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Review

HDAC6—An Emerging Target Against Chronic Myeloid Leukemia?

by
Hélène Losson
1,
Michael Schnekenburger
1,
Mario Dicato
1 and
Marc Diederich
2,*
1
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg
2
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(2), 318; https://doi.org/10.3390/cancers12020318
Submission received: 3 January 2020 / Revised: 23 January 2020 / Accepted: 27 January 2020 / Published: 29 January 2020
(This article belongs to the Special Issue Targeting Histone Deacetylases in Cancer)
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Abstract

:
Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.

1. Introduction

Chronic myeloid leukemia (CML) is a well-known hematological malignancy that is characterized in most patients by the translocation t (9; 22) (q34; q11), leading to the formation of the Philadelphia chromosome carrying the chimeric oncogene breakpoint cluster region-Abelson (BCR-ABL). The slow progression of CML can be stopped if the disease is diagnosed and managed early enough with the reference treatment, imatinib, a first-generation tyrosine kinase inhibitor (TKI). Imatinib acts to block the BCR-ABL protein, which has constitutive tyrosine kinase activity, in its inactive form. However, resistances to imatinib and the second and third generation TKIs frequently develop in patients, leading researchers to synthesize molecules targeting other proteins involved in this pathology, such as histone deacetylase 6 (HDAC6). In this review, we will discuss the characteristics and implication of the HDAC6 protein in CML.

2. Chronic Myeloid Leukemia

CML is a myeloproliferative disorder affecting myeloid progenitors and is considered as a rare cancer with an incidence of approximately 1 in 100000 cases each year in Europe and the United States [1,2]. There are an estimated 6370 new cases each year in Europe [3] and 8430 new cases have been reported in 2018 in the United States [2]. CML is characterized by an excessive proliferation of leukocytes in the bone marrow, most of which are still immature, and called blasts when they pass into the blood [4]. This pathology comprises three distinct phases: the chronic, accelerated, and blast phases [5] (Figure 1).

2.1. Chromosomal Rearrangement during Chronic Myeloid Leukemia

A chromosomal anomaly, the t (9; 22) (q34; q11) translocation between chromosome 9, which carries the ABL gene, and chromosome 22, which carries the BCR gene, is found in 95% of patients with CML. This translocation leads to the formation of the Philadelphia chromosome carrying the BCR-ABL chimeric gene (Figure 2A), and thus to the expression of the corresponding fusion oncoprotein, which has a constitutive tyrosine kinase activity. The Philadelphia or Ph+ chromosome was identified for the first time in 1960 by the researchers Hungerford and Nowell in the city of Philadelphia, for which it was named [6,7].

2.2. BCR-ABL mRNA and Protein

There are multiple breakpoints on the BCR and ABL genes that lead to the formation of different transcripts (Figure 2B). These transcripts encode BCR-ABL proteins of different sizes that have been found in patients (Table 1) [4].
The BCR-ABL protein activates many substrates (Table 2) and signaling pathways, including some involved in cell proliferation and survival, through increased activity or expression of a series of anti-apoptotic proteins including the signal transducer and transcriptional activator 5 (STAT5), Akt, phosphoinositide 3-kinase, or B-cell lymphoma-extra-large [20].

3. CML Treatments and Associated Resistance Mechanisms

3.1. Targeted Therapy with a Tyrosine Kinase Inhibitor

In the 1960s, CML was treated with chemotherapy using busulfan and hydroxyurea. Two different therapeutic strategies emerged in the 1970s: allogeneic stem cell transplantation and the use of interferon-α [5]. A new therapy was approved in 2001 by the Food and Drug Administration (FDA) using the TKI imatinib (Gleevec®) [50]. TKIs represent a major advance in the management of CML patients by enabling targeted therapy for the first time.
There are two types of TKIs: type I TKIs target the active and inactive conformation of the BCR-ABL protein and bind to the ATP binding site on the tyrosine kinase domain of the protein, whereas type II inhibitors target the inactive conformation of the protein and bind to a site adjacent to the available ATP binding site when the activation loop is not phosphorylated [51,52].
Imatinib is a type II TKI. Its action therefore prevents the binding of ATP, and thus blocks the protein in its inactive form, preventing its autophosphorylation, and therefore preventing the phosphorylation of its substrates [53]. Imatinib is the first-line treatment for CML with daily oral intake. According to the IRIS study, including 1106 new patients with CML, 76% of patients treated with imatinib also lost the Philadelphia chromosome, also called a complete cytogenetic response. This treatment with a TKI thus allowed stabilization of the pathology in the chronic phase, allowing patients to live normally. However, this treatment has numerous side effects including fatigue, headaches, anemia and myalgia, which are more common, and sometimes even leading to organ toxicity in the liver or heart, which can cause QT interval prolongation associated with a high risk of rhythm disturbances and serious ventricular disease, which are uncommon and occur in less than 1% of patients treated with imatinib [5].
Patients treated with imatinib should be closely monitored to assess their response to treatment. There are three types of responses: the hematological, cytogenetic, and molecular responses. A complete hematologic response corresponds to normalization of blood levels and spleen size. An examination is performed every two weeks until a complete hematologic response is obtained, followed by a control every three months. Then, an examination is performed every 6 months until reaching a complete cytogenetic response, then every 12 to 18 months. Finally, a complete molecular response corresponds to the total disappearance of the BCR-ABL transcript, which is measured by reverse transcription followed by real-time PCR amplification. This test is performed every 3 months according to the recommendations of the European leukemia net [54].

3.2. Imatinib Resistances

Although imatinib is the gold standard for CML treatment, 35% to 40% of patients develop resistances to this drug [55]. It is possible to distinguish between primary resistances, defined as a complete lack of hematological response after 3 months, cytogenetic response after 6 months, or a major cytogenetic response after one year of treatment; and secondary resistances, also called acquired resistances, when the previous hematologic or cytological response is lost. Resistances can also be classified according to whether or not they depend on BCR-ABL [56,57]. The emergence of resistances has led to the development of new TKIs (Table 3).

