Journal 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

Hamacher, Alexandra, Bandolik, Jan J., Schrenk, Christian, Weishaupt, Robin, Kassack, Matthias U.

2019

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Apoptosis / Benzamides - pharmacology / Benzamides - therapeutic use / Cell cycle / Cell Line, Tumor / Cell Survival / Chemotherapy / Cisplatin - therapeutic use / Cystadenocarcinoma, Serous - drug therapy / Cystadenocarcinoma, Serous - enzymology / Cystadenocarcinoma, Serous - physiopathology / Cytotoxicity / DNA methylation / Drug Synergism / Enzymes / Female / Gene expression / Gynecology / Histone Deacetylase Inhibitors - pharmacology / Histone Deacetylase Inhibitors - therapeutic use / Histone Deacetylases / Humans / Hydroxamic Acids - pharmacology / Hydroxamic Acids - therapeutic use / Investigations / Ovarian cancer / Ovarian Neoplasms - drug therapy / Ovarian Neoplasms - enzymology / Ovarian Neoplasms - physiopathology / Panobinostat - pharmacology / Panobinostat - therapeutic use / Phenylurea Compounds - pharmacology / Phenylurea Compounds - therapeutic use / Protein expression / Proteins / Pyridines - pharmacology / Pyridines - therapeutic use