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Review

HDAC Inhibitors in Acute Myeloid Leukemia

by
Edurne San José-Enériz
1,2,†,
Naroa Gimenez-Camino
1,2,†,
Xabier Agirre
1,2,* and
Felipe Prosper
1,2,3,*
1
Área de Hemato-Oncología, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra (IDISNA), Universidad de Navarra, 31008 Pamplona, Spain
2
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
3
Departamento de Hematología, Clínica Universidad de Navarra, Universidad de Navarra, 31008 Pamplona, Spain
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2019, 11(11), 1794; https://doi.org/10.3390/cancers11111794
Submission received: 8 October 2019 / Revised: 5 November 2019 / Accepted: 12 November 2019 / Published: 14 November 2019
(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)
Browse Figure
Review Reports Versions Notes

Abstract

:
Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.

1. Introduction

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by the uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors in peripheral blood and bone marrow [1,2,3,4,5,6]. AML is the most common form of acute leukemia in adults, accounting for 80% of all patients diagnosed with acute leukemia. AML is a disease of the elderly, with a median age at diagnosis of 70 years. With increasing incidence in recent years, the overall incidence of this disease is 3.4 cases per 100,000 people, with 1.2 cases per 100,000 population at age 30, and more than 20 cases per 100,000 population at age 80 years [3,4,5,6,7,8]. Despite significant advances in understanding the molecular pathogenesis of the disease, AML treatment has remained unchanged for the past four decades and is still largely based on standard chemotherapy and the use of allogeneic hematopoietic stem cell transplantation. However, new drugs have been recently approved by the United States Food and Drug Administration (FDA) for AML, such as Gemtuzumab ozogamicin, enasidenib, midostaurin, glasdegib, venetoclax, ivosidenib, and gliteritinib [9]. Although disease-free survival and overall survival have improved in recent years, improvement has been mostly observed in younger patients. In fact, approximately 40% of patients younger than 60 years of age may obtain long-term disease-free survival with current therapy. However, in older patients, survival is significantly worse, and in fact there has been very limited improvement [3,4,5,6,8,10]. Unfortunately, older patients show a high rate of relapse with a notoriously poor outcome. Considering that AML occurs more commonly in older patients, this represents a huge challenge for AML drug therapy [3].
Historically, AML has been considered a genetic disease, but a number of recent studies have demonstrated that epigenetic changes participate in the pathogenesis of AML [11,12,13]. DNA methylation and histone modifications are the most extensively described epigenetic modifications associated with regulation of chromatin structure and gene expression. These modifications are catalyzed by epigenetic regulatory enzymes, such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs) [14,15,16]. In fact, most of these enzymes have been shown to be deregulated or mutated in several cancers and specifically in AML [15,16,17,18]. This fact, together with the evidence that epigenetic modifications are pharmacologically reversible, has placed epigenetic drugs at the center of both clinical and preclinical research in AML.
Since the role of DNA methylation and the effect of hypomethylating agents in AML has been recently reviewed [19,20], we will focus on the rationale for the use of HDAC inhibitors (HDACi) for AML treatment. Additionally, we will discuss the novel evidence regarding the synergistic effects, in preclinical and clinical studies in AML, of HDACi with DNA hypomethylating agents and other inhibitors.

2. Histone Acetylation

Nucleosomes are the fundamental units of chromatin and are composed of an octamer with four-core histones (histone 2A (H2A), histone 2B (H2B), histone 3 (H3), and histone 4 (H4)), with 146 base pairs of DNA wrapped around these histones. Each histone is composed of a structural domain and an unstructured amino terminal tail of 25–40 residues. Importantly, these histone tails can be altered by different post-translational modifications that can determine the interactions between the histone and other proteins [21], playing a key role in the transition between active and inactive chromatin states [22].
Among these modifications, one of the best characterized is the (de)acetylation of the histone tail. In this process, the lysine residues present mainly in the N-terminal region of histone tails are acetylated or deacetylated, leading to gene regulation. Acetylation leads to the neutralization of positive charge in lysine, and therefore, to weakening of the electrostatic interaction between histone and negatively charged DNA. Thus, histone acetylation opens the chromatin structure, allowing for the binding of transcription factors, leading to gene expression. Meanwhile, histone deacetylation confers a close chromatin structure and inhibits or decreases gene transcription. Regulation by histone (de)acetylation is involved in important processes, such as replication, chromatin packing, DNA repair, nucleosome-non-histone proteins interactions, cell apoptosis, senescence, differentiation, angiogenesis, or immunogenicity [21,23]. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) analyses have shown that histone acetylation is distributed in genomic regions defined as promoter or enhancer regions, and also throughout the transcribed regions of active genes [16,17,24,25]. It is important to emphasize that several proteins are also able to recognize and bind acetylated histone tails, such as bromodomain proteins or proteins with plant homeodomain (PHD) finger proteins [26].
Histone (de)acetylation is a highly dynamic process regulated by the epigenetic enzymes HATs and HDACs. These two large families of enzymes have opposite actions: HATs catalyze the transfer of an acetyl group from acetyl coenzyme A to the lysine residues of the histones [27,28] and are mainly divided into three major subfamilies, the GCN5-related N-acetyltransferase (GNAT), MYST, and CREB binding protein (CBP)/p300. HDACs instead catalyze the removal of acetyl functional groups from the lysine residues of the histones (Figure 1) [27,28,29], and 18 HDAC enzymes have been identified in mammals [23,30].

2.1. HDAC Classes

HDACs are divided into four family classes, with each class showing a different subcellular location and specificity. Class I HDACs includes HDAC1, HDAC2, HDAC3, and HDAC8, which are located mostly in the nucleus. Class II is in turn divided into two groups: class IIa, including HDAC4, HDAC5, HDAC7, and HDAC9; and class IIb, with HDAC6 and HDAC10. All of them are capable of shuttling between the nucleus and the cytoplasm, depending on different signals [18,31]. Class III includes the sirtuin (SIRT)1-7 sirtuin protein family. Finally, class IV only has one member, HDAC11, which is located both in the nucleus and in the cytoplasm. Class I, II, and IV HDACs are all Zn2+-dependent enzymes. However, class III HDACs require NAD+ instead of Zn2+ as a cofactor and they do not have protein sequence homology with the other HDACs classes (Table 1) [18,31].

2.2. HDACs: More Than Histone Deacetylases

It is well reported that global histone (de)acetylation levels are aberrantly altered in cancer, but HDACs are much more than histone deacetylases. Acetylation is a common post-translational modification of non-histone proteins that are also acetylated and deacetylated. Among these non-histone proteins, there are oncogenes, tumor-suppressor genes, transcription factors, chaperones, and cell signaling molecules, such as MYC, P53, or PTEN, which result in changes in protein stability, protein–protein interactions, and protein–DNA interactions [16,17,32]. Both histone and non-histone (de)acetylations are important regulators of different biological processes of the cells. In a general sense, HDACs should be more correctly called lysine deacetylases (KDACs).
One of the best characterized non-histone substrates among the HDACs is the tumor suppressor P53, which induces anti-proliferative effects in the cells, including growth arrest, apoptosis, and cell senescence, in response to various types of stress [33,34]. P53 acetylation, by p300/CBP or by the p300/CBP-associated factor (PCAF), increases its DNA-binding ability and consequently the transcriptional activation of its target genes, finally inducing the cell cycle arrest or apoptosis, depending on the cell type and nature of the cellular stress. However, deacetylation of P53 can be mediated by two different HDACs: HDAC1 and SIRT1. The HDAC1 complex specifically interacts with P53, inducing deacetylation and leading to its degradation. SIRT1 interacts with P53, inducing deacetylation of multiple lysine residues and suppressing the P53-dependent growth arrest and apoptosis, resulting in an increased risk of tumorigenesis [34].
HDACs may also play a role in the regulation of the immune system by targeting the transcriptional regulator STAT3 [34,35]. STAT3 is implicated in the regulation of growth and apoptosis of immune cells, playing a role in a variety of autoimmune diseases. This transcriptional regulator can be acetylated on a single lysine residue at position 685 by histone acetyltransferase p300, and deacetylated by class I HDACs. Interestingly, acetylation of STAT3 is critical for its stabilization, and thus for cytokine-stimulated DNA binding and transcriptional regulation [34,36].
The cytoskeletal protein α-tubulin is another non-histone protein that is regulated by dynamic acetylation and deacetylation. Reversible acetylation of α-tubulin has been implicated in the regulation of microtubule stability. The acetyltranferase responsible for this acetylation remains unknown, whereas HDAC6 and SIRT2 were found to deacetylate lysine at position 40 of α-tubulin in vitro and in vivo. HDAC6 over-expression leads to hypoacetylation of α-tubulin, resulting in an increase in cell motility. Furthermore, the epithelial mesenchymal transition mediated by the transforming growth factor beta 1 is accompanied by the HDAC6-dependent deacetylation of α-tubulin [34,37].

2.3. Implication of HDACs in Cancer

HDACs are important proteins that are directly implicated in the epigenetic regulation of gene expression and the control of cellular activities by reversing the histone acetylation status [38]. In essence, changes in chromatin structure due to histone (de)acetylation might result in decreased or increased gene transcription, altering gene expression levels. Indeed, gene expression determined by HDAC inhibition is not always increased, although the chromatin structure is loosened [21,39]. Therefore, it is not surprising that the deregulation of HDACs is related to the development of several diseases, particularly cancer. Several types of human tumors, including gastric, colorectal, liver, breast, lung cancers, and hematological malignancies, show aberrant HDAC expression, in many cases associated with advanced disease and poor prognosis in cancer [40,41,42,43,44,45,46]. Nevertheless, the amount of evidence that demonstrates the oncogenic role of HDAC overexpression is limited. A clear example is the overexpression of HDAC1 in prostate tumor cells, inducing cell proliferation and de-differentiation [47]. Meanwhile, it is well known that knockdown of HDACs lead to cell cycle arrest, decrease of proliferation, and induction of apoptosis or differentiation, among other anti-tumor effects [42].
In addition, somatic mutations of HDAC genes are not common events in cancer and their role in tumor development has not been studied in detail. Specifically, mutations of HDAC1 have been found in human liposarcomas, HDAC2 mutations have been found in epithelial cancers and colorectal cancer, HDAC4 mutations have been found in breast cancer, and mutations in HDAC9 have been found in prostate cancers [31,48,49,50,51]. These mutations may be related to the development and progression of tumors, although further investigation will be required to elucidate the real implication of these genetic alterations in the development or progression of human tumors.
In the case of AML, mutations in HDACs genes have not been detected, but interestingly, it has been described how these HDAC proteins are aberrantly recruited to specific gene promoters by abnormal oncogenic fusion proteins that occur in this disease, such as PML-RARα, PLZF-RARα, or AML1-ETO, mediating aberrant gene silencing contributing to leukemogenesis [52]. For instance, AML1-ETO chimeric fusion protein, typical of AML patients with the translocation t(8;21)(q22;q22), recruits HDAC1, HDAC2, and HDAC3, silencing AML1 target genes, and therefore leading to differentiation arrest and transformation [53,54,55]. In addition, the fusion proteins PML-RARα and PLZF-RARα recruit both HDACs and DNA methyltransferases (DNMTs), driving repression of RARα target genes [56,57,58]. Additionally, an interaction between HDACs and non-chimeric fusion proteins, such as BCL6, whose activity is controlled by acetylation, has been described in AML [59].

3. Histone Deacetylase Inhibitors (HDACi): Mechanism of Action and Role in AML

Histone deacetylase inhibitors are a family of natural and synthetic compounds that inhibit the functional activity of HDACs, altering the regulation of histone and non-histone proteins [23,60]. HDACi activities result in an increase in the acetylated levels of histones, in turn promoting the re-expression of different silenced genes in each cell type [61]. Although the exact mechanism of action of HDACi is still unclear, these compounds play important roles in epigenetic or non-epigenetic regulation in the cells, inducing cell death, apoptosis, differentiation, and cell cycle arrest in cancer cells [23,60].
Based on their chemical structures and enzymatic activities, HDACi can be classified most commonly into five groups: hydroximates, benzamides, cyclic tetrapeptides, aliphatic acids, and electrophilic ketones. HDACi may act specifically against one or two types of HDACs (HDAC isoform selective inhibitors) or against all types of HDACs (pan-inhibitors) (Table 2). Zinc-dependent HDACi are characterized by a structure divided into three domains: (1) a cap group or a surface recognition unit, (2) a zinc binding domain (ZBD), and (3) a linker domain that combines the above two parts together. The cap and linker domains contribute to ligand–receptor interactions and affect the selectivity of HDACi, whereas ZBD binds to the zinc ion, inhibiting HDACi activity [62,63].
HDACi has emerged as a promising therapeutic strategy for cancer therapy. Furthermore, these inhibitors have shown ability to induce differentiation, cell cycle arrest, and apoptosis in AML, leading to a good alternative for treatment, especially for those AML patients not suitable for intensive chemotherapy [23,60]. Despite the promising preclinical results of HDACi, these HDACi do not seem to be clinically effective as monotherapies in AML. However, combination strategies with a variety of anticancer drugs are being tested in clinical trials, showing significant anti-leukemic activity in hematological diseases as they enhance the action of some standard-of-care anti-AML treatments [99,145,146].

3.1. Hydroximates

Hydroximates were the first HDACi to be discovered, and are thus the most extensively studied, showing strong activities and simple structures [147,148]. These HDACi are unselective inhibitors that target HDAC classes I and II. In these HDACi, the hydroxamic acid binds directly to zinc in the active site pockets of HDACs, mainly through a sulfhydryl group [148].