3.2.1. BCR-ABL-Dependent Resistance Mechanisms

BCR-ABL-dependent resistance can be caused by duplication and mutation of the BCR-ABL gene (Figure 3). Duplication of the gene has been identified in the cells of imatinib-resistant patients and could be a possible source of drug resistance [63]. Although overexpression of BCR-ABL has been reported in patients with accelerated and blastic phase CML who became resistant to imatinib, several studies have shown that only 3% of imatinib-resistant patients have amplification of BCR-ABL gene [64].
Mutations in BCR-ABL are more common than duplications and occur in 40% to 90% of imatinib-resistant patients, depending on the sensitivity of the detection method used and the stage of CML [65]. To date, more than a hundred have been discovered [66], which can explain the recently observed decrease in the effectiveness of imatinib treatment [63]. The first mutation described, which is also the most common, represents 14% of all mutations detected [64], and corresponds to the nucleotide substitution of a cytosine by a thymine at position 944 of the ABL gene. This mutation results in the substitution of the amino acid 315, initially threonine, with an isoleucine (T315I). This results in the loss of an oxygen molecule that is necessary for the hydrogen bond between imatinib and the tyrosine kinase domain, and also creates steric hindrance, preventing binding and drastically reducing treatment efficacy [67,68,69].
The seven most common mutations are: G250A/E, Y253F/H, and E255D/K/R/V located in the ATP binding P-loop, T315I located at the imatinib binding site, M351T and F359C/L/V/R located in the catalytic loop, and H396P located at the activation loop A [64]. Mutations at the P-loop represent 38% to 46% of all mutations and result in a conformational change that prevents imatinib from binding to BCR-ABL [54]. Mutations occurring at loop A prevent BCR-ABL from attaining its active conformation, thus also preventing binding to imatinib [64].
It is interesting to note that the frequency of mutations is higher in patients who have developed secondary resistance, and that the site of mutation varies according to the progression of the pathology. Mutations of amino acids at position 244, 250, and 351 are more frequent in patients in the chronic phase, whereas mutations of amino acids at position 253, 255, and 315 are more frequently encountered in patients in the accelerated or blast phases [64].

3.2.2. BCR-ABL-Independent Resistance Mechanisms

BCR-ABL-independent resistances can be explained by interindividual variability, increased export protein, decreased import protein, and also by binding of imatinib to plasma proteins [67].
Interindividual variability may underlie differences in drug metabolism, and thus a different drug response in patients. The metabolization of imatinib to its main circulating metabolite, the N-desmethyl piperazine derivative [55], progresses via cytochrome (CYP) P450, and in particular to the CYP3A4 isoform, which has variable activity. This may explain the observed lower levels of imatinib in some patients despite a similar dose. Cytochrome CYP3A4 can be activated or inhibited by many drugs. The metabolization of imatinib by CYP3A4 may therefore be important during co-medication [65].
A reduced cellular concentration of imatinib can be explained by decreased levels of import proteins or by increased levels of export proteins (Figure 3). The organic cation transporter (OCT)1 is responsible for the influx of imatinib into leukemic cells, and a polymorphism of this transporter is associated with imatinib resistance in K-562 CML cells [64]. Glycoprotein P, also known as multi-drug resistance protein 1, is an export protein that has been associated with failed leukemia treatment by chemotherapy. Recent studies have supported the notion that imatinib is also a substrate for glycoprotein P [70].
Although this hypothesis remains controversial in the literature, the binding of imatinib to plasma proteins such as alpha-1-acid glycoprotein may explain the decrease in free imatinib concentration described in some patients with little or no response to treatment [54,64].
Finally, the existence of quiescent leukemic stem cells (LSC), which are unaffected by current drug therapies, would also explain the emergence of resistance to imatinib. LSCs are derived from a group of myeloid progenitors that gain the ability to self-renew, become quiescent, and finally survive in specific microenvironments called hematopoietic niches [4]. These allow interactions between the LSCs and the cells of the microenvironment, which can promote the development of resistance mechanisms. The persistence of LSCs in the presence of TKIs could be the cause of the molecular minimal residual disease that can promote the long-term development of resistance, making them potentially responsible for the clonal evolution and progression of CML [71].

3.3. Development of Novel Tyrosine Kinase Inhibitors

The emergence of resistances to imatinib has led to the development of new TKIs with an activity against specific mutations in BCR-ABL protein. Dasatinib and nilotinib are second-generation TKIs (Table 3) used in cases of imatinib resistance, allowing a complete, lasting cytogenetic response in approximately 40% of these cases. Despite promising results, these new molecules are nevertheless not effective in patients with the T315I mutation, and lead to the appearance of new mutations generating resistance and subsequently to a decrease in their effectiveness. In addition, the benefit-risk ratio is important to consider as the side effects caused by second-generation TKIs are numerous, and for the most part similar to those generated by imatinib [5].
Ponatinib is a third generation TKI (Table 3) that are effective in second generation TKI refractory patients [72]. Only ponatinib is effective in patients with imatinib resistance associated with the T315I mutation. A complete cytogenetic response was observed in 46% of chronic phase patients receiving ponatinib who had already been treated with other TKIs. Data from a phase II study suggest an increased incidence of arterial thrombotic events in patients receiving ponatinib, thus ending a phase III study. In addition, third generation TKIs do not escape the appearance of resistance phenomena [5,62]. Third generation TKIs also include radotinib, a TKI with structural similarities to imatinib and nilotinib, which was approved in Korea in 2012 for the second-line treatment of CML [73]. This TKI is one of the most effective treatments for chronic phase CML [74] but has side effects including pigment changes such as eruptive melanocytic nevi [75].

4. Histone Deacetylase 6

The HDAC6 protein is part of the HDAC family, which are enzymes catalyzing the deacetylation of proteins, which corresponds to the removal of an acetyl group from lysine residues [76]. The 18 HDACs found in mammals are divided into four classes according to their sequence homology. For classes I (HDAC1, 2, 3, and 8), IIa (HDAC4, 5, 7, and 9), IIb (HDAC6 and 10), and IV (HDAC11), the deacetylation of lysine occurs through a transfer of charge, and their essential component is a zinc ion (Zn2+) present at the bottom of the catalytic pocket of HDAC enzymes [77]. For class III [sirtuins (SIRT) 1-7] HDACs, the presence of a cofactor, nicotinamide adenine dinucleotide (NAD+), is essential for the reaction [78,79].
Class I HDACs are ubiquitously present in many human cell lines and tissues, while class II HDACs exhibit a specific expression profile in certain human tissues such as the heart (HDAC5), the breast (HDAC6), the ovary (HDAC7 and 9), and the kidney (HDAC10) [80,81].

