Oncoscience

The therapeutic properties of resminostat for hepatocellular carcinoma

Jun Zhao 1, Steven G. Gray 2, Martin Wabitsch 3, Catherine M. Greene 4, Matthew W. Lawless 1

1 Experimental Medicine, UCD School of Medicine and Medical Science, Mater Misericordiae University Hospital, Dublin 7, Ireland

2 Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity Translational Medicine Institute, St. James’s Hospital & Trinity College Dublin, Ireland

3 Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, University of Ulm, Ulm, Germany

4 Clinical Microbiology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland

Correspondence to:

Jun Zhao, email: zhaoju@tcd.ie

Keywords: HDAC inhibitor resminostat, HCC, adipocytes, HSP90 inhibitor 17-AAG, ER stress/UPR

Received: August 16, 2017 Accepted: March 02, 2018 Published: June 23, 2018

Abstract

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with increases in new cases being reported annually. Histopathologists have identified hepatic steatosis as a characteristic of a broad range of chronic liver diseases that are associated with the onset and development of HCC. In this context, epigenetic modifications may serve as precancerous factors predisposing normal cells to the initiation of carcinogenesis. This study demonstrated that hepatic tumorigenesis and differentiated adipocytes may modulate both global histone deacetylase (HDAC) expression and specific class I HDAC genes in the tumour microenvironment. The novel class I HDAC inhibitor Resminostat was shown to reduce the proliferation of HCC cells along with its specificity in targeting class I HDACs and oncogenes. The combined effect of Resminostat with several pharmaceutical agents such as Sorafenib, Cisplatin and Doxorubicin was also demonstrated. The inhibition of heat shock protein 90 (HSP90) has been demonstrated as a potential therapeutic option for HCC. In line with this, the specific HSP90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was selected and it was found that the combination of Resminostat and 17-AAG may provide a “smart” clinical strategy for HCC patients by targeting cellular communication within the tumour microenvironment. This study provides an insight into the use of Resminostat as an epigenetic based therapeutic for HCC along with other pharmaceutical options, in particular by targeting the cell-to-cell communication that occurs between hepatoma and adipocytes.


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