3.1.1. Trichostatin A

Trichostatin A (TSA) was the first described hydroxamate-based HDACi. It is an antifungal antibiotic isolated from Streptomyces hygroscopicus with cytostatic and differentiating properties in mammalian cell culture [149]. Apparently, TSA promotes the expression of apoptosis-related genes, leading to reduced survival of cancer cells, thus slowing the progression of cancer [150,151]. TSA has also been described to induce cell differentiation by inhibition of HDACs in different tumors [152,153,154]. In vitro experiments carried out with AML cell lines showed that TSA decreased the main pathway for DNA repair, namely non-homologous end-joining (NHEJ). Its mechanism of action was the acetylation of repair factors and trapping of PARP1 at DNA double-strand brakes in chromatin, inducing leukemic toxicity and suggesting a possible synergistic effect of TSA with an inhibitor of PARP1 [155]. Other studies showed promising results with TSA in combination with Chaetocin, an inhibitor of the histone 3 lysine 9 methyltransferase SUV39H1, inducing apoptosis of AML cell lines and primary patient samples [64]. Moreover, the triple combination of TSA, the demethylating agent 5-aza-2′-deoxcytidine (Decitabine, 5-AZA-CdR), and the EZH2 inhibitor DZNep induced a significant synergistic anti-leukemic effect in AML cells by re-expressing several tumor suppressor genes [65]. However, this HDACi was only used in the laboratory because of its high toxicity.

3.1.2. Vorinostat

Vorinostat (SAHA) was the first marketed HDACi which promotes protein acetylation, modulates gene expression, induces differentiation, growth arrest, and apoptosis of tumor cells [156,157,158]. By binding to the active site of HDACs, this drug inhibits class I and class II HDAC enzymes, with predominant effects on class I HDACs, and has shown promising clinical activity against different hematological tumors [156,157]. Vorinostat rapidly moved through preclinical and clinical studies, and after several studies was approved by the United States Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL) [40,147,159,160]. Regarding AML, Vorinostat has demonstrated in vitro activity against AML cell lines, inducing apoptosis and inhibiting cell growth, and increasing differentiation induced by retinoic acid (ATRA) of acute promyelocytic leukemia (APL) cells [66,67,68]. These effects seem to be mediated by the induction of double-strand breaks and oxidative DNA damage by Vorinostat [161]. This HDACi also improved survival of mice with APL [67]. In spite of these preclinical promising results, a phase 2 study of Vorinostat as a monotherapy showed minimal activity in patients with relapsed AML and in selected untreated patients with high-risk AML, suggesting that future studies should focus on combinations with other drugs [162].
Numerous studies have demonstrated the synergistic effect in AML of Vorinostat in combination with other compounds, such as the aurora kinase inhibitor MK-0457 [69], the proteosome inhibitor NPI-0052 [70], cytosine arabinoside (also known as Cytarabine), Etoposide [71], the BH3-mimetic GX15-070 [72], the Wee1 inhibitor AZD1775 [73], or the FLT3 inhibitor BPR1J-340 [74], among others. Interestingly, several novel hybrid anticancer drugs with activity against AML cells have been developed, such as the SAHA–Bendamustine hybrid NL-101 [163] and the piperlongumine–SAHA hybrid inhibitor [75]. NL-101, which was developed by replacing the side chain of the alkylating agent Bendamustine with the hydroxamic acid of Vorinostat, presenting properties related to HDAC inhibition, DNA damage, and induced apoptosis of leukemic cells. The combination of the SAHA–Bendamustine hybrid inhibitor with the PARP inhibitor BMN673 had a strong synergistic effect in AML, inducing apoptosis and arresting cell cycle in vitro and prolonging mouse survival in vivo [164]. Once more, the mechanism of action of this drug is the induction of DNA damage. Several clinical trials have been carried out with Vorinostat in combination with several compounds, including Decitabine [76,77], Idarubicin [78], Idarubicin plus Cytarabine [79], Alvocidib [80], Gemtuzumab ozogamicin plus Azacitidine (AZA) [81,82], or Sorafenib plus Bortezomib [83]. The phase II trial of Vorinostat with chemotherapy agents Idarubicin and Cytarabine showed that when combined in this way, this epigenetic drug is safe and active in AML treatment. Indeed, this combination has been associated with high induction response rates without any changes in toxicity compare with Idarubicin–Cytarabine regimen [79]. A phase I/II study of Gemtuzumab ozogamicin in combination with Vorinostat and AZA showed that this triple combination has activity in older patients with refractory or relapsed AML [81]. However, when combining Vorinostat with AZA, overall survival of AML patients did not increase in comparison with those that were treated only with AZA [165]. Vorinostat has also been examined in combination with decitabine, administered either sequentially or concurrently in older patients with untreated AML or patients with relapsed or refractory AML, with both schedules being safe and tolerable. In spite of the number of patients evaluated being small, this study showed a better response in the concurrent schedule (response rate 46%) than the sequential treatment (response rate 14%) [76,77]. Another phase I clinical trial with Vorinostat in combination with Decitabine and Cytarabine in relapsed or refractory AML patients showed that this combination was generally well tolerated, with an overall response rate of 35% [166]. Recently, a phase I trial showed clinical response in poor-risk AML patients with the combination of sorafenib (FLT3/RAF inhibitor) and Vorinostat. Moreover, the clinical response was greater with the addition of Bortezomib to the previous combination (3% complete response (CR), 16% complete response with incomplete platelet recovery (CRi), and 5% partial response (PR)). In both studies, the up-regulation of tumor suppressor genes was observed in responding patients [83].

3.1.3. Panobinostat

Panobinostat (LBH589) is another hydroxamic acid-based HDACi found in all class I, II, and IV HDAC enzymes, with predominant effect on HDAC 1, 2, 3, and 6 and which is implicated in cancer development. This compound has been shown to increase the levels of CDKN1A (p21) and to induce hyperacetylation of H3 and H4 [167,168]. By inhibiting the functional activity of all HDACs, this drug promotes the accumulation of the acetylated histones and other non-histone proteins, which induces cell cycle arrest and apoptosis [168,169]. According to several studies, the median IC50 values of Panobinostat in different cancer cell lines are significantly lower and had at least ten-fold greater potency when compared with Vorinostat [170]. This drug has been approved by the FDA for the treatment of multiple myeloma (MM) [40,159,160]. In preclinical studies on AML, Panobinostat was shown to modulate the activity of multiple genes, demonstrating a potent anti-leukemic activity in cell lines and primary samples [62,99]. Nevertheless, Panobinostat showed a modest effect as a single agent in early phase clinical trials in advanced hematological malignancies, including AML, showing very low overall and partial response rates [101]. Thus, combination treatment is necessary to achieve a clinical effect. Many drugs have been explored in combination with Panobinostat in AML, such as Decitabine [84,85], AZA [86], BCL-2 inhibitor ABT-199 [87], Wee1 inhibitor MK-1175 [88], β-catenin antagonist BC2059 [89], LSD1 inhibitor SP2509 [90], BRD4 inhibitor JQ1 [91], FLT3 inhibitor AC220 [92], Bortezomib [93], CXCR4 antagonists [94], Doxorubicin [95], or DZnep [96].
All of these combinations showed anti-leukemic effects, inducing apoptosis and inhibiting cell proliferation of AML cell lines as well as primary leukemic cells from patients, and in most cases, improving survival of mice with AML. However, only a few of them have been tested in clinical trials. Preclinically, the combination of Panobinostat with the demethylating agent Decitabine led to a significant reduction in primary AML cell viability compared with either compound alone [85]. Additionally, the use of both compounds led to transcriptional changes in more genes than any drug alone [84]. Similar results were obtained with the combination of Panobinostat and AZA in AML, showing synergistic effects both in vitro and in vivo [86]. However, despite the promising data derived from the first phase Ib/II trial in high risk AML patients [171], the latest results of the clinical trials on AML examining Panobinostat and AZA were to some extent disappointing, with the combination of both drugs not demonstrating a significant advantage in comparison with AZA alone [97]. The combination of Panobinostat with LSD1 inhibitors has also shown synergistic effects [90]. However, a phase I trial with the LSD1 inhibitor GSK2879552 was stopped due to a negative risk–benefit assessment [98]. Finally, the phase Ib/II panobidara study showed that Panobinostat in combination with chemotherapy agents Cytarabine and Idarubicin is a safe and effective treatment for AML patients over 65 years of age. This study evaluated the activity of Panobinostat in combination with chemotherapy, followed by a maintenance phase with Panobinostat in monotherapy [99]. The combination of Panobinostat with Daunorubicin and Cytarabine was well tolerated and the results of this phase I clinical trial were promising [100]. However, another clinical trial showed that the addition of Panobinostat to Cytarabine and Mitoxantrane did not improve the treatment efficacy [101].

3.1.4. Belinostat

Belinostat (Beleodaq or PXD101) belongs to a new class of hydroxymic-type HDACi that acts by blocking zinc-based deacetylase enzymes of classes I, II, and IV (with predominant effect on HDAC1, 2, 3, and 6), thus inducing apoptosis of cancer cells. In several in vitro studies, this drug has shown cytotoxic effects or growth inhibition of solid tumors correlated with hyperacetylation of H4. Belinostat has been approved by the FDA in peripheral T-cell lymphoma [172,173,174]. Regarding AML, Belinostat has demonstrated an effective anti-leukemic effect in AML cell lines, especially in APL cells, promoting cell cycle arrest, inhibiting cell proliferation, and inducing apoptosis. Moreover, in combination with ATRA it accelerates granulocytic differentiation in APL cell lines [102,103]. However, in a phase II clinical study with patients with AML, the effect of Belinostat as a single agent was found to be minimal [175]. Some combinations have been explored in preclinical studies in AML, with the combination of Belinostat with DZnep being the most widely studied. Both compounds in combination with ATRA or ATRA plus Idarubicin induced apoptosis, inhibited cell growth, and enhanced cell differentiation of AML cell lines and patient samples in vitro [104], and increased survival in a mouse model of AML [105]. Additionally, interactions between Belinostat and the proteasome inhibitor Bortezomib, which has been approved for the treatment of refractory MM and mantle cell lymphoma, were investigated in AML. This study showed that Belinostat interacted synergistically with Bortezomib to induce apoptosis in both cultured and primary AML cells [106]. Finally, Zhou et al. reported in their study that the NEDD8-activating enzyme (NAE) inhibitors Pevenedistat and Belinostat interact synergistically by reciprocally disabling the DDR in diverse AML cell types. This Pevenedistat–Belinostat co-administration synergistically induced AML cell apoptosis with or without p53 deficiency or FLT3–internal tandem duplication, supporting further investigations of HDAC/NAE co-inhibitory strategy in AML [107].
Other hydroxamate-based HDACi have been recently tested in clinical studies, such as Givinostat (ITF2357) [176,177,178,179], Resminostat (4SC201) [180], Abexinostat (PCI-24781) [181,182,183,184], Quisinostat (JNJ-26481585) [185], and Pracinostat (SB939) [109,110], with all of them being HDAC pan-inhibitors except for Givinostat, which more specifically targets HDAC1, 2, 3, and 6. However, little information is available regarding AML. Givinostat has potent anti-leukemic activity in vitro and in vivo, inhibiting cell proliferation, inducing apoptosis of AML cell lines and primary samples, and increasing survival in mice with AML [186,187]. Interestingly, those cell lines positive for AML1/ETO were more sensitive to this inhibitor [186]. In the case of Abexinostat, this HDACi was tested in a phase I trial in AML patients with limited clinical benefit [182]. Pracinostat showed potent efficacy on AML in preclinical studies. Furthermore, treatment with Pracinostat in combination with the JAK2 inhibitor SB1518 showed in vitro and in vivo synergism, blocking cell proliferation, inducing apoptosis, and decreasing tumor growth [108]. A phase I clinical trial of Pracinostat alone or in combination with AZA in patients with AML or myelodysplastic syndromes (MDS) demonstrated that the efficacy of this agent was modest as a monotherapy, increasing clinical responses in combination with AZA in MDS patients [109]. Nevertheless, a phase 2 study in older patients with newly diagnosed AML showed very promising results, with CR rate of 42% [110]. Considering these encouraging results, in June 2017 a phase 3 study of Pracinostat in combination with AZA was initiated for the treatment of adults with newly diagnosed AML who are unfit to receive intensive chemotherapy. In this multicenter, double-bind, randomized study, patients will be divided in two groups: an experimental group that will receive Pracinostat plus AZA and a control group that will receive placebo plus AZA. Study treatment is to be continued until disease progression, relapse from complete remission, or unacceptable toxicity. Results for this trial are expected by 2021 [111]. These good results could be related to improved pharmacokinetic and pharmacodynamic properties in contrast to other HDACi, including higher oral bioavailability and accumulation in tumor tissues offering potent efficacy and safety advantages over other HDACi [108,188]. Tefinostat (CHR-2845) is a new pan-HDACi. Tefinostat is cleaved to its active acid by the intracellular esterase human carboxylesterase 1, which is only expressed in monocyte/macrophages and some hepatocytes, resulting in the accumulation of active drug selectively in these cells. This HDACi has been tested in a phase I clinical trial in patients with relapsed or refractory hematological malignancies, showing little clinical effectiveness [189,190]. Finally, Nanatinostat (CHR-3996) is a next-generation hydroxamic acid-based HDACi with greater potency against class I HDACs and promising results in clinical trials [191,192].

3.2. Benzamides

Benzamides or amino anilides have been shown to bind to the zinc-chelating moiety for interaction with the catalytic Zn2+ in HDAC active sites [167]. These HDACi are selective and potent inhibitors of class I HDACs, but have shown lower activity than hydroxamic acids or cyclic peptides [148].

