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The Therapeutic Properties of Resminostat for Hepatocellular Carcinoma

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The Therapeutic Properties of Resminostat for Hepatocellular Carcinoma www.impactjournals.com/oncoscience Oncoscience, Vol. 5(5-6), May 2018 The therapeutic properties of resminostat for hepatocellular carcinoma Jun Zhao1, Steven G. Gray2, Martin Wabitsch3, Catherine M. Greene4 and Matthew W. Lawless1 1 Experimental Medicine, UCD School of Medicine and Medical Science, Mater Misericordiae University Hospital, Dublin, 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, Ireland Correspondence to: Jun Zhao, email: [email protected] Keywords: HDAC inhibitor resminostat; HCC; adipocytes; HSP90 inhibitor 17-AAG; ER stress/UPR Received: August 16, 2017 Accepted: March 03, 2018 Published: June 23, 2018 Copyright: Zhao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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. INTRODUCTION such as DNA methylation, histone modification, chromatin structure remodelling and non-coding RNA interactions The concept of epigenetics was first introduced [4]. While the onset and development of hepatocellular as an important element in embryonic development by carcinoma (HCC) have been attributed to several factors Conrad Hal Waddington in 1942 [1]. Recent advances at both cellular and physiological levels, epigenetic have elucidated epigenetic functions in many biological alterations are receiving an increased attention in the processes and global alterations in the epigenetic investigation of the pathogenesis and pharmaceutical landscape have been proposed as a hallmark of cancer targeting of liver cancer due to their nature of reversibility. [2, 3]. In fact, epigenetic mechanisms are fundamental in To-date, several independent genome-wide cellular homeostasis and include a broad range of activities methylation profiling studies have revealed an aberrant www.impactjournals.com/oncoscience 196 Oncoscience DNA methylation pattern in HCC tumour samples thus allowing gene transcription. In contrast, HDACs compared to adjacent normal liver tissue suggesting generate a non-permissive chromatin structure inhibiting potential diagnostic and prognostic epigenetic signatures the expression of their target genes. Moreover, epigenetic for liver cancer patients [5-7]. At the cellular level, targeted therapy such as HDAC inhibition has become DNA strands are coiled around the histone tails to form one of the most promising anti-cancer strategies due to chromatin. Histone modifications such as acetylation/ the reversibility of aberrant epigenetic changes during deacetylation and methylation on histone tails allow the oncogenesis [12]. Currently, Sorafenib is the only Food activation or inhibition of specific genes, the aberrant and Drug Administration (FDA) approved pharmaceutical expression of which are associated with HCC onset and agent for advanced HCC patients, giving them a 3 month progression. Indeed, a recent cohort study carried out in extended survival time. Resminostat is a novel oral pan- 170 HCC patients has shown that class I HDACs (HDAC HDAC inhibitor specifically targeting class I HDACs that 1, 2 and 3) were highly expressed in HCC tumour tissues has attracted attention from its use in a phase II clinical compared to adjacent normal tissues [8]. In addition, trial for HCC patients. The recent SHELTER study overexpression of HDAC1 and 2 is strongly associated examining Resminostat in combination with Sorafenib with poor prognosis and higher mortality rates in HCC showed a promising 8 month survival time for advanced patients [9-11]. Histone acetylation and deacetylation HCC patients [13]. are sub-types of epigenetic mechanisms balancing the We have previously described that close interactions expression of critical genes involved in tumorigenesis between hepatic tumorigenesis and adipocytes are such as proliferation, cell-cycle regulation and apoptosis. associated with a series of negative cellular events Histone acetylation is regulated by histone acetyl involving, angiogenesis, inflammation, insulin transferases (HATs) loosening the chromatin structure, homeostasis and immunomodulation that may give rise to B. A. ** C. ** * Hep3B * * + SGBS CM (Day 14) Figure 1: Effects of CM on HDACs in human adipocytes and liver cancer cells.Liver cancer cell line (Hep3B) and differentiated human adipocyte SGBS were cultured alone or treated with 30% of the CM from each other for 24 hours (n = 3). Their global HDAC activities were measured with FluoroFire HDAC Activity Assay Kit. (A) Global HDAC activity in Hep3B and differentiated SGBS cells. (B) Global HDAC activities in Hep3B and differentiated SGBS cells treated with CM from each other.(C) The mRNA expression levels of class I HDACs (HDAC 1, 2, 3 and 8) and class II HDAC (HDAC6) were measured in Hep3B cells treated with 30% differentiated SGBS CM by RT-PCR and presented as fold change compared to control (untreated cells). www.impactjournals.com/oncoscience 197 Oncoscience hepatocarcinogenesis [14]. Here we investigate epigenetic Surprisingly, CM from Hep3B cells increased the global alterations in the tumour microenvironment involving cell- HDAC activities of differentiated SGBS cells by nearly to-cell communication between HCC and adipocytes. 3-fold (Figure 1B). While CM from differentiated Simpson-Golabi-Behmel syndrome (SGBS) cells did not RESULTS change the global HDAC activities of Hep3B cells, it did however specifically increase the expression of the class I HDACs (HDAC 1, 2 and 8) at the mRNA level (Figure Effects of conditioned medium on HDACs in 1C). Differentiated SGBS CM also decreased the gene human adipocytes and liver cancer cells expression of HDAC6 in Hep3B cells at the mRNA level (Figure 1C). A recent cohort study carried out in 170 HCC Class I HDAC inhibitor Resminostat inhibits the patients has shown that class I HDACs (HDAC 1, 2 proliferation of HCC cells and 3) were highly expressed in HCC tumour tissues compared to adjacent normal tissues [8]. We examined the global HDAC activities in liver cancer Hep3B cells We selected a class I HDAC inhibitor Resminostat and differentiated human adipocytes SGBS cells. We as a potential pharmaceutical agent against HCC. found that differentiated human adipocytes had 62.33% Resminostat underwent a phase II clinical trial exhibiting less HDAC activity compared to HCC cells (Figure 1A). promising clinical outcomes in both safety and survival We then measured the global HDAC alterations in (i) in advanced HCC patients. Hep3B cells were treated with Hep3B cells treated with 30% conditioned medium (CM) Resminostat in a dose range of 20 nM, 40 nM, 60 nM, 80 from differentiated SGBS cells and (ii) differentiated nM and 100 nM for 24 hours. Resminostat showed an anti- SGBS cells treated with 30% CM from Hep3B cells. proliferative effect on Hep3B cells in a dose dependent A. ** ** B. C. *** ** ** * * ** * * ** + Resminostat (80 nM) Figure 2: The anti-proliferative effect of Class I HDAC inhibitor Remininostat on HCC cells with and without SGBS CM. (A) Hep3B cells were treated with Resminostat in a dose range from 20 nM to 100 nM for 24 hours and their proliferation was measured with FluoroFire-Blue ProViaTox assay and presented as fold change compared to control (untreated cells) (n = 3). (B) Hep3B, HepG2 and Huh7 cells were treated with Resminostat (80 nM) and their proliferation were measured and presented as fold change compared to control (untreated cells). (C) The proliferation of Hep3B, HepG2 and Huh7 cells treated with SGBS CM (30%) alone or SGBS CM (30%) in combination with Resminostat (80 nM) for
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