Elsevier

International Journal of Cardiology

Volume 219, 15 September 2016, Pages 396-403
International Journal of Cardiology

Cardiovascular effects of histone deacetylase inhibitors epigenetic therapies: Systematic review of 62 studies and new hypotheses for future research

https://doi.org/10.1016/j.ijcard.2016.06.012Get rights and content

Abstract

Background

Epigenetic regulation by Histone Deacetylases (HDACs) plays an important role in multiple pathophysiological processes, including tumor growth and cardiovascular diseases. HDAC inhibitors (HDACi) have emerged as important therapeutic agents for multiple human cancers, and several randomized clinical trials have been recently undertaken to test their safety and efficacy in cancer patients. Although HDACi have shown beneficial effects in several preclinical models of cardiovascular diseases, concerns have emerged regarding their potential cardiac toxic effects. The present study assessed the extent and possible significance of cardiovascular adverse effects induced by HDACi administration.

Methods and results

Based on the available published clinical trials reporting cardiovascular effects of HDACi therapy in cancer patients, 62 studies for a total patient population of 3268 were included to perform a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) requirements. A further analysis was conducted to evaluate cardiovascular effects of the different drugs among the HDACi class. Overall, only a minority of studies reported cardiovascular effect of HDACi, and showed mild but frequent cardiovascular side effects after HDACi treatment in cancer patients.

Conclusions

Future studies will be required to better determine the role and the mechanisms underlying cardiovascular effects of HDACi in the context of oncological therapy and beyond.

Introduction

Cardiovascular diseases (CVD) and cancer are the leading global causes of death. One of the most rapidly expanding areas of research in both fields is epigenetics, entailing DNA methylation and post-translational modifications (PTMs) of histones modulating gene expression without alterations of the DNA sequence [1]. Acetylation, the most widely studied PTM, is tightly regulated by histone acetyl-transferases (HATs) and de-acetylases (HDACs) [1], and its role has been extensively investigated over the last decades in CVD [2]. HDACs are conventionally classified in four classes (I, II, III and IV) wherein class I, II and IV are “zinc-dependent” enzymes and class III includes a particular subgroup of “nicotinamide adenine dinucleotide (NAD)-dependent” proteins called sirtuins. Reduced gene expression coupled with increased activity of HDACs (mostly class I, II and IV) is a hallmark of different types of cancer, and therefore targeting HDACs is emerging as an important therapeutic option in several malignancies [3]. Compounds acting as HDAC inhibitors (HDACi) [4] have been shown to reduce cell proliferation, promote differentiation and/or apoptosis of cancer cells in vitro and in vivo [4], [5]. The biological and therapeutic outcome of HDAC inhibition is dependent on the specificity of the compound. Since sirtuins are not inhibited by conventional HDACi, the majority of HDACi “class-effects” depend on the inhibition of class I, II and IV HDACs [6]. So far, three HDACi have been approved by the U.S. Food and Drug Administration (FDA) for patients with cutaneous T-cell lymphoma (CTCL): Vorinostat (ZOLINZA™, Merck), Romidepsin (ISTODAX™, Celegene Corporation) and Belinostat (BELEODAQ™, Spectrum Pharmaceuticals, Inc.), and one has been approved for multiple myeloma: Panobinostat (FARYDAK™, Novartis Pharms Corp.). Other molecules, such as Entinostat, also proved their activity as HDACi in pre-clinical and clinical settings [6], but have not yet received the approval by the FDA. The anticonvulsant valproic acid (VPA) has HDAC inhibitory activity, as well, and has been extensively used in combination with more common anti-cancer drugs (i.e. cisplatin, epirubicin, doxorubicin).

Although genetic inhibition of specific classes of HDACs has yielded controversial results in terms of cardiac remodeling and function under pathological conditions, global pharmacological HDACs inhibition has shown potential beneficial effects in preclinical models of CVD [7]. However, phase I and II clinical trials of HDACi in cancer have recently raised concerns on potential cardiac toxicity of HDACi, suggesting a potential cardiotoxic effect [8], that has been subsequently re-dimensioned [9]. Given such spare and contrasting evidence, we performed a systematic analysis based on published clinical trials, in order to elucidate the potential detrimental cardiovascular effects of HDACi used in phase I, II and III oncological trials.

Section snippets

Study selection

The study was designed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) requirements. PubMed and ISI Web of Science were searched by entering the following terms in the searching algorithm: HDACi or Romidepsin or Valproate or Vorinostat or Belinostat or Panobinostat or Entinostat and cardiac side effect and heart. No temporal limitation was applied. English was set as a language restriction. Two authors (AS and GGS) independently examined the title and

Results

The initial search identified 808 articles, of which 85 were retrieved for more detailed evaluation, and 62 [6], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71] trials were finally

Discussion

This systematic review shows that HDACi administration to cancer patients induces mild but frequent cardiac side effects, mainly ECG abnormalities including ST/T abnormalities and QT prolongation. Unfortunately, the real incidence of cardiac side events induced by HDACi is difficult to establish, since the vast majority of clinical trials involving these drugs did not assess or report this information. Future studies will be needed to determine the extent, prognostic significance and mechanisms

Sources of funding

This work was supported, in part, by grants from the Italian Ministry of Health (GR-2009-1,596,220) and from the Italian Ministry of University (RBFR124FEN) to CP (Naples, ITALY).

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

Disclosures

None.

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