3.2.1. Entinostat

Entinostat (MS-275) is a synthetic benzamide derivative class I HDACi that potently and selectively leads to cell cycle arrest and hyperacetylation of histones H3 and H4 [167,193,194]. In AML, Entinostat induced growth arrest and apoptosis in cell lines and patient samples, downregulating anti-apoptotic molecules BCL-2 and MCL-1, increasing p21, and inducing acetylation of H3 [195]. The in vivo efficacy of Entinostat has also been demonstrated in a murine AML model [196]. Nishioka et al. reported in their study that Entinostat induced degradation of FLT3 through the inhibition of the chaperon activity of the heat shock protein 90 in AML cells, suggesting that this inhibitor may be useful for the treatment of AML patients with FLT3 mutations [195]. In a phase I study with AML patients, Entinostat treatment was safe and had cellular and molecular effects, inducing acetylation of H3/H4, expression of p21, and activating caspase 3 in bone marrow mononuclear cells. However, no responses were observed by clinical criteria [197]. Preclinically, synergy of Entinostat with the inhibitor of MEK/ERK AZD6244 [112], the mTOR inhibitor RAD001 [113], and Decitabine [114] has been described. Interestingly, a phase I clinical trial showed that the combination of AZA with Entinostat was effective and tolerable for patients with AML [115]. Nevertheless, a phase II study concluded that the addition of Entinostat to AZA did not increase the clinical response in patients with AML or myelodysplastic syndromes (MDS) [116].

3.2.2. Mocetinostat

Mocetinostat (MGCD0103) is also a selective class I and IV HDACi that has been shown to induce histone hyperacetylation, apoptosis, anti-proliferative activities against a wide range of tumor cell lines, and tumor growth inhibition in multiple cancer models, including hematological malignancies [167]. In AML, Mocetinostat reduced cell viability and induced apoptosis in vitro [198]. Mocetinostat exhibited a safe anti-leukemic activity in a phase I clinical trial in patients with AML or MDS [199]. Subsequent controlled studies, with Mocetinostat alone and in combination with other cytotoxic therapies, will be necessary to characterize the efficacy of this HDACi in AML.

3.3. Cyclic Peptides

Cyclic peptides comprise both epoxyketone- and non-epoxy ketone-containing tetrapeptides, and represent the most structurally complicated and diverse class of HDACi [148,200,201,202]. The selectivity of these HDACi against different HDACs depends on their cap group variation. These HDACi can be subdivided into two families: bicyclic depsipeptides (Romidepsin) and cyclic tetrapeptides (Trapoxin A, Apicidin).

3.3.1. Romidepsin

Romidepsin (also known as FK228) is a novel and potent HDACi isolated from Chromobacterium violaceum. This natural product is a pro-drug that is activated by cellular reduction to a metabolite-containing a thiol group that chelates the zinc ions in the active center of the HDACs [167]. It is a potent inhibitor of HDAC activity, particularly, it inhibits class I HDAC enzymes better than class II. In addition of histone deacetylation, Romidepsin modulates additional targets involved in cancer initiation and progression such as c-MYC, HSP90, or P53 [201]. In 2009, Romidepsin received the FDA approval for the treatment of the relapsed or refractory cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL) [40,159,160,200]. Romidepsin has in vitro and in vivo effects on AML cells, inducing apoptosis and differentiation of APL cell lines [117,118]. Furthermore, this HDACi induced apoptosis of chemoresistant cells, reversed the gene expression profile of resistant cells, and removed chemoresistant leukemia blasts in a xenograft AML mouse model [203]. Romidepsin was also highly efficient in combination with ATRA [117], Decitabine [118], or AZA [119]. Despite the promising preclinical results, several phase I clinical trials showed that Romidepsin has limited clinical activity in AML patients, at least as a monotherapy [204,205].

3.3.2. Apicidin

Apicidin, a cyclic tetrapeptide, is a natural fugal metabolite that selectively inhibits HDAC2 and HDAC3 in the low nano-molar range and HDAC8 in the high nano-molar range, but does not affect HDAC1 or class II HDACs [206]. It exhibits an anti-proliferative activity against various cancer cell lines and induces selective changes in P21WAF1/Cip1 and gelsolin gene expression, which control cell cycle and cell morphology, respectively. Relatively little is known about the effect of Apicidin on AML. Only one study has demonstrated that this cyclic tetrapeptide induces apoptosis via a mitochondrial/cytochrome-c-dependent pathway, activating caspase-3 in AML cell lines [207].

3.3.3. Trapoxin A

Trapoxin A is a microbial cyclic tetrapeptide that is essentially an irreversible inhibitor of class I HDACs, and it was also found to reversibly inhibit the class II enzyme HDAC6 [208]. Regarding AML, Trapoxin A induced differentiation in combination with ATRA in AML cell lines [120]. Interestingly, Trapoxin A treatment led to the up-regulation of costimulatory and adhesion molecules (CD80, CD86, HLA-DR, HLA-ABC, and ICAM-1) in AML cells, inducing tumor immunity [209].

3.4. Aliphatic Acids

Aliphatic acids, the short-chain fatty acids, are structurally the simplest class of HDACi. Due to their weak inhibitory activity, low bioavailability, and fast metabolism, they are the least attractive HDACi [148].
Valproic acid (VPA) is an inhibitor of class I and IIa HDACs that has shown antitumor effects [39,62]. VPA functions as an HDACi, causing in vitro and in vivo hyperacetylation of the N-terminal tails of H3 and H4, most likely by union with the catalytic center, thus blocking substrate access. Furthermore, several preclinical studies have shown that VPA induces differentiation and inhibits proliferation and apoptosis of AML cells [210,211,212,213]. However, there are few clinical studies that have analyzed VPA as a monotherapy in AML, and according to the ones that have, this HDACi has no clinical effect when used as a single-agent therapy for AML [121,137,138].
The effect of the combination of VPA with several drugs in AML has been explored, demonstrating synergy with ATRA [121,122,137,138,139,140], Decitabine [123,124,125], Gemtuzumab ozogamicin (GO) [126], AZA [127], retinoid IIF [128], proteasome inhibitors NPI-0052 or PR-171 [129], Curcumin [130], hydroxiurea or 6-mercaptopurine [131], Dasatinib [132], Bortezomib [133,134], Cytarabine [135,142,143], or the Mouse Double Minute 2 (MDM2) inhibitor Nutlin-3 [136], among others. These combinations induced a synergistic effect on apoptosis and inhibition of cell proliferation of AML cells. However, for most of these combinations there are only preclinical data, and only a few of them have been studied in clinical trials. One of the most widely studied drugs in combination with VPA is ATRA, which has demonstrated anti-leukemic activity in experimental in vitro studies [121,122] but yielded poor responses in several clinical trials in poor-risk or elderly AML patients [137,138,139,140,141]. VPA has been used in combination with Cytarabine, resulting in synergistic anti-leukemic activity in AML cell lines and patient samples and in a murine AML model [135]. In a clinical trial in elderly AML patients, the combination of low doses of Cytarabine with VPA showed good therapeutic activity [142]. However, in a subsequent trial testing this combination in elderly patients with AML, limited clinical activity was shown [143]. The discrepancy between these two trials may be due to the different number of patients, different patient population, or different doses or treatment schedules. Interestingly, a clinical trial demonstrated that the VPA therapy combined with hydroxyurea or 6-mercaptopurin may be effective for advanced AML patients [131]. Finally, the possible benefits of adding VPA to a demethylating agent, such as Decitabine or AZA, have also been studied for AML treatment. The combination of Decitabine with VPA was safe and active, and was associated with transient reversal of aberrant epigenetic marks in a first phase I/II clinical trial in patients with leukemia [125]. Unfortunately, in a second phase I trial testing this combination in patients with AML, the addition of VPA led to encephalopathy, even at low doses [124]. A subsequent phase II study with VPA and low dose of Decitabine did not show any difference in relation to complete response, overall response, or cell survival when comparing the addition of VPA to Decitabine versus Decitabine alone [123]. In the case of AZA, a clinical trial with the triple combination of VPA, AZA, and ATRA was carried out in AML or high-risk MDS patients, demonstrating an overall response of 42% with global DNA demethylation and histone acetylation [127]. Therefore, this triple combination was deemed safe and had significant clinical activity. These results provide significant evidence that VPA is an attractive prospect for use in combination therapy with other anti-leukemic agents for the treatment of AML.
Other HDACi in this aliphatic acid class are B=butyric acid and phenylbutyric acid, which are known to be weak inhibitors of HDAC classes I and II, respectively. Butyric acid enhanced granulocytic maturation of AML cells [214], and just like other HDACi, induced expression of costimulatory and adhesion molecules (CD80, CD86, HLA-DR, HLA-ABC, and ICAM-1) in AML cells, inducing anti-tumor immune responses [209]. A pilot study of phenylbutyric acid in combination with AZA involving patients with AML and MDS showed that this combination strategy is safe and produces biological and clinical outcomes [215].

3.5. Electrophilic Ketones

The mechanism of electrophilic ketone HDACi appears to be similar to electrophilic ketone protease inhibitors. The zinc binding in the active site of HDACs is coordinated by the hydrated form of the ketone, which acts in a similar way as a transition state analogue [216]. Several trifluoromethyl ketones and α-ketoamides belong to this group of HDACi. Different studies have shown that trifluoromethyl ketones are active as HDACi, with micromolar inhibitory activity for HDACs, with some of them being submicromolar HDACi with antiproliferative effects [217]. In general, electrophilic ketones showed short half-life because of a rapid reduction in the corresponding inactive alcohols. The fluoride present in some ketones makes these types of ketones, such as trifluoromethyl ketones, much more electrophilic. This is due to the presence of a strong electron withdrawing effect of the fluoride [62]. However, in this case, there is no evidence regarding the anti-leukemic effect of these HDACi.

4. Conclusions

Epigenetic therapy is still poorly developed in AML, but it is a very promising field that is rapidly evolving. Different studies have indicated that HDACi have shown some limited effects, such as with single agents in AML. Despite the therapeutic efficacy improvement observed in combination with conventional chemotherapy or other epigenetic inhibitors, the results are still modest. However, some clinical trials with HDACi, especially Pracinostat, in combination with DNA hypomehtylating agents or chemotherapy showed encouraging results. These results place HDACi in a very interesting scenario, in which future studies will be essential to elucidate their potential role as anti-leukemic agents in AML. This is especially important in the case of next-generation HDACi, with which perhaps the long-awaited improvement in the therapeutic response of AML patients might be achieved.

Author Contributions

Conceptualization, E.S.J.-E., N.G.-C., X.A., and F.P.; writing—original draft preparation, E.S.J.-E., N.G.-C., and X.A.; writing—review and editing, E.S.J.-E., N.G-C., X.A., and F.P.

Funding

This study was financed by Instituto de Salud Carlos III and co-financed by FEDER (Fondo Europeo de Desarrollo Regional) (RTICC (Red Temática de Investigación Cooperativa en Cáncer) RD12/0036/0068, PI16/02024, PI17/00701, Centro de Investigación Biomédica en Red Cáncer (CIBERONC) CB16/12/00489, ERANET-TRANSCAN-2 (Aligning national/regional translational cancer research programmes and activities) EPICA (Dual EPigenetic targeting and Immunotherapy to fight against Cancer) AC16/00041) and Gobierno de Navarra Salud and cofinanced by FEDER (40/2016, Proyecto DIANA).

Conflicts of Interest

Authors declare no conflicts of interest related to the present manuscript.

