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

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

doi:10.3390/ijms20123052

Jan J Bandolik, Alexandra Hamacher + Show 3 more

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https://doi.org/10.3390/ijms20123052

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Abstract

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.

Highlights

Ovarian cancer is one of the most lethal gynecological cancer subtypes, such as uterus, breast, cervical or vulva cancer
HDAC inhibitors (HDACi) are able to enhance the chemosensitivity of tumors for platinum-based drugs by normalizing the dysregulated process
Pan-HDACi have no selectivity towards an histone deacetylase (HDAC) isoform or class and can cause severe side effects as known for panobinostat [47,48,49]

Summary

Introduction

Ovarian cancer is one of the most lethal gynecological cancer subtypes, such as uterus, breast, cervical or vulva cancer. Compared to the other gynecological cancers, ovarian cancers have the worst survival rate over five years (47.6%, USA; 41%, Germany). Type II ovarian cancer is clinically very aggressive and consists of high grade serous ovarian cancer (HGSOC). Resistance develops and leads to relapse and therapeutic failure. Combination therapies with small molecule inhibitors are a widely used strategy to increase the platinum sensitivity of the tumor or to prevent/delay the development of therapeutic resistance [13,14]. There are several known overexpression patterns of histone deacetylase (HDAC) enzymes in different cancer subtypes leading to transcriptional repression [15]. An overexpression of HDACs - especially of class I HDACs - is described and correlates with its aggressiveness. It is described that chemotherapy leads to an upregulation of HDAC1 expression [19]

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Conclusion