Cardiovascular effects of histone deacetylase inhibitors epigenetic therapies: Systematic review of 62 studies and new hypotheses for future research
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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2020, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsCitation Excerpt :Also, deaths were reported to occur in clinical trials with HDAC inhibitors, but it is uncertain whether death incidence was higher than what usually reported in clinical trials in the field of cancer [37]. With respect to possible cardiac toxicity, a systematic review reported that the use of HDAC inhibitors frequently caused the appearance of mild cardiac side effects, but it was not possible to state a clear incidence of cardiac side effect [38] due to the lack of the complete cardiac parameters and the concomitant use of other therapies. Of note, the clinical trial with MS-275 (Entinostat) included in this review showed 10.7% of incidence in heart failure.
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2018, Vascular PharmacologyCitation Excerpt :In this context, enzymes mediating histone de-acetylation (histone deacetylases, HDACs) negatively affect transcription. The recently emerged availability of clinically approved HDACs inhibitors (HDACi) has further highlighted the paramount importance of these epigenetic modifications in human diseases [8]. The patterns of histone lysine methylation and the transcriptional effects of this epigenetic mark are more complex.
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G.G.S. and A.S. equally contributed to this work.