References

  1. Wrighton, K.H. Regulatory networks in AML. Nat. Rev. Cancer 2019, 19, 6–7. [Google Scholar] [CrossRef]
  2. Assi, S.A.; Imperato, M.R.; Coleman, D.J.L.; Pickin, A.; Potluri, S.; Ptasinska, A.; Chin, P.S.; Blair, H.; Cauchy, P.; James, S.R.; et al. Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nat. Genet. 2019, 51, 151–162. [Google Scholar] [CrossRef] [PubMed]
  3. Tallman, M.S.; Gilliland, D.G.; Rowe, J.M. Drug therapy for acute myeloid leukemia. Blood 2005, 106, 1154–1163. [Google Scholar] [CrossRef] [PubMed]
  4. Estey, E.; Döhner, H. Acute myeloid leukaemia. Lancet 2006, 368, 1894–1907. [Google Scholar] [CrossRef]
  5. Saultz, J.; Garzon, R. Acute Myeloid Leukemia: A Concise Review. J. Clin. Med. 2016, 5, 33. [Google Scholar] [CrossRef]
  6. Döhner, H.; Weisdorf, D.J.; Bloomfield, C.D. Acute Myeloid Leukemia. N. Engl. J. Med. 2015, 373, 1136–1152. [Google Scholar] [CrossRef]
  7. De Kouchkovsky, I.; Abdul-Hay, M. Acute myeloid leukemia: A comprehensive review and 2016 update. Blood Cancer J. 2016, 6, e441. [Google Scholar] [CrossRef]
  8. Watts, J.; Nimer, S. Recent advances in the understanding and treatment of acute myeloid leukemia. F1000Research 2018, 7. [Google Scholar] [CrossRef]
  9. Kucukyurt, S.; Eskazan, A.E. New drugs approved for acute myeloid leukemia (AML) in 2018. Br. J. Clin. Pharmacol. 2019. [Google Scholar] [CrossRef]
  10. Lowenberg, B.; Rowe, J.M. Blood; American Society of Hematology: Washington, DC, USA, 2016; p. 1. [Google Scholar]
  11. Plass, C.; Oakes, C.; Blum, W.; Marcucci, G. Epigenetics in Acute Myeloid Leukemia. Semin. Oncol. 2008, 35, 378–387. [Google Scholar] [CrossRef]
  12. Lagunas-Rangel, F.A.; Chávez-Valencia, V.; Gómez-Guijosa, M.Á.; Cortes-Penagos, C. Acute Myeloid Leukemia-Genetic Alterations and Their Clinical Prognosis. Int. J. Hematol. Stem Cell Res. 2017, 11, 328–339. [Google Scholar]
  13. Cai, S.F.; Levine, R.L. Genetic and epigenetic determinants of AML pathogenesis. Semin. Hematol. 2019, 56, 84–89. [Google Scholar] [CrossRef] [PubMed]
  14. Berger, S.L.; Kouzarides, T.; Shiekhattar, R.; Shilatifard, A. An operational definition of epigenetics. Genes Dev. 2009, 23, 781–783. [Google Scholar] [CrossRef] [PubMed]
  15. Baylin, S.B.; Jones, P.A. A decade of exploring the cancer epigenome-biological and translational implications. Nat. Rev. Cancer 2011, 11, 726–734. [Google Scholar] [CrossRef]
  16. Dawson, M.A.; Kouzarides, T. Cancer epigenetics: From mechanism to therapy. Cell 2012, 150, 12–27. [Google Scholar] [CrossRef]
  17. Roy, D.M.; Walsh, L.A.; Chan, T.A. Driver mutations of cancer epigenomes. Protein Cell 2014, 5, 265–296. [Google Scholar] [CrossRef]
  18. Han, M.; Jia, L.; Lv, W.; Wang, L.; Cui, W. Epigenetic enzyme mutations: Role in tumorigenesis and molecular inhibitors. Front. Oncol. 2019, 9. [Google Scholar] [CrossRef]
  19. Gardin, C.; Dombret, H. Hypomethylating Agents as a Therapy for AML. Curr. Hematol. Malig. Rep. 2017, 12, 1–10. [Google Scholar] [CrossRef]
  20. Bohl, S.R.; Bullinger, L.; Rücker, F.G. Epigenetic therapy: Azacytidine and decitabine in acute myeloid leukemia. Expert Rev. Hematol. 2018, 11, 361–371. [Google Scholar] [CrossRef]
  21. Grant, P.A. A tale of histone modifications. Genome Biol. 2001, 2, REVIEWS0003. [Google Scholar] [CrossRef]
  22. Biterge, B.; Schneider, R. Histone variants: Key players of chromatin. Cell Tissue Res. 2014, 356, 457–466. [Google Scholar] [CrossRef] [PubMed]
  23. Zucchetti, B.; Shimada, A.K.; Katz, A.; Curigliano, G. The role of histone deacetylase inhibitors in metastatic breast cancer. Breast 2019, 43, 130–134. [Google Scholar] [CrossRef] [PubMed]
  24. Heintzman, N.D.; Stuart, R.K.; Hon, G.; Fu, Y.; Ching, C.W.; Hawkins, R.D.; Barrera, L.O.; Van Calcar, S.; Qu, C.; Ching, K.A.; et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 2007, 39, 311–318. [Google Scholar] [CrossRef] [PubMed]
  25. Wang, Z.; Zang, C.; Rosenfeld, J.A.; Schones, D.E.; Barski, A.; Cuddapah, S.; Cui, K.; Roh, T.-Y.; Peng, W.; Zhang, M.Q.; et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet. 2008, 40, 897–903. [Google Scholar] [CrossRef]
  26. Taverna, S.D.; Li, H.; Ruthenburg, A.J.; Allis, C.D.; Patel, D.J. How chromatin-binding modules interpret histone modifications: Lessons from professional pocket pickers. Nat. Struct. Mol. Biol. 2007, 14, 1025–1040. [Google Scholar] [CrossRef]
  27. Seto, E.; Yoshida, M. Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 2014, 6, a018713. [Google Scholar] [CrossRef]
  28. Haberland, M.; Montgomery, R.L.; Olson, E.N. The many roles of histone deacetylases in development and physiology: Implications for disease and therapy. Nat. Rev. Genet. 2009, 10, 32–42. [Google Scholar] [CrossRef]
  29. Marmorstein, R.; Roth, S.Y. Histone acetyltransferases: Function, structure, and catalysis. Curr. Opin. Genet. Dev. 2001, 11, 155–161. [Google Scholar] [CrossRef]
  30. Gräff, J.; Tsai, L.H. Histone acetylation: Molecular mnemonics on the chromatin. Nat. Rev. Neurosci. 2013, 14, 97–111. [Google Scholar] [CrossRef]
  31. Ropero, S.; Esteller, M. The role of histone deacetylases (HDACs) in human cancer. Mol. Oncol. 2007, 1, 19–25. [Google Scholar] [CrossRef]
  32. Iyer, N.G.; Ozdag, H.; Caldas, C. p300/CBP and cancer. Oncogene 2004, 23, 4225–4231. [Google Scholar] [CrossRef] [PubMed]
  33. Roy, S.; Packman, K.; Jeffrey, R.; Tenniswood, M. Histone deacetylase inhibitors differentially stabilize acetylated p53 and induce cell cycle arrest or apoptosis in prostate cancer cells. Cell Death Differ. 2005, 12, 482–491. [Google Scholar] [CrossRef] [PubMed]
  34. Peng, L.; Seto, E. Deacetylation of nonhistone proteins by HDACs and the implications in cancer. Handb. Exp. Pharmacol. 2011, 206, 39–56. [Google Scholar] [PubMed]
  35. Sun, Y.; Iyer, M.; Mceachin, R.; Zhao, M.; Wu, Y.M.; Cao, X.; Oravecz-Wilson, K.; Zajac, C.; Mathewson, N.; Wu, S.R.J.; et al. Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells. J. Innate Immun. 2017, 9, 126–144. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Aggarwal, B.B.; Kunnumakkara, A.B.; Harikumar, K.B.; Gupta, S.R.; Tharakan, S.T.; Koca, C.; Dey, S.; Sung, B. Signal transducer and activator of transcription-3, inflammation, and cancer: How intimate is the relationship. In Annals of the New York Academy of Sciences; Blackwell Publishing Inc.: Hoboken, NJ, USA, 2009; Volume 1171, pp. 59–76. [Google Scholar]
  37. Glozak, M.A.; Sengupta, N.; Zhang, X.; Seto, E. Acetylation and deacetylation of non-histone proteins. Gene 2005, 363, 15–23. [Google Scholar] [CrossRef] [PubMed]
  38. Hull, E.E.; Montgomery, M.R.; Leyva, K.J. HDAC Inhibitors as Epigenetic Regulators of the Immune System: Impacts on Cancer Therapy and Inflammatory Diseases. Biomed Res. Int. 2016, 2016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Eckschlager, T.; Plch, J.; Stiborova, M.; Hrabeta, J. Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci. 2017, 18. [Google Scholar] [CrossRef]
  40. Li, Y.; Seto, E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med. 2016, 6, a026831. [Google Scholar] [CrossRef] [Green Version]
  41. Weichert, W.; Röske, A.; Gekeler, V.; Beckers, T.; Ebert, M.P.; Pross, M.; Dietel, M.; Denkert, C.; Röcken, C. Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: A retrospective analysis. Lancet Oncol. 2008, 9, 139–148. [Google Scholar] [CrossRef]
  42. West, A.C.; Johnstone, R.W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Investig. 2014, 124, 30–39. [Google Scholar] [CrossRef] [Green Version]
  43. Weichert, W.; Röske, A.; Niesporek, S.; Noske, A.; Buckendahl, A.C.; Dietel, M.; Gekeler, V.; Boehm, M.; Beckers, T.; Denkert, C. Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: Specific role of class I histone deacetylases in vitro and in vivo. Clin. Cancer Res. 2008, 14, 1669–1677. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Weichert, W.; Röske, A.; Gekeler, V.; Beckers, T.; Stephan, C.; Jung, K.; Fritzsche, F.R.; Niesporek, S.; Denkert, C.; Dietel, M.; et al. Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br. J. Cancer 2008, 98, 604–610. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Minamiya, Y.; Ono, T.; Saito, H.; Takahashi, N.; Ito, M.; Mitsui, M.; Motoyama, S.; Ogawa, J. Expression of histone deacetylase 1 correlates with a poor prognosis in patients with adenocarcinoma of the lung. Lung Cancer 2011, 74, 300–304. [Google Scholar] [CrossRef] [PubMed]
  46. Osada, H.; Tatematsu, Y.; Saito, H.; Yatabe, Y.; Mitsudomi, T.; Takahashi, T. Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients. Int. J. Cancer 2004, 112, 26–32. [Google Scholar] [CrossRef]
  47. Halkidou, K.; Gaughan, L.; Cook, S.; Leung, H.Y.; Neal, D.E.; Robson, C.N. Upregulation and Nuclear Recruitment of HDACl in Hormone Refractory Prostate Cancer. Prostate 2004, 59, 177–189. [Google Scholar] [CrossRef]
  48. Berger, M.F.; Lawrence, M.S.; Demichelis, F.; Drier, Y.; Cibulskis, K.; Sivachenko, A.Y.; Sboner, A.; Esgueva, R.; Pflueger, D.; Sougnez, C.; et al. The genomic complexity of primary human prostate cancer. Nature 2011, 470, 214–220. [Google Scholar] [CrossRef] [Green Version]
  49. Ropero, S.; Fraga, M.F.; Ballestar, E.; Hamelin, R.; Yamamoto, H.; Boix-Chornet, M.; Caballero, R.; Alaminos, M.; Setien, F.; Paz, M.F.; et al. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nat. Genet. 2006, 38, 566–569. [Google Scholar] [CrossRef]
  50. Sjöblom, T.; Jones, S.; Wood, L.D.; Parsons, D.W.; Lin, J.; Barber, T.D.; Mandelker, D.; Leary, R.J.; Ptak, J.; Silliman, N.; et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006, 314, 268–274. [Google Scholar] [CrossRef]
  51. Hanigan, C.L.; van Engeland, M.; De Bruine, A.P.; Wouters, K.A.; Weijenberg, M.P.; Eshleman, J.R.; Herman, J.G. An Inactivating Mutation in HDAC2 Leads to Dysregulation of Apoptosis Mediated by APAF1. Gastroenterology 2008, 135, 1654–1664. [Google Scholar] [CrossRef]
  52. Johnstone, R.W.; Licht, J.D. Histone deacetylase inhibitors in cancer therapy: Is transcription the primary target? Cancer Cell 2003, 4, 13–18. [Google Scholar] [CrossRef] [Green Version]
  53. Licht, J.D. AML1 and the AML1-ETO fusion protein in the pathogenesis of t (8; 21) AML. Oncogene 2001, 20, 5660–5679. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Liu, Y.; Cheney, M.D.; Gaudet, J.J.; Chruszcz, M.; Lukasik, S.M.; Sugiyama, D.; Lary, J.; Cole, J.; Dauter, Z.; Minor, W.; et al. The tetramer structure of the Nervy homology two domain, NHR2, is critical for AML1/ETO’s activity. Cancer Cell 2006, 9, 249–260. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Peterson, L.F.; Zhang, D.-E. The 8; 21 translocation in leukemogenesis. Oncogene 2004, 23, 4255–4262. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Minucci, S.; Pelicci, P.G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer 2006, 6, 38–51. [Google Scholar] [CrossRef] [Green Version]
  57. Di Croce, L.; Raker, V.A.; Corsaro, M.; Fazi, F.; Fanelli, M.; Faretta, M.; Fuks, F.; Lo Coco, F.; Kouzarides, T.; Nervi, C.; et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 2002, 295, 1079–1082. [Google Scholar] [CrossRef] [Green Version]
  58. Rego, E.M.; He, L.Z.; Warrell, R.P.; Wang, Z.G.; Pandolfi, P.P. Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARa and PLZF-RARα oncoproteins. Proc. Natl. Acad. Sci. USA 2000, 97, 10173–10178. [Google Scholar] [CrossRef] [Green Version]
  59. Bereshchenko, O.R.; Gu, W.; Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nat. Genet. 2002, 32, 606–613. [Google Scholar] [CrossRef]