4.1. Structure

Here, we will focus more specifically on HDAC6 belonging to class IIb. This enzyme is the only HDAC to possess two functional active catalytic sites, and has a nuclear localization sequence, a nuclear export sequence, and a repetitive region of eight consecutive serine-glutamic acid tetradecapeptides, a cytoplasmic retention signal, and is mainly present in the cytoplasm [82]. HDAC6 also has a C-terminal ubiquitin-binding domain required when binding to poly-ubiquitinated proteins (Figure 4).

4.2. Function

The HDAC6 protein deacetylates many substrates [83] (Table 4) including α-tubulin, cortactin, and heat shock protein (HSP)90α, and is thus involved in many cell processes, some of which are described below [84].
The HDAC6 protein plays an important role in the dynamism of two components of the cytoskeleton, actin filaments (or F-actin) and microtubules, α- and β-tubulin polymers, which are involved in particular in cell mobility and division. Cortactin, which improves the polymerization of actin filaments, and α-tubulin, a constituent of microtubules, are substrates of HDAC6. The deacetylation of cortactin by HDAC6 and SIRT1 leads to its binding to F-actin, improving its polymerization, and thus contributing to cytoskeletal dynamics (Figure 5A). The deacetylation of α-tubulin by HDAC6 and SIRT2 is associated with microtubule depolymerization, thus contributing to the dynamism of microtubules (Figure 5B), and to proteasome-independent protein degradation. When the proteasome is degraded, the polyubiquitinated misfolded proteins are transported to the microtubule-organizing center and are supported by HDAC6 via its ubiquitin binding domain, leading to the formation of aggresomes through deacetylation of cortactin. The aggresomes thus formed are subsequently removed after autophagosome fusion with lysosomes via autophagy (Figure 5C). A decrease in the acetylation of microtubule-associated protein 1 light chain 3 by HDAC6 was observed during autophagic degradation [68,102]. The HDAC6 protein is also involved in proteasome-dependent protein degradation via its interaction with HSP90α, a chaperone that stabilizes other proteins when deacetylated by HDAC6. In its acetylated form, HSP90α loses its chaperone function, which leads to the degradation of its client proteins by the proteasome (Figure 5D). An accumulation of misfolded proteins causes dissociation of the complex containing HSP90α, heat shock factor 1 (HSF) 1, chaperone valosin-containing protein/ATPase, and HDAC6. In complex in inactive form, during dissociation, the release of HSF1 induces the transcription of many HSPs (Figure 5E), and HDAC6 will allow its binding to misfolded proteins [68].
HDAC6 is also involved in apoptosis by deacetylating the Ku70 protein, which then forms a complex with BAX, a proapoptotic protein, allowing the inhibition of apoptosis (Figure 5F). Similarly, inhibition of the catalytic activity of HDAC6 promotes the dephosphorylation of AKT and ERK, associated with decreased cell proliferation and death of cancer cells [68].
Furthermore, HDAC6 regulates endocytosis and exocytosis vesicles. When the epidermal growth factor receptor (EGFR) receptor is bound to its ligand, it interacts with HDAC6 and inactivates it by phosphorylation, which then leads to the hyperacetylation of microtubules and finally the internalization of the receptor. The inhibition of HDAC6 induces the increase of the acetylation of peroxiredoxins 1 and 2, which are antioxidant enzymes, increasing their activity and causing a reduction in cell resistance to chemotherapy [68]. HDAC6 is involved in the process of autophosphorylation of tau protein, giving it the ability to form aggregates called neurofibrillary tangles that can cause neurotoxicity [103].

4.3. Post-Transcriptional Regulation

There is a lack of current data explaining the post-transcriptional regulation of HDAC6 protein. Nevertheless, some microRNAs stimulating cancer cell proliferation and metastasis formation (miR-22, miR-221, miR-433, and miR-548) [84], and stem cell differentiation (miR-26a) [104], are predicted to interact with HDAC6 protein, thus inducing a destabilization or repression of the translation of its mRNA.

4.4. Post-Translational Regulation

Post-translational modifications such as phosphorylation and acetylation have a significant impact on HDAC6 functions. Indeed, although EGFR induces an inhibitory phosphorylation of HDAC6, in the majority of cases it is established that the phosphorylation of HDAC6 improves its deacetylase activity, whereas acetylation decreases its enzymatic activity, preventing the deacetylation of α-tubulin. Examples of post-translational modifications of the HDAC6 protein influencing its activity are shown in Table 5.
In addition to these known post-translational modifications, there are proteins interacting directly with the HDAC6 protein and inducing its inhibition by direct interaction (Table 6).

4.5. HDAC6 Inhibitors

HDAC6 is overexpressed in many types of cancer (Table 7) and may be implicated in disease progression.
The ability to specifically target HDAC6 would have valuable clinical utility in the treatment of these cancers. However, despite a large number of pan-HDAC inhibitors, very few compounds are capable of selectively inhibiting HDAC6 (Table 8). This type of inhibitor can be divided into 2 groups according to their chemical structure: benzamides and hydroxamates [68].
The compounds ACY-241 (Citarinostat) and ACY-1215 (Ricolinostat) are derivatives of hydroxamic acid, which shows a specific inhibitory activity against HDAC6 with IC50 values of 2.6 and 5 nM, respectively. They are the only HDAC6 inhibitors in currently clinical trials (Table 9) [130,160]. To date, no HDAC6 inhibitor has yet been approved by the FDA, unlike pan HDAC inhibitors such as romidepsin, SAHA, PXD101, and LBH589 [173].
It is important to note that inactivation of HDAC6 protein in mice does not result in abnormal development or major organ problems [166], suggesting that HDAC6 inhibition would have few side effects, unlike pan-HDAC inhibitors.

