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Article

Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines

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Institute for Pharmaceutical and Medicinal Chemistry, University of Duesseldorf, 40225 Duesseldorf, Germany
2
Institute for Computer Science, Computational Complexity and Cryptology, University of Duesseldorf, 40225 Duesseldorf, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(12), 3052; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20123052
Received: 30 May 2019 / Revised: 19 June 2019 / Accepted: 20 June 2019 / Published: 22 June 2019
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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 (CDNK1A, APAF1, PUMA, BAK1) and downregulation of survivin. 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. View Full-Text
Keywords: cisplatin; high grade serous ovarian cancer (HGSOC); histone deacetylase inhibitors; caspase activity; antitumor platinum agents; combination treatment; panobinostat; entinostat; nexturastat A cisplatin; high grade serous ovarian cancer (HGSOC); histone deacetylase inhibitors; caspase activity; antitumor platinum agents; combination treatment; panobinostat; entinostat; nexturastat A
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MDPI and ACS Style

Bandolik, J.J.; Hamacher, A.; Schrenk, C.; Weishaupt, R.; Kassack, M.U. Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines. Int. J. Mol. Sci. 2019, 20, 3052. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20123052

AMA Style

Bandolik JJ, Hamacher A, Schrenk C, Weishaupt R, Kassack MU. 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. 2019; 20(12):3052. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20123052

Chicago/Turabian Style

Bandolik, Jan J., Alexandra Hamacher, Christian Schrenk, Robin Weishaupt, and Matthias U. Kassack 2019. "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 20, no. 12: 3052. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20123052

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