  60. Hyun-Chung, K.; Suk-Chul, B. HDAC inhibitors as anti-cancer drugs. Am. J. Transl. Res. 2011, 3, 166–179. [Google Scholar]
  61. Bertrand, P. Inside HDAC with HDAC inhibitors. Eur. J. Med. Chem. 2010, 45, 2095–2116. [Google Scholar] [CrossRef]
  62. Mottamal, M.; Zheng, S.; Huang, T.L.; Wang, G. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 2015, 20, 3898–3941. [Google Scholar] [CrossRef] [Green Version]
  63. Zhang, L.; Zhang, J.; Jiang, Q.; Zhang, L.; Song, W. Zinc binding groups for histone deacetylase inhibitors. J. Enzyme Inhib. Med. Chem. 2018, 33, 714–721. [Google Scholar] [CrossRef] [PubMed]
  64. Tran, H.T.T.; Kim, H.N.; Lee, I.K.; Nguyen-Pham, T.N.; Ahn, J.S.; Kim, Y.K.; Lee, J.J.; Park, K.S.; Kook, H.; Kim, H.J. Improved therapeutic effect against leukemia by a combination of the histone methyltransferase inhibitor chaetocin and the histone deacetylase inhibitor trichostatin A. J. Korean Med. Sci. 2013, 28, 237–246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Momparler, R.L.; Côté, S.; Momparler, L.F.; Idaghdour, Y. Epigenetic therapy of acute myeloid leukemia using 5-aza-2’-deoxycytidine (decitabine) in combination with inhibitors of histone methylation and deacetylation. Clin. Epigenet. 2014, 6, 19. [Google Scholar] [CrossRef] [PubMed]
  66. Amin, H.M.; Saeed, S.; Alkan, S. Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t (15; 17). Br. J. Haematol. 2001, 115, 287–297. [Google Scholar] [CrossRef]
  67. He, L.-Z.; Tolentino, T.; Grayson, P.; Zhong, S.; Warrell, R.P.; Rifkind, R.A.; Marks, P.A.; Richon, V.M.; Pandolfi, P.P. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J. Clin. Investig. 2001, 108, 1321–1330. [Google Scholar] [CrossRef]
  68. Yu, C.; Rahmani, M.; Almenara, J.; Subler, M.; Krystal, G.; Conrad, D.; Varticovski, L.; Dent, P.; Grant, S. Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and -resistant Bcr/Abl+ human myeloid leukemia cells. Cancer Res. 2003, 63, 2118–2126. [Google Scholar]
  69. Fiskus, W.; Wang, Y.; Joshi, R.; Rao, R.; Yang, Y.; Chen, J.; Kolhe, R.; Balusu, R.; Eaton, K.; Lee, P.; et al. Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells. Clin. Cancer Res. 2008, 14, 6106–6115. [Google Scholar] [CrossRef]
  70. Miller, C.P.; Rudra, S.; Keating, M.J.; Wierda, W.G.; Palladino, M.; Chandra, J. Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: A mechanism for synergy in leukemia cells. Blood 2009, 113, 4289–4299. [Google Scholar] [CrossRef] [Green Version]
  71. Shiozawa, K.; Nakanishi, T.; Tan, M.; Fang, H.B.; Wang, W.C.; Edelman, M.J.; Carlton, D.; Gojo, I.; Sausville, E.A.; Ross, D.D. Preclinical studies of vorinostat (suberoylanilide hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute leukemias. Clin. Cancer Res. 2009, 15, 1698–1707. [Google Scholar] [CrossRef]
  72. Wei, Y.; Kadia, T.; Tong, W.; Zhang, M.; Jia, Y.; Yang, H.; Hu, Y.; Viallet, J.; O’Brien, S.; Garcia-Manero, G. The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Autophagy 2010, 6, 976–978. [Google Scholar] [CrossRef] [Green Version]
  73. Zhou, L.; Zhang, Y.; Chen, S.; Kmieciak, M.; Leng, Y.; Lin, H.; Rizzo, K.A.; Dumur, C.I.; Ferreira-Gonzalez, A.; Dai, Y.; et al. A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations. Leukemia 2015, 29, 807–818. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Lin, W.H.; Yeh, T.K.; Jiaang, W.T.; Yen, K.J.; Chen, C.H.; Huang, C.T.; Yen, S.C.; Hsieh, S.Y.; Chou, L.H.; Chen, C.P.; et al. Evaluation of the antitumor effects of BPR1J-340, a potent and selective FLT3 inhibitor, alone or in combination with an HDAC inhibitor, vorinostat, in AML cancer. PLoS ONE 2014, 9, e83160. [Google Scholar] [CrossRef] [PubMed]
  75. Liao, Y.; Niu, X.; Chen, B.; Edwards, H.; Xu, L.; Xie, C.; Lin, H.; Polin, L.; Taub, J.W.; Ge, Y.; et al. Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells. J. Med. Chem. 2016, 59, 7974–7990. [Google Scholar] [CrossRef] [PubMed]
  76. Kirschbaum, M.; Gojo, I.; Goldberg, S.L.; Bredeson, C.; Kujawski, L.A.; Yang, A.; Marks, P.; Frankel, P.; Sun, X.; Tosolini, A.; et al. A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Br. J. Haematol. 2014, 167, 185–193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. How, J.; Minden, M.D.; Brian, L.; Chen, E.X.; Brandwein, J.; Schuh, A.C.; Schimmer, A.D.; Gupta, V.; Webster, S.; Degelder, T.; et al. A phase i trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia. Leuk. Lymphoma 2015, 56, 2793–2802. [Google Scholar] [CrossRef] [Green Version]
  78. Kadia, T.M.; Yang, H.; Ferrajoli, A.; Maddipotti, S.; Schroeder, C.; Madden, T.L.; Holleran, J.L.; Egorin, M.J.; Ravandi, F.; Thomas, D.A.; et al. A phase i study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia: Research paper. Br. J. Haematol. 2010, 150, 72–82. [Google Scholar]
  79. Garcia-Manero, G.; Tambaro, F.P.; Bekele, N.B.; Yang, H.; Ravandi, F.; Jabbour, E.; Borthakur, G.; Kadia, T.M.; Konopleva, M.Y.; Faderl, S.; et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J. Clin. Oncol. 2012, 30, 2204–2210. [Google Scholar] [CrossRef]
  80. Holkova, B.; Supko, J.G.; Ames, M.M.; Reid, J.M.; Shapiro, G.I.; Perkins, E.B.; Ramakrishnan, V.; Tombes, M.B.; Honeycutt, C.; McGovern, R.M.; et al. A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Clin. Cancer Res. 2013, 19, 1873–1883. [Google Scholar] [CrossRef]
  81. Walter, R.B.; Medeiros, B.C.; Gardner, K.M.; Orlowski, K.F.; Gallegos, L.; Scott, B.L.; Hendrie, P.C.; Estey, E.H. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: A phase I/II study. Haematologica 2014, 99, 54–59. [Google Scholar] [CrossRef]
  82. Walter, R.B.; Medeiros, B.C.; Powell, B.L.; Schiffer, C.A.; Appelbaum, F.R.; Estey, E.H. Phase II trial of vorinostat and gemtuzumab ozogamicin as induction and post-remission therapy in older adults with previously untreated acute myeloid leukemia. Haematologica 2012, 97, 739–742. [Google Scholar] [CrossRef]
  83. Sayar, H.; Cripe, L.D.; Saliba, A.N.; Abu Zaid, M.; Konig, H.; Boswell, H.S. Combination of sorafenib, vorinostat and bortezomib for the treatment of poor-risk AML: Report of two consecutive clinical trials. Leuk. Res. 2019, 77, 30–33. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Blagitko-Dorfs, N.; Schlosser, P.; Greve, G.; Pfeifer, D.; Meier, R.; Baude, A.; Brocks, D.; Plass, C.; Lübbert, M. Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: Predominant synergistic gene downregulation associated with gene body demethylation. Leukemia 2019, 33, 945–956. [Google Scholar] [CrossRef] [PubMed]
  85. Fiskus, W.; Buckley, K.; Rao, R.; Mandawat, A.; Yang, Y.; Joshi, R.; Wang, Y.; Balusu, R.; Chen, J.; Koul, S.; et al. Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol. Ther. 2009, 8, 939–950. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Gopalakrishnapillai, A.; Kolb, E.A.; McCahan, S.M.; Barwe, S.P. Epigenetic drug combination induces remission in mouse xenograft models of pediatric acute myeloid leukemia. Leuk. Res. 2017, 58, 91–97. [Google Scholar] [CrossRef]
  87. Schwartz, J.; Niu, X.; Walton, E.; Hurley, L.; Lin, H.; Edwards, H.; Taub, J.W.; Wang, Z.; Ge, Y. Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemia ex vivo. Am. J. Transl. Res. 2016, 8, 3893–3902. [Google Scholar]
  88. Qi, W.; Zhang, W.; Edwards, H.; Chu, R.; Madlambayan, G.J.; Taub, J.W.; Wang, Z.; Wang, Y.; Li, C.; Lin, H.; et al. Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo. Cancer Biol. Ther. 2015, 16, 1784–1793. [Google Scholar] [CrossRef] [Green Version]
  89. Fiskus, W.; Sharma, S.; Saha, S.; Shah, B.; Devaraj, S.G.T.; Sun, B.; Horrigan, S.; Leveque, C.; Zu, Y.; Iyer, S.; et al. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells. Leukemia 2015, 29, 1267–1278. [Google Scholar] [CrossRef]
  90. Fiskus, W.; Sharma, S.; Shah, B.; Portier, B.P.; Devaraj, S.G.T.; Liu, K.; Iyer, S.P.; Bearss, D.; Bhalla, K.N. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia 2014, 28, 2155–2164. [Google Scholar] [CrossRef] [Green Version]
  91. Fiskus, W.; Sharma, S.; Qi, J.; Valenta, J.A.; Schaub, L.J.; Shah, B.; Peth, K.; Portier, B.P.; Rodriguez, M.; Devaraj, S.G.T.; et al. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol. Cancer Ther. 2014, 13, 1142–1154. [Google Scholar] [CrossRef] [Green Version]
  92. Pietschmann, K.; Bolck, H.A.; Buchwald, M.; Spielberg, S.; Polzer, H.; Spiekermann, K.; Bug, G.; Heinzel, T.; Bohmer, F.D.; Krämer, O.H. Breakdown of the FLT3-ITD/STAT5 axis and synergistic apoptosis induction by the histone deacetylase inhibitor panobinostat and FLT3-specific inhibitors. Mol. Cancer Ther. 2012, 11, 2373–2383. [Google Scholar] [CrossRef]
  93. Jiang, X.J.; Huang, K.K.; Yang, M.; Qiao, L.; Wang, Q.; Ye, J.Y.; Zhou, H.S.; Yi, Z.S.; Wu, F.Q.; Wang, Z.X.; et al. Synergistic effect of panobinostat and bortezomib on chemoresistant acute myelogenous leukemia cells via AKT and NF-κB pathways. Cancer Lett. 2012, 326, 135–142. [Google Scholar] [CrossRef] [PubMed]
  94. Mandawat, A.; Fiskus, W.; Buckley, K.M.; Robbins, K.; Rao, R.; Balusu, R.; Navenot, J.M.; Wang, Z.X.; Ustun, C.; Chong, D.G.; et al. Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists. Blood 2010, 116, 5306–5315. [Google Scholar] [CrossRef] [PubMed]
  95. Maiso, P.; Colado, E.; Ocio, E.M.; Garayoa, M.; Martín, J.; Atadja, P.; Pandiella, A.; San-Miguel, J.F. The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair. Leukemia 2009, 23, 2265–2274. [Google Scholar] [CrossRef] [PubMed]
  96. Fiskus, W.; Wang, Y.; Sreekumar, A.; Buckley, K.M.; Shi, H.; Jillella, A.; Ustun, C.; Rao, R.; Fernandez, P.; Chen, J.; et al. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 2009, 114, 2733–2743. [Google Scholar] [CrossRef] [Green Version]
  97. Garcia-Manero, G.; Sekeres, M.A.; Egyed, M.; Breccia, M.; Graux, C.; Cavenagh, J.D.; Salman, H.; Illes, A.; Fenaux, P.; Deangelo, D.J.; et al. A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ≤30% blasts. Leukemia 2017, 31, 2799–2806. [Google Scholar] [CrossRef] [Green Version]
  98. Bewersdorf, J.P.; Shallis, R.; Stahl, M.; Zeidan, A.M. Epigenetic therapy combinations in acute myeloid leukemia: What are the options? Ther. Adv. Hematol. 2019, 10, 2040620718816698. [Google Scholar] [CrossRef] [Green Version]
  99. Ocio, E.M.; Herrera, P.; Olave, M.-T.; Castro, N.; Pérez-Simón, J.A.; Brunet, S.; Oriol, A.; Mateo, M.; Sanz, M.-Á.; López, J.; et al. Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: Phase Ib/II panobidara study. Haematologica 2015, 100, 1294–1300. [Google Scholar] [CrossRef] [Green Version]
  100. Wieduwilt, M.J.; Pawlowska, N.; Thomas, S.; Olin, R.; Logan, A.C.; Damon, L.E.; Martin, T.; Kang, M.; Sayre, P.H.; Boyer, W.; et al. Histone Deacetylase Inhibition with Panobinostat Combined with Intensive Induction Chemotherapy in Older Patients with Acute Myeloid Leukemia: Phase I Study Results. Clin. Cancer Res. 2019, 25, 4917–4923. [Google Scholar] [CrossRef]
  101. Schlenk, R.F.; Krauter, J.; Raffoux, E.; Kreuzer, K.A.; Schaich, M.; Noens, L.; Pabst, T.; Vusirikala, M.; Bouscary, D.; Spencer, A.; et al. Panobinostat monotherapy and combination therapy in patients with acute myeloid leukemia: Results from two clinical trials. Haematologica 2018, 103, E25–E28. [Google Scholar] [CrossRef] [Green Version]
  102. Valiuliene, G.; Stirblyte, I.; Cicenaite, D.; Kaupinis, A.; Valius, M.; Navakauskiene, R. Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling. J. Cell. Mol. Med. 2015, 19, 1742–1755. [Google Scholar] [CrossRef]