5. HDAC6 in CML

Several studies have demonstrated the influence of HDAC6 in neurodegenerative, cardiovascular and renal diseases, as well as in inflammation [174] and viral response [84]. The role of the HDAC6 protein in cancer is also now well better understood. Although its oncogenic or tumor suppressor potential is dependent on the type of cancer [68], its involvement in oncogenic cell transformation, tumor development, and cancer immunity regulation makes a strong therapeutic candidate [113]. The overexpression of HDAC6 in many cancer types led researchers to test the effects of HDAC6 inhibitors on these cancers. Despite the observation of a moderate overexpression of the HDAC6 protein in urothelial cancerous tissues, the inhibition of the protein had limited efficacy compared to the use of inhibitors targeting several HDACs [175]. On the other hand, HDAC6 inhibitors have notable anti-cancer properties in prostate cancer [136], breast cancer [176], melanoma [138], and ovarian cancer [102]. These effects could be explained by the implication of HDAC6 in metastasis formation by epithelial-mesenchymal transition induction via its recruitment by TGFβ [177], in cell migration via α-tubulin deacetylation and in angiogenesis via cortactin deacetylation [178]. In contrast to some selective HDAC6 inhibitors, currently approved pan-HDAC inhibitors failed to show any clinical benefits in solid tumors [166]. The reasons of such therapeutic failures, compared to the treatment of leukemia and lymphoma, are not fully understood; however, some hypotheses have been raised. For example, the hypothesis of some researchers is based on the cellular composition of solid tumors, which tend to arise from more differentiated cells with reduced epigenetic reprogramming capacity [179]. In addition, solid tumor complexity including genomic, epigenomic, and phenotypical changes, can be a part of the explanation [180]. Moreover, the lack of response of solid tumors treated with HDAC inhibitors could be due to the pharmacokinetic profile of those drugs, which generally have a short half-life [181]. For such reasons, some researchers are investigating new methods and routes of administration of these inhibitors. Accordingly, Wang et al. have demonstrated that the use of nanoparticles to administrate HDAC inhibitors allowing a slow release of the drug directly in solid tumors could induce a higher therapeutic efficacy than classic administration routes [182].
Similar to pan-HDAC inhibitors approved for the treatment of hematological cancers, specific HDAC6 inhibitors showed anti-cancer properties in various cancer types such as multiple myeloma [183], chronic lymphocytic leukemia [114], and acute myeloid leukemia [184]. Here, we will focus on the involvement of HDAC6 in CML.

5.1. Nuclear HDAC6 and Its Implication in Leukemia

The cytoplasmic localization of HDAC6 is well described. In leukemia cells, a significant amount of nuclear HDAC6 was revealed, considering the interaction between the nuclear localization sequence (NLS) of HDAC6 and importin-α, which translocates HDAC6 into the nucleus. This region can be heavily acetylated resulting in a reduction of the NLS-importin-α interaction [185]. Consequently, the presence of HDAC6 in the nucleus of leukemia cells could be explained by red levels of acetylation within the NLS region, compared to other cell types. After nuclear translocation, HDAC6 interacts with nuclear proteins, transcriptional repressors, and transcription factors to regulate gene expression. For example, HDAC6 inhibition has been linked to increased expression of the pro-apoptotic protein BIM in acute myeloid leukemia cells [186]. Moreover, in a model exhibiting significant nuclear HDAC6 levels, chemical HDAC6 inhibition reduces its nuclear localization and p53-HDAC6 interactions inducing cell cycle arrest and apoptosis via changes of p53 target gene expression [187]. The specific nuclear localization of HDAC6 in leukemia cells might offer a therapeutic advantage to specifically target those cells.

5.2. Degradation of BCR-ABL via Deacetylation of HSP90α by HDAC6 in the Cytoplasm

Although little research exists on HDAC6 in the context of CML, this protein has a function that makes it particularly interesting in the context of such pathology. HDAC6 deacetylates HSP90α, which is involved in the stabilization BCR-ABL [186]. In the acetylated form, HSP90α loses its chaperone function, which leads to the degradation of its client proteins by the proteasome (Figure 6A). The importance of the acetylation status of HSP90α in the protein degradation of BCR-ABL makes HDAC6 inhibitors potentially promising molecules for the treatment of CML. Pan-HDAC inhibitors are capable of inducing the inhibition of HDAC6, as well as the downregulation of HDAC6 using si-RNA, which increases the acetylation of HSP90α, and in turn increases the ubiquitination of the BCR-ABL protein, decreasing its expression in K562 cells [188,189].

5.3. OverExpression of HDAC6 in CML Stem Cells

LSCs that are not targeted by TKI and are characterized by a capacity for self-renewal play a crucial role in CML relapse. Although HDAC6 is necessary for the repression of genes involved in the differentiation targeted by the Tip60-p400 complex in embryonic stem cells (ESCs) [190], no study has provided evidence for this in LSCs, more differentiated. In contrast, studies have shown that several proteins in the HDAC family are overexpressed in LCSs of CML. Indeed, SIRT1 is activated by BCR-ABL via STAT5 and its expression is increased in LSCs compared to in CML cells [191]. Finally, overexpression of isoforms of HDAC (HDAC1, HDAC2, HDAC3, HDAC4, and HDAC5) and in particular HDAC6 was more frequently observed in LSCs (CD34+ CD38-) isolated from patients with CML than in K562 cells [117] (Figure 6B), making it a protein of interest in the search for treatments to prevent relapse in patients with CML.

