingShingle |
Jan J. Bandolik Alexandra Hamacher Christian Schrenk Robin Weishaupt Matthias U. Kassack Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines International Journal of Molecular Sciences cisplatin high grade serous ovarian cancer (HGSOC) histone deacetylase inhibitors caspase activity antitumor platinum agents combination treatment panobinostat entinostat nexturastat A |
author_facet |
Jan J. Bandolik Alexandra Hamacher Christian Schrenk Robin Weishaupt Matthias U. Kassack |
author_sort |
Jan J. Bandolik |
title |
Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines |
title_short |
Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines |
title_full |
Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines |
title_fullStr |
Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines |
title_full_unstemmed |
Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines |
title_sort |
class i-histone deacetylase (hdac) inhibition is superior to pan-hdac inhibition in modulating cisplatin potency in high grade serous ovarian cancer cell lines |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-06-01 |
description |
High grade serous ovarian cancer (HGSOC) is the most common and aggressive ovarian cancer subtype with the worst clinical outcome due to intrinsic or acquired drug resistance. Standard treatment involves platinum compounds. Cancer development and chemoresistance is often associated with an increase in histone deacetylase (HDAC) activity. The purpose of this study was to examine the potential of HDAC inhibitors (HDACi) to increase platinum potency in HGSOC. Four HGSOC cell lines with different cisplatin sensitivity were treated with combinations of cisplatin and entinostat (class I HDACi), panobinostat (pan-HDACi), or nexturastat A (class IIb HDACi), respectively. Inhibition of class I HDACs by entinostat turned out superior in increasing cisplatin potency than pan-HDAC inhibition in cell viability assays (MTT), apoptosis induction (subG1), and caspase 3/7 activation. Entinostat was synergistic with cisplatin in all cell lines in MTT and caspase activation assays. MTT assays gave combination indices (CI values) < 0.9 indicating synergism. The effect of HDAC inhibitors could be attributed to the upregulation of pro-apoptotic genes (<i>CDNK1A</i>, <i>APAF1</i>, <i>PUMA</i>, <i>BAK1</i>) and downregulation of <i>survivin</i>. In conclusion, the combination of entinostat and cisplatin is synergistic in HGSOC and could be an effective strategy for the treatment of aggressive ovarian cancer. |
topic |
cisplatin high grade serous ovarian cancer (HGSOC) histone deacetylase inhibitors caspase activity antitumor platinum agents combination treatment panobinostat entinostat nexturastat A |
url |
https://www.mdpi.com/1422-0067/20/12/3052 |
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