  103. Savickiene, J.; Treigyte, G.; Valiuliene, G.; Stirblyte, I.; Navakauskiene, R. Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells. Anticancer. Drugs 2014, 25, 938–949. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Valiulienė, G.; Stirblytė, I.; Jasnauskaitė, M.; Borutinskaitė, V.; Navakauskienė, R. Anti-leukemic effects of HDACi Belinostat and HMTi 3-Deazaneplanocin A on human acute promyelocytic leukemia cells. Eur. J. Pharmacol. 2017, 799, 143–153. [Google Scholar] [CrossRef] [PubMed]
  105. Valiuliene, G.; Treigyte, G.; Savickiene, J.; Matuzevičius, D.; Alksne, M.; Jarašiene-Burinskaja, R.; Bukelskiene, V.; Navakauskas, D.; Navakauskiene, R. Histone modifications patterns in tissues and tumours from acute promyelocytic leukemia xenograft model in response to combined epigenetic therapy. Biomed. Pharmacother. 2016, 79, 62–70. [Google Scholar] [CrossRef] [PubMed]
  106. Dai, Y.; Chen, S.; Wang, L.; Pei, X.Y.; Kramer, L.B.; Dent, P.; Grant, S. Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbations in NF-κB and Bim. Br. J. Haematol. 2011, 153, 222–235. [Google Scholar] [CrossRef] [Green Version]
  107. Zhou, L.; Chen, S.; Zhang, Y.; Kmieciak, M.; Leng, Y.; Li, L.; Lin, H.; Rizzo, K.A.; Dumur, C.I.; Ferreira-Gonzalez, A.; et al. The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR. Blood 2016, 127, 2219–2230. [Google Scholar] [CrossRef]
  108. Novotny-Diermayr, V.; Hart, S.; Goh, K.C.; Cheong, A.; Ong, L.-C.; Hentze, H.; Pasha, M.K.; Jayaraman, R.; Ethirajulu, K.; Wood, J.M. The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML. Blood Cancer J. 2012, 2, e69. [Google Scholar] [CrossRef] [Green Version]
  109. Abaza, Y.M.; Kadia, T.M.; Jabbour, E.J.; Konopleva, M.Y.; Borthakur, G.; Ferrajoli, A.; Estrov, Z.; Wierda, W.G.; Alfonso, A.; Chong, T.H.; et al. Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies. Cancer 2017, 123, 4851–4859. [Google Scholar] [CrossRef] [Green Version]
  110. Garcia-Manero, G.; Montalban-Bravo, G.; Berdeja, J.G.; Abaza, Y.; Jabbour, E.; Essell, J.; Lyons, R.M.; Ravandi, F.; Maris, M.; Heller, B.; et al. Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes. Cancer 2017, 123, 994–1002. [Google Scholar] [CrossRef] [Green Version]
  111. Garcia-Manero, G.; Fong, C.Y.; Venditti, A.; Mappa, S.; Spezia, R.; Ades, L. A phase 3, randomized study of pracinostat (PRAN) in combination with azacitidine (AZA) versus placebo in patients ≥18 years with newly diagnosed acute myeloid leukemia (AML) unfit for standard induction chemotherapy (IC). J. Clin. Oncol. 2018, 36, TPS7078. [Google Scholar] [CrossRef]
  112. Nishioka, C.; Ikezoe, T.; Yang, J.; Koeffler, H.P.; Yokoyama, A. Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21waf1 promoter in acute myelogenous leukemia cell. Leukemia 2008, 22, 1449–1452. [Google Scholar] [CrossRef]
  113. Nishioka, C.; Ikezoe, T.; Yang, J.; Koeffler, H.P.; Yokoyama, A. Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia 2008, 22, 2159–2168. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Nishioka, C.; Ikezoe, T.; Yang, J.; Udaka, K.; Yokoyama, A. Simultaneous inhibition of DNA methyltransferase and histone deacetylase induces p53-independent apoptosis via down-regulation of Mcl-1 in acute myelogenous leukemia cells. Leuk. Res. 2011, 35, 932–939. [Google Scholar] [CrossRef] [PubMed]
  115. Fandy, T.E.; Herman, J.G.; Kerns, P.; Jiemjit, A.; Sugar, E.A.; Choi, S.H.; Yang, A.S.; Aucott, T.; Dauses, T.; Odchimar-Reissig, R.; et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood 2009, 114, 2764–2773. [Google Scholar] [CrossRef] [PubMed]
  116. Prebet, T.; Sun, Z.; Figueroa, M.E.; Ketterling, R.; Melnick, A.; Greenberg, P.L.; Herman, J.; Juckett, M.; Wang, E.S.; Smith, M.R.; et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: Results of the US Leukemia intergroup trial E1905. J. Clin. Oncol. 2014, 32, 1242–1248. [Google Scholar] [CrossRef] [Green Version]
  117. Kosugi, H.; Ito, M.; Yamamoto, Y.; Towatari, M.; Ito, M.; Ueda, R.; Saito, H.; Naoe, T. In vivo effects of a histone deacetylase inhibitor, FK228, on human acute promyelocytic leukemia in NOD/Shi-scid/scid mice. Jpn. J. Cancer Res. 2001, 92, 529–536. [Google Scholar] [CrossRef] [PubMed]
  118. Klisovic, D.D.; Katz, S.E.; Effron, D.; Klisovic, M.I.; Wickham, J.; Parthun, M.R.; Guimond, M.; Marcucci, G. Depsipeptide (FR901228) inhibits proliferation and induces apoptosis in primary and metastatic human uveal melanoma cell lines. investig. Ophthalmol. Vis. Sci. 2003, 44, 2390–2398. [Google Scholar] [CrossRef] [Green Version]
  119. Shaker, S.; Bernstein, M.; Momparler, L.F.; Momparler, R.L. Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2’-deoxycytidine) and histone deacetylation (trichostatin A, depsipeptide) in combination against myeloid leukemic cells. Leuk. Res. 2003, 27, 437–444. [Google Scholar] [CrossRef]
  120. Kosugi, H.; Towatari, M.; Hatano, S.; Kitamura, K.; Kiyoi, H.; Kinoshita, T.; Tanimoto, M.; Murate, T.; Kawashima, K.; Saito, H.; et al. Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: A new approach to anti-leukemia therapy. Leukemia 1999, 13, 1316–1324. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Fredly, H.; Gjertsen, B.T.; Bruserud, Ø. Histone deacetylase inhibition in the treatment of acute myeloid leukemia: The effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents. Clin. Epigenet. 2013, 5, 12. [Google Scholar] [CrossRef] [Green Version]
  122. Trus, M.R.; Yang, L.; Suarez Saiz, F.; Bordeleau, L.; Jurisica, I.; Minden, M.D. The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells. Leukemia 2005, 19, 1161–1168. [Google Scholar] [CrossRef] [Green Version]
  123. Issa, J.P.; Garcia-Manero, G.; Huang, X.; Cortes, J.; Ravandi, F.; Jabbour, E.; Borthakur, G.; Brandt, M.; Pierce, S.; Kantarjian, H.M. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer 2015, 121, 556–561. [Google Scholar] [CrossRef] [PubMed]
  124. Blum, W.; Klisovic, R.B.; Hackanson, B.; Liu, Z.; Liu, S.; Devine, H.; Vukosavljevic, T.; Huynh, L.; Lozanski, G.; Kefauver, C.; et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J. Clin. Oncol. 2007, 25, 3884–3891. [Google Scholar] [CrossRef] [PubMed]
  125. Garcia-Manero, G.; Kantarjian, H.M.; Sanchez-Gonzalez, B.; Yang, H.; Rosner, G.; Verstovsek, S.; Rytting, M.; Wierda, W.G.; Ravandi, F.; Koller, C.; et al. Phase 1/2 study of the combination of 5-aza-2’-deoxycytidine with valproic acid in patients with leukemia. Blood 2006, 108, 3271–3279. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Ten Cate, B.; Samplonius, D.F.; Bijma, T.; De Leij, L.F.M.H.; Helfrich, W.; Bremer, E. The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells. Leukemia 2007, 21, 248–252. [Google Scholar] [CrossRef] [PubMed]
  127. Soriano, A.O.; Yang, H.; Faderl, S.; Estrov, Z.; Giles, F.; Ravandi, F.; Cortes, J.; Wierda, W.G.; Ouzounian, S.; Quezada, A.; et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 2007, 110, 2302–2308. [Google Scholar] [CrossRef] [PubMed]
  128. Bartolini, G.; Orlandi, M.; Papi, A.; Ammar, K.; Tonelli, R.; Franzoni, M.; Pession, A.; Rocchi, P.; Ferreri, A.M. Growth inhibition and proapoptotic activity induction by IIF and valproic acid on RA-resistant leukemia cells. Anticancer Res. 2008, 28, 283–288. [Google Scholar] [PubMed]
  129. Fuchs, O.; Provaznikova, D.; Marinov, I.; Kuzelova, K.; Spicka, I. Antiproliferative and proapoptotic effects of proteasome inhibitors and their combination with histone deacetylase inhibitors on leukemia cells. Cardiovasc. Hematol. Disord. Drug Targets 2009, 9, 62–77. [Google Scholar] [CrossRef]
  130. Chen, J.; Wang, G.; Wang, L.; Kang, J.; Wang, J. Curcumin p38-dependently enhances the anticancer activity of valproic acid in human leukemia cells. Eur. J. Pharm. Sci. 2010, 41, 210–218. [Google Scholar] [CrossRef]
  131. Fredly, H.; Stapnes Bjørnsen, C.; Gjertsen, B.T.; Bruserud, Ø. Combination of the histone deacetylase inhibitor valproic acid with oral hydroxyurea or 6-mercaptopurin can be safe and effective in patients with advanced acute myeloid leukaemia–a report of five cases. Hematology 2010, 15, 338–343. [Google Scholar] [CrossRef]
  132. Heo, S.-K.; Noh, E.-K.; Yoon, D.-J.; Jo, J.-C.; Park, J.-H.; Kim, H. Dasatinib accelerates valproic acid-induced acute myeloid leukemia cell death by regulation of differentiation capacity. PLoS ONE 2014, 9, e98859. [Google Scholar] [CrossRef] [Green Version]
  133. Nie, D.; Huang, K.; Yin, S.; Li, Y.; Xie, S.; Ma, L.; Wang, X.; Wu, Y.; Xiao, J. Synergistic/additive interaction of valproic acid with bortezomib on proliferation and apoptosis of acute myeloid leukemia cells. Leuk. Lymphoma 2012, 53, 2487–2495. [Google Scholar] [CrossRef] [PubMed]
  134. Wang, A.-H.; Wei, L.; Chen, L.; Zhao, S.-Q.; Wu, W.-L.; Shen, Z.-X.; Li, J.-M. Synergistic effect of bortezomib and valproic acid treatment on the proliferation and apoptosis of acute myeloid leukemia and myelodysplastic syndrome cells. Ann. Hematol. 2011, 90, 917–931. [Google Scholar] [CrossRef]
  135. Liu, N.; Wang, C.; Wang, L.; Gao, L.; Cheng, H.; Tang, G.; Hu, X.; Wang, J. Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis. Int. J. Mol. Med. 2016, 37, 1686–1696. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. McCormack, E.; Haaland, I.; Venås, G.; Forthun, R.B.; Huseby, S.; Gausdal, G.; Knappskog, S.; Micklem, D.R.; Lorens, J.B.; Bruserud, O.; et al. Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia 2012, 26, 910–917. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Kuendgen, A.; Schmid, M.; Schlenk, R.; Knipp, S.; Hildebrandt, B.; Steidl, C.; Germing, U.; Haas, R.; Dohner, H.; Gattermann, N. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer 2006, 106, 112–119. [Google Scholar] [CrossRef]
  138. Kuendgen, A.; Knipp, S.; Fox, F.; Strupp, C.; Hildebrandt, B.; Steidl, C.; Germing, U.; Haas, R.; Gattermann, N. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann. Hematol. 2005, 84, 61–66. [Google Scholar] [CrossRef]
  139. Raffoux, E.; Chaibi, P.; Dombret, H.; Degos, L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica 2005, 90, 986–988. [Google Scholar]
  140. Bug, G.; Ritter, M.; Wassmann, B.; Schoch, C.; Heinzel, T.; Schwarz, K.; Romanski, A.; Kramer, O.H.; Kampfmann, M.; Hoelzer, D.; et al. Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer 2005, 104, 2717–2725. [Google Scholar] [CrossRef]
  141. Tassara, M.; Döhner, K.; Brossart, P.; Held, G.; Götze, K.; Horst, H.-A.; Ringhoffer, M.; Köhne, C.-H.; Kremers, S.; Raghavachar, A.; et al. Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. Blood 2014, 123, 4027–4036. [Google Scholar] [CrossRef] [Green Version]
  142. Corsetti, M.T.; Salvi, F.; Perticone, S.; Baraldi, A.; De Paoli, L.; Gatto, S.; Pietrasanta, D.; Pini, M.; Primon, V.; Zallio, F.; et al. Hematologic improvement and response in elderly AML/RAEB patients treated with valproic acid and low-dose Ara-C. Leuk. Res. 2011, 35, 991–997. [Google Scholar] [CrossRef]
  143. Lane, S.; Gill, D.; McMillan, N.A.J.; Saunders, N.; Murphy, R.; Spurr, T.; Keane, C.; Fan, H.M.; Mollee, P. Valproic acid combined with cytosine arabinoside in elderly patients with acute myeloid leukemia has in vitro but limited clinical activity. Leuk. Lymphoma 2012, 53, 1077–1083. [Google Scholar] [CrossRef] [PubMed]
  144. Bradner, J.E.; West, N.; Grachan, M.L.; Greenberg, E.F.; Haggarty, S.J.; Warnow, T.; Mazitschek, R. Chemical phylogenetics of histone deacetylases. Nat. Chem. Biol. 2010, 6, 238–243. [Google Scholar] [CrossRef] [PubMed]