6. Conclusions

Despite the success of imatinib and TKIs, the emergence of resistance and the presence of LSCs that are unaffected by these treatments and are responsible for relapse mean that the development of new treatments for CML remains urgent. HDACs represent potential therapeutic targets for the treatment of CML [188,189,192]. Inhibitors of the HDAC family have promising results in combination with TKIs [193], some of which also inhibit HDAC6 [194,195,196]. The combination of HDAC class I inhibitors [197] or HDAC inhibitors including HDAC6 [198] and TKIs induces elimination of the quiescent LSCs that are not eradicated during treatment with imatinib alone. Although a decrease in HDAC6 expression, an increase in HSP90α acetylation, and a decrease in BCR-ABL expression were observed in imatinib-resistant K562 cells, these cells still showed sensitivity to SAHA, an inhibitor of HDACs including HDAC6 [186]. However, the high toxicity of HDAC inhibitors and their many side effects [183] has necessitated targeting of particular HDAC isoforms.
The targeting of HDAC6 appears promising because it is overexpressed in many types of cancers, including certain leukemia subtypes. A recent study showed that dasatinib inhibits the phosphorylation of BCR-ABL without inducing the death of LSCs, suggesting that LSCs use signaling pathways that are activated by the BCR-ABL protein and are independent of its tyrosine kinase activity. The simple inhibition of the tyrosine kinase activity of the BCR-ABL protein is therefore not sufficient [199]. Since HDAC6 is overexpressed in CML stem cells and that its inhibition can potentially cause BCR-ABL degradation [68], this deacetylase appears as a strong candidate for CML treatment. Accordingly, HDAC6 inhibitors could be further tested in combination with TKIs or other molecules capable of targeting BCR-ABL such as bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and -5 molecules, and 1, 3, 4 thiadiazole derivatives, to potentially reduce resistance to treatment [200]. In the future, further development of selective PROTAC E3 ubiquitin ligase degraders triggering HDAC6 degradation [201] will provide further therapeutic options against various types of cancer, including CML.

Author Contributions

All authors have read and agreed to the published version of the manuscript.

Funding

H.L. was supported by the “Recherche Cancer et Sang” foundation. LBMCC was also supported the “Recherches Scientifiques Luxembourg” association, by the “Een Häerz fir kriibskrank Kanner” association, by the Action LIONS “Vaincre le Cancer” association, and by Télévie Luxembourg. M.D. (Marc Diederich) was also supported by National Research Foundation (NRF) [Grant Number 019R1A2C1009231] and by a grant from the MEST of Korea for Tumor Microenvironment Global Core Research Center (GCRC) [Grant Number 2011-0030001]. Support from Brain Korea (BK21) PLUS program and Creative-Pioneering Researchers Program at Seoul National University [Funding number: 370C-20160062] are acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Hoffmann, V.S.; Baccarani, M.; Hasford, J.; Castagnetti, F.; Di Raimondo, F.; Casado, L.F.; Turkina, A.; Zackova, D.; Ossenkoppele, G.; Zaritskey, A.; et al. Treatment and outcome of 2904 CML patients from the EUTOS population-based registry. Leukemia 2017, 31, 593–601. [Google Scholar] [CrossRef] [PubMed]
  2. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30. [Google Scholar] [CrossRef] [PubMed]
  3. Hoffmann, V.S.; Baccarani, M.; Hasford, J.; Lindoerfer, D.; Burgstaller, S.; Sertic, D.; Costeas, P.; Mayer, J.; Indrak, K.; Everaus, H.; et al. The EUTOS population-based registry: Incidence and clinical characteristics of 2904 CML patients in 20 European Countries. Leukemia 2015, 29, 1336–1343. [Google Scholar] [CrossRef] [PubMed]
  4. Apperley, J.F. Part I: Mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007, 8, 1018–1029. [Google Scholar] [CrossRef]
  5. Apperley, J.F. Chronic myeloid leukaemia. Lancet 2015, 385, 1447–1459. [Google Scholar] [CrossRef]
  6. Nowell, P.C. Discovery of the Philadelphia chromosome: A personal perspective. J. Clin. Investig. 2007, 117, 2033–2035. [Google Scholar] [CrossRef] [Green Version]
  7. Kang, Z.J.; Liu, Y.F.; Xu, L.Z.; Long, Z.J.; Huang, D.; Yang, Y.; Liu, B.; Feng, J.X.; Pan, Y.J.; Yan, J.S.; et al. The Philadelphia chromosome in leukemogenesis. Chin. J. Cancer 2016, 35, 48. [Google Scholar] [CrossRef] [Green Version]
  8. Colicelli, J. ABL tyrosine kinases: Evolution of function, regulation, and specificity. Sci. Signal. 2010, 3, re6. [Google Scholar] [CrossRef] [Green Version]
  9. Khatri, A.; Wang, J.; Pendergast, A.M. Multifunctional Abl kinases in health and disease. J. Cell Sci. 2016, 129, 9–16. [Google Scholar] [CrossRef] [Green Version]
  10. Wang, J.Y. The capable ABL: What is its biological function? Mol. Cell. Biol. 2014, 34, 1188–1197. [Google Scholar] [CrossRef] [Green Version]
  11. Laurent, E.; Talpaz, M.; Kantarjian, H.; Kurzrock, R. The BCR gene and philadelphia chromosome-positive leukemogenesis. Cancer Res. 2001, 61, 2343–2355. [Google Scholar] [PubMed]
  12. Drummond, M.W.; Lush, C.J.; Vickers, M.A.; Reid, F.M.; Kaeda, J.; Holyoake, T.L. Imatinib mesylate-induced molecular remission of Philadelphia chromosome-positive myelodysplastic syndrome. Leukemia 2003, 17, 463–465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Schultheis, B.; Wang, L.; Clark, R.E.; Melo, J.V. BCR-ABL with an e6a2 fusion in a CML patient diagnosed in blast crisis. Leukemia 2003, 17, 2054–2055. [Google Scholar] [CrossRef] [PubMed]
  14. Vergilio, J.; Bagg, A. Myeloproliferative disorders and myelodysplastic syndromes. In Molecular Pathology in Clinical Practice; Leonard, D.G.B., Ed.; Springer: New York, NY, USA, 2007; pp. 383–396. [Google Scholar]
  15. Withey, J.M.; Marley, S.B.; Kaeda, J.; Harvey, A.J.; Crompton, M.R.; Gordon, M.Y. Targeting primary human leukaemia cells with RNA interference: Bcr-Abl targeting inhibits myeloid progenitor self-renewal in chronic myeloid leukaemia cells. Br. J. Haematol. 2005, 129, 377–380. [Google Scholar] [CrossRef]
  16. Beran, M.; Pisa, P.; O’Brien, S.; Kurzrock, R.; Siciliano, M.; Cork, A.; Andersson, B.S.; Kohli, V.; Kantarjian, H. Biological properties and growth in SCID mice of a new myelogenous leukemia cell line (KBM-5) derived from chronic myelogenous leukemia cells in the blastic phase. Cancer Res. 1993, 53, 3603–3610. [Google Scholar]
  17. Yaghmaie, M.; Ghaffari, S.H.; Ghavamzadeh, A.; Alimoghaddam, K.; Jahani, M.; Mousavi, S.A.; Irvani, M.; Bahar, B.; Bibordi, I. Frequency of BCR-ABL fusion transcripts in Iranian patients with chronic myeloid leukemia. Arch. Iranian Med. 2008, 11, 247–251. [Google Scholar]
  18. Van der Velden, V.H.; Beverloo, H.B.; Hoogeveen, P.G.; Zwaan Ch, M. A novel BCR-ABL fusion transcript (e18a2) in a child with chronic myeloid leukemia. Leukemia 2007, 21, 833–835. [Google Scholar] [CrossRef] [Green Version]
  19. Hochhaus, A.; Reiter, A.; Skladny, H.; Melo, J.V.; Sick, C.; Berger, U.; Guo, J.Q.; Arlinghaus, R.B.; Hehlmann, R.; Goldman, J.M.; et al. A novel BCR-ABL fusion gene (e6a2) in a patient with Philadelphia chromosome-negative chronic myelogenous leukemia. Blood 1996, 88, 2236–2240. [Google Scholar] [CrossRef] [Green Version]
  20. O’Hare, T.; Deininger, M.W.; Eide, C.A.; Clackson, T.; Druker, B.J. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin. Cancer Res. 2011, 17, 212–221. [Google Scholar] [CrossRef] [Green Version]
  21. Dai, Z.; Quackenbush, R.C.; Courtney, K.D.; Grove, M.; Cortez, D.; Reuther, G.W.; Pendergast, A.M. Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway. Genes Dev. 1998, 12, 1415–1424. [Google Scholar] [CrossRef] [Green Version]
  22. Los, M. Tumor Growth and Cell Proliferation. In The Impact of Tumor Biology on Cancer Treatment and Multidisciplinary Strategies; Molls, M., Vaupel, P., Nieder, C., Anscher, M.S., Eds.; Springer: Berlin/Heidelberg, Germany, 2009. [Google Scholar]
  23. Reuther, G.W.; Fu, H.; Cripe, L.D.; Collier, R.J.; Pendergast, A.M. Association of the protein kinases c-Bcr and Bcr-Abl with proteins of the 14-3-3 family. Science 1994, 266, 129–133. [Google Scholar] [CrossRef] [PubMed]
  24. Goldman, J.M.; Melo, J.V. Chronic myeloid leukemia--advances in biology and new approaches to treatment. N. Engl. J. Med. 2003, 349, 1451–1464. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Goss, V.L.; Lee, K.A.; Moritz, A.; Nardone, J.; Spek, E.J.; MacNeill, J.; Rush, J.; Comb, M.J.; Polakiewicz, R.D. A common phosphotyrosine signature for the Bcr-Abl kinase. Blood 2006, 107, 4888–4897. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Morotti, A.; Carra, G.; Panuzzo, C.; Crivellaro, S.; Taulli, R.; Guerrasio, A.; Saglio, G. Protein Kinase CK2: A Targetable BCR-ABL Partner in Philadelphia Positive Leukemias. Adv. Hematol. 2015, 2015, 612567. [Google Scholar] [CrossRef] [Green Version]