  145. Corrales-Medina, F.F.; Manton, C.A.; Orlowski, R.Z.; Chandra, J. Efficacy of panobinostat and marizomib in acute myeloid leukemia and bortezomib-resistant models. Leuk. Res. 2015, 39, 371–379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Martínez-Iglesias, O.; Ruiz-Llorente, L.; Sánchez-Martínez, R.; García, L.; Zambrano, A.; Aranda, A. Histone deacetylase inhibitors: Mechanism of action and therapeutic use in cancer. Clin. Transl. Oncol. 2008, 10, 395–398. [Google Scholar] [CrossRef]
  147. McClure, J.J.; Li, X.; Chou, C.J. Advances and Challenges of HDAC Inhibitors in Cancer Therapeutics. In Advances in Cancer Research; Academic Press Inc.: Cambridge, MA, USA, 2018; Volume 138, pp. 183–211. [Google Scholar]
  148. Guo, S.Q.; Zhang, Y.Z. Histone deacetylase inhibition: An important mechanism in the treatment of lymphoma. Cancer Biol. Med. 2012, 9, 85–89. [Google Scholar]
  149. Vigushin, D.M.; Ali, S.; Pace, P.E.; Mirsaidi, N.; Ito, K.; Adcock, I.; Coombes, R.C. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin. Cancer Res. 2001, 7, 971–976. [Google Scholar]
  150. Gonçalves, J.; Malta-Vacas, J.; Louis, M.; Brault, L.; Bagrel, D.; Monteiro, C.; Brito, M. Modulation of translation factor’s gene expression by histone deacetylase inhibitors in breast cancer cells. Clin. Chem. Lab. Med. 2005, 43, 151–156. [Google Scholar] [CrossRef] [Green Version]
  151. Hrgovic, I.; Doll, M.; Kleemann, J.; Wang, X.-F.; Zoeller, N.; Pinter, A.; Kippenberger, S.; Kaufmann, R.; Meissner, M. The histone deacetylase inhibitor trichostatin a decreases lymphangiogenesis by inducing apoptosis and cell cycle arrest via p21-dependent pathways. BMC Cancer 2016, 16, 763. [Google Scholar] [CrossRef] [Green Version]
  152. Sakai, N.; Maruyama, T.; Sakurai, R.; Masuda, H.; Yamamoto, Y.; Shimizu, A.; Kishi, I.; Asada, H.; Yamagoe, S.; Yoshimura, Y. Involvement of histone acetylation in ovarian steroid-induced decidualization of human endometrial stromal cells. J. Biol. Chem. 2003, 278, 16675–16682. [Google Scholar] [CrossRef] [Green Version]
  153. Uchida, H.; Maruyama, T.; Nagashima, T.; Asada, H.; Yoshimura, Y. Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin. Endocrinology 2005, 146, 5365–5373. [Google Scholar] [CrossRef] [Green Version]
  154. Marks, P.A.; Richon, V.M.; Rifkind, R.A. Histone deacetylase inhibitors: Inducers of differentiation or apoptosis of transformed cells. J. Natl. Cancer Inst. 2000, 92, 1210–1216. [Google Scholar] [CrossRef] [PubMed]
  155. Robert, C.; Nagaria, P.K.; Pawar, N.; Adewuyi, A.; Gojo, I.; Meyers, D.J.; Cole, P.A.; Rassool, F.V. Histone deacetylase inhibitors decrease NHEJ both by acetylation of repair factors and trapping of PARP1 at DNA double-strand breaks in chromatin. Leuk. Res. 2016, 45, 14–23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Silva, G.; Cardoso, B.A.; Belo, H.; Almeida, A.M. Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies: Genetic and Molecular Mechanisms. PLoS ONE 2013, 8, e53766. [Google Scholar] [CrossRef] [PubMed]
  157. Bubna, A.K. Vorinostat-An overview. Indian J. Dermatol. 2015, 60, 419. [Google Scholar] [CrossRef] [PubMed]
  158. Montalban-Bravo, G.; Garcia-Manero, G. Novel drugs for older patients with acute myeloid leukemia. Leukemia 2015, 29, 760–769. [Google Scholar] [CrossRef]
  159. Yoon, S.; Eom, G.H. HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases. Chonnam Med. J. 2016, 52, 1–11. [Google Scholar] [CrossRef] [PubMed]
  160. Suraweera, A.; O’Byrne, K.J.; Richard, D.J. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: Achieving the full therapeutic potential of HDACi. Front. Oncol. 2018, 8. [Google Scholar] [CrossRef] [Green Version]
  161. Petruccelli, L.A.; Dupéré-Richer, D.; Pettersson, F.; Retrouvey, H.; Skoulikas, S.; Miller, W.H. Vorinostat induces reactive oxygen species and dna damage in acute myeloid leukemia cells. PLoS ONE 2011, 6, e20987. [Google Scholar] [CrossRef] [Green Version]
  162. Schaefer, E.W.; Loaiza-Bonilla, A.; Juckett, M.; DiPersio, J.F.; Roy, V.; Slack, J.; Wu, W.; Laumann, K.; Espinoza-Delgado, I.; Gore, S.D. A phase 2 study of vorinostat in acute myeloid leukemia. Haematologica 2009, 94, 1375–1382. [Google Scholar] [CrossRef]
  163. Yu, J.; Qiu, S.; Ge, Q.; Wang, Y.; Wei, H.; Guo, D.; Chen, S.; Liu, S.; Li, S.; Xing, H.; et al. A novel SAHA-bendamustine hybrid induces apoptosis of leukemia cells. Oncotarget 2015, 6, 20121–20131. [Google Scholar] [CrossRef] [Green Version]
  164. Li, X.; Li, C.; Jin, J.; Wang, J.; Huang, J.; Ma, Z.; Huang, X.; He, X.; Zhou, Y.; Xu, Y.; et al. High PARP-1 expression predicts poor survival in acute myeloid leukemia and PARP-1 inhibitor and SAHA-bendamustine hybrid inhibitor combination treatment synergistically enhances anti-tumor effects. EBioMedicine 2018, 38, 47–56. [Google Scholar] [CrossRef] [PubMed]
  165. Craddock, C.F.; Houlton, A.E.; Quek, L.S.; Ferguson, P.; Gbandi, E.; Roberts, C.; Metzner, M.; Garcia-Martin, N.; Kennedy, A.; Hamblin, A.; et al. Outcome of azacitidine therapy in acute myeloid leukemia is not improved by concurrent vorinostat therapy but is predicted by a diagnostic molecular signature. Clin. Cancer Res. 2017, 23, 6430–6440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Mims, A.S.; Mishra, A.; Orwick, S.; Blachly, J.; Klisovic, R.B.; Garzon, R.; Walker, A.R.; Devine, S.M.; Walsh, K.J.; Vasu, S.; et al. A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: Results of phase 1 study NCI 8485. Haematologica 2018, 103, 982–987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Wagner, J.M.; Hackanson, B.; Lübbert, M.; Jung, M. Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin. Epigenet. 2010, 1, 117–136. [Google Scholar] [CrossRef] [Green Version]
  168. Vilas-Zornoza, A.; Agirre, X.; Abizanda, G.; Moreno, C.; Segura, V.; De Martino Rodriguez, A.; José-Eneriz, E.S.; Miranda, E.; Martín-Subero, J.I.; Garate, L.; et al. Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia. Leukemia 2012, 26, 1517–1526. [Google Scholar] [CrossRef]
  169. Van Veggel, M.; Westerman, E.; Hamberg, P. Clinical Pharmacokinetics and Pharmacodynamics of Panobinostat. Clin. Pharmacokinet. 2018, 57, 21–29. [Google Scholar] [CrossRef]
  170. Anne, M.; Sammartino, D.; Barginear, M.F.; Budman, D. Profile of panobinostat and its potential for treatment in solid tumors: An update. Onco. Targets. Ther. 2013, 6, 1613–1624. [Google Scholar] [CrossRef] [Green Version]
  171. Tan, P.; Wei, A.; Mithraprabhu, S.; Cummings, N.; Liu, H.B.; Perugini, M.; Reed, K.; Avery, S.; Patil, S.; Walker, P.; et al. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J. 2014, 4, e170. [Google Scholar] [CrossRef] [Green Version]
  172. Lee, H.Z.; Kwitkowski, V.E.; Del Valle, P.L.; Ricci, M.S.; Saber, H.; Habtemariam, B.A.; Bullock, J.; Bloomquist, E.; Shen, Y.L.; Chen, X.H.; et al. FDA approval: Belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin. Cancer Res. 2015, 21, 2666–2670. [Google Scholar] [CrossRef]
  173. Poole, R.M. Belinostat: First global approval. Drugs 2014, 74, 1543–1554. [Google Scholar] [CrossRef]
  174. Beleodaq approved for rare lymphomas. Cancer Discov. 2014, 4, 978.
  175. Kirschbaum, M.H.; Foon, K.A.; Frankel, P.; Ruel, C.; Pulone, B.; Tuscano, J.M.; Newman, E.M. A phase 2 study of belinostat (PXD101) in patients with relapsed or refractory acute myeloid leukemia or patients over the age of 60 with newly diagnosed acute myeloid leukemia: A California Cancer Consortium Study. Leuk. Lymphoma 2014, 55, 2301–2304. [Google Scholar] [CrossRef] [PubMed]
  176. Finazzi, G.; Vannucchi, A.M.; Martinelli, V.; Ruggeri, M.; Nobile, F.; Specchia, G.; Pogliani, E.M.; Olimpieri, O.M.; Fioritoni, G.; Musolino, C.; et al. A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. Br. J. Haematol. 2013, 161, 688–694. [Google Scholar] [CrossRef] [PubMed]
  177. Furlan, A.; Monzani, V.; Reznikov, L.L.; Leoni, F.; Fossati, G.; Modena, D.; Mascagni, P.; Dinarello, C.A. Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Mol. Med. 2011, 17, 353–362. [Google Scholar] [CrossRef]
  178. Rambaldi, A.; Dellacasa, C.M.; Finazzi, G.; Carobbio, A.; Ferrari, M.L.; Guglielmelli, P.; Gattoni, E.; Salmoiraghi, S.; Finazzi, M.C.; Di Tollo, S.; et al. A pilot study of the Histone-Deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br. J. Haematol. 2010, 150, 446–455. [Google Scholar] [CrossRef]
  179. Ganai, S.A. Histone deacetylase inhibitor givinostat: The small-molecule with promising activity against therapeutically challenging haematological malignancies. J. Chemother. 2016, 28, 247–254. [Google Scholar] [CrossRef]
  180. Brunetto, A.T.; Ang, J.E.; Lal, R.; Olmos, D.; Molife, L.R.; Kristeleit, R.; Parker, A.; Casamayor, I.; Olaleye, M.; Mais, A.; et al. First-in-human, pharmacokinetic and pharmacodynamic phase i study of resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 2013, 19, 5494–5504. [Google Scholar] [CrossRef]
  181. Ribrag, V.; Kim, W.S.; Bouabdallah, R.; Lim, S.T.; Coiffier, B.; Illes, A.; Lemieux, B.; Dyer, M.J.S.; Offner, F.; Felloussi, Z.; et al. Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: Results of a phase II study. Haematologica 2017, 102, 903–909. [Google Scholar] [CrossRef] [Green Version]
  182. Vey, N.; Prebet, T.; Thalamas, C.; Charbonnier, A.; Rey, J.; Kloos, I.; Liu, E.; Luan, Y.; Vezan, R.; Graef, T.; et al. Phase 1 dose-escalation study of oral abexinostat for the treatment of patients with relapsed/refractory higher-risk myelodysplastic syndromes, acute myeloid leukemia, or acute lymphoblastic leukemia. Leuk. Lymphoma 2017, 58, 1880–1886. [Google Scholar] [CrossRef]
  183. Evens, A.M.; Balasubramanian, S.; Vose, J.M.; Harb, W.; Gordon, L.I.; Langdon, R.; Sprague, J.; Sirisawad, M.; Mani, C.; Yue, J.; et al. A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma. In Proceedings of the Clinical Cancer Research; American Association for Cancer Research Inc.: Denver, CO, USA, 2016; Volume 22, pp. 1059–1066. [Google Scholar]
  184. Morschhauser, F.; Terriou, L.; Coiffier, B.; Bachy, E.; Varga, A.; Kloos, I.; Lelièvre, H.; Sarry, A.L.; Depil, S.; Ribrag, V. Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia. Investig. New Drugs 2015, 33, 423–431. [Google Scholar] [CrossRef]
  185. Venugopal, B.; Baird, R.; Kristeleit, R.S.; Plummer, R.; Cowan, R.; Stewart, A.; Fourneau, N.; Hellemans, P.; Elsayed, Y.; McClue, S.; et al. A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors. Clin. Cancer Res. 2013, 19, 4262–4272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Barbetti, V.; Gozzini, A.; Rovida, E.; Morandi, A.; Spinelli, E.; Fossati, G.; Mascagni, P.; Lübbert, M.; Dello Sbarba, P.; Santini, V. Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells. Oncogene 2008, 27, 1767–1778. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  187. Golay, J.; Cuppini, L.; Leoni, F.; Micò, C.; Barbui, V.; Domenghini, M.; Lombardi, L.; Neri, A.; Barbui, A.M.; Salvi, A.; et al. The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells. Leukemia 2007, 21, 1892–1900. [Google Scholar] [CrossRef] [PubMed]
  188. Novotny-Diermayr, V.; Sausgruber, N.; Loh, Y.K.; Pasha, M.K.; Jayaraman, R.; Hentze, H.; Yong, W.P.; Goh, B.C.; Toh, H.C.; Ethirajulu, K.; et al. Pharmacodynamic evaluation of the target efficacy of SB939, an oral HDAC inhibitor with selectivity for tumor tissue. Mol. Cancer Ther. 2011, 10, 1207–1217. [Google Scholar] [CrossRef] [PubMed]