  27. Shin, S.; Lee, Y.; Kim, W.; Ko, H.; Choi, H.; Kim, K. Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8. EMBO J. 2005, 24, 3532–3542. [Google Scholar] [CrossRef] [Green Version]
  28. St-Denis, N.A.; Derksen, D.R.; Litchfield, D.W. Evidence for regulation of mitotic progression through temporal phosphorylation and dephosphorylation of CK2alpha. Mol. Cell. Biol. 2009, 29, 2068–2081. [Google Scholar] [CrossRef] [Green Version]
  29. Feller, S.M. Crk family adaptors-signalling complex formation and biological roles. Oncogene 2001, 20, 6348–6371. [Google Scholar] [CrossRef] [Green Version]
  30. Mashima, R.; Hishida, Y.; Tezuka, T.; Yamanashi, Y. The roles of Dok family adapters in immunoreceptor signaling. Immunol. Rev. 2009, 232, 273–285. [Google Scholar] [CrossRef]
  31. Lionberger, J.M.; Smithgall, T.E. The c-Fes protein-tyrosine kinase suppresses cytokine-independent outgrowth of myeloid leukemia cells induced by Bcr-Abl. Cancer Res. 2000, 60, 1097–1103. [Google Scholar]
  32. Shi, C.S.; Tuscano, J.; Kehrl, J.H. Adaptor proteins CRK and CRKL associate with the serine/threonine protein kinase GCKR promoting GCKR and SAPK activation. Blood 2000, 95, 776–782. [Google Scholar] [CrossRef]
  33. Puil, L.; Liu, J.; Gish, G.; Mbamalu, G.; Bowtell, D.; Pelicci, P.G.; Arlinghaus, R.; Pawson, T. Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J. 1994, 13, 764–773. [Google Scholar] [CrossRef] [PubMed]
  34. Li, S.; Couvillon, A.D.; Brasher, B.B.; Van Etten, R.A. Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: A novel regulatory mechanism for tyrosine kinase signaling. EMBO J. 2001, 20, 6793–6804. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Frietsch, J.J.; Kastner, C.; Grunewald, T.G.; Schweigel, H.; Nollau, P.; Ziermann, J.; Clement, J.H.; La Rosee, P.; Hochhaus, A.; Butt, E. LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia. Oncotarget 2014, 5, 5257–5271. [Google Scholar] [CrossRef] [PubMed]
  36. Orth, M.F.; Cazes, A.; Butt, E.; Grunewald, T.G. An update on the LIM and SH3 domain protein 1 (LASP1): A versatile structural, signaling, and biomarker protein. Oncotarget 2015, 6, 26–42. [Google Scholar] [CrossRef] [PubMed]
  37. Liang, X.; Hajivandi, M.; Veach, D.; Wisniewski, D.; Clarkson, B.; Resh, M.D.; Pope, R.M. Quantification of change in phosphorylation of BCR-ABL kinase and its substrates in response to Imatinib treatment in human chronic myelogenous leukemia cells. Proteomics 2006, 6, 4554–4564. [Google Scholar] [CrossRef] [PubMed]
  38. Lopez-Colome, A.M.; Lee-Rivera, I.; Benavides-Hidalgo, R.; Lopez, E. Paxillin: A crossroad in pathological cell migration. J. Hematol. Oncol 2017, 10, 50. [Google Scholar] [CrossRef] [Green Version]
  39. Wang, Y.; Tomar, A.; George, S.P.; Khurana, S. Obligatory role for phospholipase C-gamma(1) in villin-induced epithelial cell migration. Am. J. Physiol. Cell Physiol. 2007, 292, C1775–C1786. [Google Scholar] [CrossRef] [Green Version]
  40. Kuchay, S.; Duan, S.; Schenkein, E.; Peschiaroli, A.; Saraf, A.; Florens, L.; Washburn, M.P.; Pagano, M. FBXL2- and PTPL1-mediated degradation of p110-free p85beta regulatory subunit controls the PI(3)K signalling cascade. Nat. Cell Biol. 2013, 15, 472–480. [Google Scholar] [CrossRef] [Green Version]
  41. Roy, A.; Ye, J.; Deng, F.; Wang, Q.J. Protein kinase D signaling in cancer: A friend or foe? Biochim. Biophys. Acta Rev. Cancer 2017, 1868, 283–294. [Google Scholar] [CrossRef]
  42. Grimmler, M.; Wang, Y.; Mund, T.; Cilensek, Z.; Keidel, E.M.; Waddell, M.B.; Jakel, H.; Kullmann, M.; Kriwacki, R.W.; Hengst, L. Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell 2007, 128, 269–280. [Google Scholar] [CrossRef] [Green Version]
  43. Pamonsinlapatham, P.; Hadj-Slimane, R.; Lepelletier, Y.; Allain, B.; Toccafondi, M.; Garbay, C.; Raynaud, F. p120-Ras GTPase activating protein (RasGAP): A multi-interacting protein in downstream signaling. Biochimie 2009, 91, 320–328. [Google Scholar] [CrossRef] [PubMed]
  44. Kim, D.H.; Sarbassov, D.D.; Ali, S.M.; King, J.E.; Latek, R.R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002, 110, 163–175. [Google Scholar] [CrossRef] [Green Version]
  45. Audero, E.; Cascone, I.; Maniero, F.; Napione, L.; Arese, M.; Lanfrancone, L.; Bussolino, F. Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells. J. Biol. Chem. 2004, 279, 13224–13233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Freeburn, R.W.; Wright, K.L.; Burgess, S.J.; Astoul, E.; Cantrell, D.A.; Ward, S.G. Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-trisphosphate metabolism in T lymphocytes and can regulate novel phosphoinositide 3-kinase effectors. J. Immunol. 2002, 169, 5441–5450. [Google Scholar] [CrossRef] [Green Version]
  47. Berger, A.; Hoelbl-Kovacic, A.; Bourgeais, J.; Hoefling, L.; Warsch, W.; Grundschober, E.; Uras, I.Z.; Menzl, I.; Putz, E.M.; Hoermann, G.; et al. PAK-dependent STAT5 serine phosphorylation is required for BCR-ABL-induced leukemogenesis. Leukemia 2014, 28, 629–641. [Google Scholar] [CrossRef]
  48. Rahikainen, R.; von Essen, M.; Schaefer, M.; Qi, L.; Azizi, L.; Kelly, C.; Ihalainen, T.O.; Wehrle-Haller, B.; Bastmeyer, M.; Huang, C.; et al. Mechanical stability of talin rod controls cell migration and substrate sensing. Sci. Rep. 2017, 7, 3571. [Google Scholar] [CrossRef]
  49. La, S.H.; Kim, S.J.; Kang, H.G.; Lee, H.W.; Chun, K.H. Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism. Oncotarget 2016, 7, 57117–57130. [Google Scholar] [CrossRef] [Green Version]
  50. Zitvogel, L.; Rusakiewicz, S.; Routy, B.; Ayyoub, M.; Kroemer, G. Immunological off-target effects of imatinib. Nat. Rev. Clin. Oncol. 2016, 13, 431–446. [Google Scholar] [CrossRef]
  51. Sorel, N.; Cayssials, E.; Brizard, F.; Chomel, J.C. Treatment and molecular monitoring update in chronic myeloid leukemia management. Annales de biologie clinique 2017, 75, 129–145. [Google Scholar] [CrossRef]