  189. Zabkiewicz, J.; Gilmour, M.; Hills, R.; Vyas, P.; Bone, E.; Davidson, A.; Burnett, A.; Knapper, S. The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias. Oncotarget 2016, 7, 16650–16662. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  190. Ossenkoppele, G.J.; Lowenberg, B.; Zachee, P.; Vey, N.; Breems, D.; Van de Loosdrecht, A.A.; Davidson, A.H.; Wells, G.; Needham, L.; Bawden, L.; et al. A phase I first-in-human study with tefinostat–a monocyte/macrophage targeted histone deacetylase inhibitor–in patients with advanced haematological malignancies. Br. J. Haematol. 2013, 162, 191–201. [Google Scholar] [CrossRef]
  191. Moffat, D.; Patel, S.; Day, F.; Belfield, A.; Donald, A.; Rowlands, M.; Wibawa, J.; Brotherton, D.; Stimson, L.; Clark, V.; et al. Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo [3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor. J. Med. Chem. 2010, 53, 8663–8678. [Google Scholar] [CrossRef]
  192. Banerji, U.; van Doorn, L.; Papadatos-Pastos, D.; Kristeleit, R.; Debnam, P.; Tall, M.; Stewart, A.; Raynaud, F.; Garrett, M.D.; Toal, M.; et al. A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors. Clin. Cancer Res. 2012, 18, 2687–2694. [Google Scholar] [CrossRef] [Green Version]
  193. Wightman, F.; Lu, H.K.; Solomon, A.E.; Saleh, S.; Harman, A.N.; Cunningham, A.L.; Gray, L.; Churchill, M.; Cameron, P.U.; Dear, A.E.; et al. Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells. AIDS 2013, 27, 2853–2862. [Google Scholar] [CrossRef]
  194. Connolly, R.M.; Rudek, M.A.; Piekarz, R. Entinostat: A promising treatment option for patients with advanced breast cancer. Futur. Oncol. 2017, 13, 1137–1148. [Google Scholar] [CrossRef]
  195. Nishioka, C.; Ikezoe, T.; Yang, J.; Takeuchi, S.; Phillip Koeffler, H.; Yokoyama, A. MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. Leuk. Res. 2008, 32, 1382–1392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  196. Ramsey, J.M.; Kettyle, L.M.J.; Sharpe, D.J.; Mulgrew, N.M.; Dickson, G.J.; Bijl, J.J.; Austin, P.; Mayotte, N.; Cellot, S.; Lappin, T.R.J.; et al. Entinostat prevents leukemia maintenance in a collaborating oncogene-dependent model of cytogenetically normal acute myeloid leukemia. Stem Cells 2013, 31, 1434–1445. [Google Scholar] [CrossRef] [PubMed]
  197. Gojo, I.; Jiemjit, A.; Trepel, J.B.; Sparreboom, A.; Figg, W.D.; Rollins, S.; Tidwell, M.L.; Greer, J.; Chung, E.J.; Lee, M.-J.; et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 2007, 109, 2781–2790. [Google Scholar] [CrossRef] [PubMed]
  198. Lillico, R.; Lawrence, C.K.; Lakowski, T.M. Selective DOT1L, LSD1, and HDAC Class i Inhibitors Reduce HOXA9 Expression in MLL-AF9 Rearranged Leukemia Cells, but Dysregulate the Expression of Many Histone-Modifying Enzymes. J. Proteome Res. 2018, 17, 2657–2667. [Google Scholar] [CrossRef] [PubMed]
  199. Garcia-Manero, G.; Assouline, S.; Cortes, J.; Estrov, Z.; Kantarjian, H.; Yang, H.; Newsome, W.M.; Miller, W.H.; Rousseau, C.; Kalita, A.; et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 2008, 112, 981–989. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  200. Piekarz, R.L.; Frye, R.; Prince, H.M.; Kirschbaum, M.H.; Zain, J.; Allen, S.L.; Jaffe, E.S.; Ling, A.; Turner, M.; Peer, C.J.; et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 2011, 117, 5827–5834. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  201. Campàs-Moya, C. Romidepsin for the treatment of cutaneous T-cell lymphoma. Drugs Today 2009, 45, 787. [Google Scholar] [CrossRef]
  202. Rajak, H.; Singh, A.; Dewangan, P.K.; Patel, V.; Jain, D.K.; Tiwari, S.K.; Veerasamy, R.; Sharma, P.C. Peptide Based Macrocycles: Selective Histone Deacetylase Inhibitors with Antiproliferative Activity. Curr. Med. Chem. 2013, 20, 1887–1903. [Google Scholar] [CrossRef]
  203. Yan, B.; Chen, Q.; Shimada, K.; Tang, M.; Li, H.; Gurumurthy, A.; Khoury, J.D.; Xu, B.; Huang, S.; Qiu, Y. Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia. Leukemia 2019, 33, 931–944. [Google Scholar] [CrossRef]
  204. Byrd, J.C.; Marcucci, G.; Parthun, M.R.; Xiao, J.J.; Klisovic, R.B.; Moran, M.; Lin, T.S.; Liu, S.; Sklenar, A.R.; Davis, M.E.; et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 2005, 105, 959–967. [Google Scholar] [CrossRef]
  205. Klimek, V.M.; Fircanis, S.; Maslak, P.; Guernah, I.; Baum, M.; Wu, N.; Panageas, K.; Wright, J.J.; Pandolfi, P.P.; Nimer, S.D. Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin. Cancer Res. 2008, 14, 826–832. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. Chuang, D.M.; Leng, Y.; Marinova, Z.; Kim, H.J.; Chiu, C.T. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci. 2009, 32, 591–601. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  207. Kwon, S.H.; Ahn, S.H.; Kim, Y.K.; Bae, G.-U.; Yoon, J.W.; Hong, S.; Lee, H.Y.; Lee, Y.-W.; Lee, H.-W.; Han, J.-W. Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells. J. Biol. Chem. 2002, 277, 2073–2080. [Google Scholar] [CrossRef] [Green Version]
  208. Porter, N.J.; Christianson, D.W. Binding of the Microbial Cyclic Tetrapeptide Trapoxin A to the Class i Histone Deacetylase HDAC8. ACS Chem. Biol. 2017, 12, 2281–2286. [Google Scholar] [CrossRef] [PubMed]
  209. Maeda, T.; Towatari, M.; Kosugi, H.; Saito, H. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 2000, 96, 3847–3856. [Google Scholar] [CrossRef] [PubMed]
  210. Tang, R.; Faussat, A.-M.; Majdak, P.; Perrot, J.-Y.; Chaoui, D.; Legrand, O.; Marie, J.-P. Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1. Leukemia 2004, 18, 1246–1251. [Google Scholar] [CrossRef] [PubMed]
  211. Liu, S.; Klisovic, R.B.; Vukosavljevic, T.; Yu, J.; Paschka, P.; Huynh, L.; Pang, J.; Neviani, P.; Liu, Z.; Blum, W.; et al. Targeting AML1/ETO-histone deacetylase repressor complex: A novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETO-positive acute myeloid leukemia cells. J. Pharmacol. Exp. Ther. 2007, 321, 953–960. [Google Scholar] [CrossRef]
  212. Cheng, Y.C.; Lin, H.; Huang, M.J.; Chow, J.M.; Lin, S.; Liu, H.E. Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia. Leuk. Res. 2007, 31, 1403–1411. [Google Scholar] [CrossRef]
  213. Göttlicher, M.; Minucci, S.; Zhu, P.; Krämer, O.H.; Schimpf, A.; Giavara, S.; Sleeman, J.P.; Lo Coco, F.; Nervi, C.; Pelicci, P.G.; et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001, 20, 6969–6978. [Google Scholar] [CrossRef] [Green Version]
  214. Gozzini, A.; Rovida, E.; Dello Sbarba, P.; Galimberti, S.; Santini, V.; Galimbert, S. Butyrates, as a single drug, induce histone acetylation and granulocytic maturation: Possible selectivity on core binding factor-acute myeloid leukemia blasts. Cancer Res. 2003, 63, 8955–8961. [Google Scholar]
  215. Maslak, P.; Chanel, S.; Camacho, L.H.; Soignet, S.; Pandolfi, P.P.; Guernah, I.; Warrell, R.; Nimer, S. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 2006, 20, 212–217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  216. Miller, T.A.; Witter, D.J.; Belvedere, S. Histone deacetylase inhibitors. J. Med. Chem. 2003, 46, 5097–5116. [Google Scholar] [CrossRef] [PubMed]
  217. Frey, R.R.; Wada, C.K.; Garland, R.B.; Curtin, M.L.; Michaelides, M.R.; Li, J.; Pease, L.J.; Glaser, K.B.; Marcotte, P.A.; Bouska, J.J.; et al. Trifluoromethyl ketones as inhibitors of histone deacetylase. Bioorg. Med. Chem. Lett. 2002, 12, 3443–3447. [Google Scholar] [CrossRef]
Cancers 11 01794 g001 550
Figure 1. HDAC inhibitor (HDACi) effect on chromatin remodeling. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are responsible for the balance of histone acetylation, and thereby regulate gene expression. Whereas HDACs deacetylate histones, promoting transcription repression, HATs are responsible for acetylating histones and inducing transcriptional activation. HDACi inhibits HDACs, and thus maintain an open chromatin conformation.
Figure 1. HDAC inhibitor (HDACi) effect on chromatin remodeling. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are responsible for the balance of histone acetylation, and thereby regulate gene expression. Whereas HDACs deacetylate histones, promoting transcription repression, HATs are responsible for acetylating histones and inducing transcriptional activation. HDACi inhibits HDACs, and thus maintain an open chromatin conformation.
Cancers 11 01794 g001
Table
Table 1. Description of the HDAC families and their dependence on the Zn2+ or NAD+ cofactors.
Table 1. Description of the HDAC families and their dependence on the Zn2+ or NAD+ cofactors.
HDAC ClassesHDAC MembersCofactor
Class IHDAC1, HDAC2, HDAC3, and HDAC8Zn2+-dependent
Class IIaHDAC4, HDAC5, HDAC7, and HDAC9Zn2+-dependent
Class IIbHDAC6 and HDAC10Zn2+-dependent
Class III (Sirtuins)SIRT1-7NAD+-dependent
Class IVHDAC11Zn2+-dependent
Table
Table 2. Overview of the main HDAC inhibitors and the combinations tested.
Table 2. Overview of the main HDAC inhibitors and the combinations tested.
HDACi ClassesHDAC InhibitorTarget HDAC ClassPreclinical CombinationsClinical Trials Combinations
HydroximatesTrichostatin Apan *Chaetocin [64]
Decitabine + DZNep [65]
Vorinostat (SAHA)pan *ATRA [66,67,68]
MK-0457 [69]
NPI-0052 [70]
Cytarabine [71]
Etoposide [71]
GX15-070 [72]
AZD1775 [73]
BPR1J-340 [74]
BMN673 [75]		Decitabine [76,77]
Idarubicin [78]
Idarubicin + Cytarabine [79]
Alvocidib [80]
GO + AZA [81,82]
Sorafenib + Bortezomib [83]
Panobinostat (LBH589)pan *Decitabine [84,85]
AZA [86]
ABT-199 [87]
MK-1775 [88]
BC2059 [89]
SP2509 [90]
JQ1 [91]
AC220 [92]
Bortezomib [93]
CXCR4 antagonist [94]
Doxorubicin [95]
DZNep [96]		AZA [97]
GSK2879552 [98]
Cytarabine + Idarubicin [99]
Daunorubicin + Cytarabine [100]
Cytarabine + Mitoxantrane [101]
Belinostat (PXD101)pan *ATRA [102,103]
DZNep + ATRA [104,105]
DZNep + ATRA + Idarubicin [104,105]
Bortezomib [106]
Pevenedistat [107]
Givinostat (ITF2357)pan *
Resminostat (4SC201)pan
Abexinostat (PCI-24781)pan
Quisinostat (JNJ-26481585)pan
Pracinostat (SB939)panSB1518 [108]AZA [109,110,111]
Tefinostat (CHR-2845)pan
CHR-3996I
BenzamidesEntinostatIAZD6244 [112]
RAD001 [113]
Decitabine [114]		AZA [115,116]
MocetinostatI, IV
Cyclic peptidesRomidepsinIATRA [117]
Decitabine [118]
AZA [119]
ApicidinI
Trapoxin AI, IIATRA [120]
Aliphatic acidsValproic acidI, IIaATRA [121,122]
Decitabine [123,124,125]
GO [126]
AZA [127]
Retinoid IIF [128]
NPI-0052 [129]
PR-171 [129]
Curcumin [130]
Hydroxiurea [131]
6-mercaptopurine [131]
Dasatinib [132]
Bortezomib [133,134]
Cytarabine [135]
Nutlin-3 [136]		ATRA [137,138,139,140,141]
Cytarabine [142,143]
Hydroxiurea [131]
6-mercaptopurine [131]
Decitabine [123,124,125]
AZA [127]
Butyric acidI, II
Phenylbutyric acidI, II
* According to Bradner et al. [144] these HDACi do not demonstrate a preference for Class IIa enzymes at pharmacologically relevant concentrations, suggesting that the target HDAC classes for these HDACi are HDAC I, II, III, and VI. GO: Gemtuzumab ozogamicin; AZA: Azacitidine; ATRA: retinoic acid.

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MDPI and ACS Style

San José-Enériz, E.; Gimenez-Camino, N.; Agirre, X.; Prosper, F. HDAC Inhibitors in Acute Myeloid Leukemia. Cancers 2019, 11, 1794. https://doi.org/10.3390/cancers11111794

AMA Style

San José-Enériz E, Gimenez-Camino N, Agirre X, Prosper F. HDAC Inhibitors in Acute Myeloid Leukemia. Cancers. 2019; 11(11):1794. https://doi.org/10.3390/cancers11111794

Chicago/Turabian Style

San José-Enériz, Edurne, Naroa Gimenez-Camino, Xabier Agirre, and Felipe Prosper. 2019. "HDAC Inhibitors in Acute Myeloid Leukemia" Cancers 11, no. 11: 1794. https://doi.org/10.3390/cancers11111794

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