  52. Hantschel, O. Structure, regulation, signaling, and targeting of abl kinases in cancer. Genes Cancer 2012, 3, 436–446. [Google Scholar] [CrossRef] [Green Version]
  53. Modugno, M. New resistance mechanisms for small molecule kinase inhibitors of Abl kinase. Drug Discov. Today Technol. 2014, 11, 5–10. [Google Scholar] [CrossRef] [PubMed]
  54. An, X.; Tiwari, A.K.; Sun, Y.; Ding, P.R.; Ashby, C.R., Jr.; Chen, Z.S. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review. Leukemia Res. 2010, 34, 1255–1268. [Google Scholar] [CrossRef]
  55. Ankathil, R.; Azlan, H.; Dzarr, A.A.; Baba, A.A. Pharmacogenetics and the treatment of chronic myeloid leukemia: How relevant clinically? An update. Pharmacogenomics 2018, 19, 393–475. [Google Scholar] [CrossRef] [PubMed]
  56. Danisz, K.; Blasiak, J. Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors. Acta Biochim. Polonica 2013, 60, 503–514. [Google Scholar] [CrossRef]
  57. Alikian, M.; Gale, R.P.; Apperley, J.F.; Foroni, L. Molecular techniques for the personalised management of patients with chronic myeloid leukaemia. Biomol. Detect. Quantif. 2017, 11, 4–20. [Google Scholar] [CrossRef] [PubMed]
  58. Yang, K.; Fu, L.W. Mechanisms of resistance to BCR-ABL TKIs and the therapeutic strategies: A review. Crit. Rev. Oncol. Hematol. 2015, 93, 277–292. [Google Scholar] [CrossRef] [PubMed]
  59. Soverini, S.; Mancini, M.; Bavaro, L.; Cavo, M.; Martinelli, G. Chronic myeloid leukemia: The paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy. Mol. Cancer 2018, 17, 49. [Google Scholar] [CrossRef]
  60. Keskin, D.; Sadri, S.; Eskazan, A.E. Dasatinib for the treatment of chronic myeloid leukemia: Patient selection and special considerations. Drug Des. Dev. Ther. 2016, 10, 3355–3361. [Google Scholar] [CrossRef] [Green Version]
  61. Emole, J.; Talabi, T.; Pinilla-Ibarz, J. Update on the management of Philadelphia chromosome positive chronic myelogenous leukemia: Role of nilotinib. Biol. Targets Ther. 2016, 10, 23–31. [Google Scholar] [CrossRef] [Green Version]
  62. Ault, P.S.; Rose Pharm, D.J.; Nodzon Ph, D.L.; Kaled, E.S. Bosutinib Therapy in Patients With Chronic Myeloid Leukemia: Practical Considerations for Management of Side Effects. J. Adv. Pract. Oncol. 2016, 7, 160–175. [Google Scholar] [CrossRef]
  63. Bu, Q.; Cui, L.; Li, J.; Du, X.; Zou, W.; Ding, K.; Pan, J. SAHA and S116836, a novel tyrosine kinase inhibitor, synergistically induce apoptosis in imatinib-resistant chronic myelogenous leukemia cells. Cancer Biol. Ther. 2014, 15, 951–962. [Google Scholar] [CrossRef] [PubMed]
  64. Jabbour, E.J.; Cortes, J.E.; Kantarjian, H.M. Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: A clinical perspective and emerging treatment options. Clin. Lymphoma Myeloma Leuk. 2013, 13, 515–529. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Balabanov, S.; Braig, M.; Brummendorf, T.H. Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia. Drug Discov. Today Technol. 2014, 11, 89–99. [Google Scholar] [CrossRef] [PubMed]
  66. Etienne, G.; Dulucq, S.; Huguet, F.; Schmitt, A.; Lascaux, A.; Hayette, S.; Fort, M.P.; Sujobert, P.; Bijou, F.; Morisset, S.; et al. Incidence and outcome of BCR-ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors. Cancer Med. 2019, 8, 5173–5182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Bixby, D.; Talpaz, M. Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance. Hematol. Am. Soc. Hematol. Educ. Program. 2009. [Google Scholar] [CrossRef] [Green Version]
  68. Seidel, C.; Schnekenburger, M.; Dicato, M.; Diederich, M. Histone deacetylase 6 in health and disease. Epigenomics 2015, 7, 103–118. [Google Scholar] [CrossRef] [Green Version]
  69. Linev, A.J.; Ivanov, H.J.; Zhelyazkov, I.G.; Ivanova, H.; Goranova-Marinova, V.S.; Stoyanova, V.K. Mutations Associated with Imatinib Mesylate Resistance—Review. Folia Med. (Plovdiv.) 2018, 60, 617–623. [Google Scholar] [CrossRef]
  70. Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer 2013, 13, 714–726. [Google Scholar] [CrossRef]
  71. Loscocco, F.; Visani, G.; Galimberti, S.; Curti, A.; Isidori, A. BCR-ABL Independent Mechanisms of Resistance in Chronic Myeloid Leukemia. Front. Oncol. 2019, 9, 939. [Google Scholar] [CrossRef] [Green Version]
  72. Fachi, M.M.; Tonin, F.S.; Leonart, L.P.; Aguiar, K.S.; Lenzi, L.; Figueiredo, B.C.; Fernandez-Llimos, F.; Pontarolo, R. Comparative efficacy and safety of tyrosine kinase inhibitors for chronic myeloid leukaemia: A systematic review and network meta-analysis. Eur. J. Cancer 2018, 104, 9–20. [Google Scholar] [CrossRef]
  73. Zabriskie, M.S.; Vellore, N.A.; Gantz, K.C.; Deininger, M.W.; O’Hare, T. Radotinib is an effective inhibitor of native and kinase domain-mutant BCR-ABL1. Leukemia 2015, 29, 1939–1942. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Tang, L.; Zhang, H.; Peng, Y.Z.; Li, C.G.; Jiang, H.W.; Xu, M.; Mei, H.; Hu, Y. Comparative efficacy and tolerability of front-line treatments for newly diagnosed chronic-phase chronic myeloid leukemia: An update network meta-analysis. BMC Cancer 2019, 19, 849. [Google Scholar] [CrossRef] [Green Version]
  75. Park, E.; Jue, M.S. Radotinib-induced eruptive melanocytic nevi in patient with chronic myeloid leukemia: A case report and literature review. Ann. Hematol. 2019, 98, 533–535. [Google Scholar] [CrossRef]
  76. Losson, H.; Schnekenburger, M.; Dicato, M.; Diederich, M. Natural Compound Histone Deacetylase Inhibitors (HDACi): Synergy with Inflammatory Signaling Pathway Modulators and Clinical Applications in Cancer. Molecules 2016, 21, 1608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Finnin, M.S.; Donigian, J.R.; Cohen, A.; Richon, V.M.; Rifkind, R.A.; Marks, P.A.; Breslow, R.; Pavletich, N.P. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 1999, 401, 188–193. [Google Scholar] [CrossRef] [PubMed]
  78. Carafa, V.; Rotili, D.; Forgione, M.; Cuomo, F.; Serretiello, E.; Hailu, G.S.; Jarho, E.; Lahtela-Kakkonen, M.; Mai, A.; Altucci, L. Sirtuin functions and modulation: From chemistry to the clinic. Clin. Epigenetics 2016, 8, 61. [Google Scholar] [CrossRef] [PubMed]
  79. Mei, Z.; Zhang, X.; Yi, J.; Huang, J.; He, J.; Tao, Y. Sirtuins in metabolism, DNA repair and cancer. J. Exp. Clin. Cancer Res. 2016, 35, 182. [Google Scholar] [CrossRef] [Green Version]
  80. Thiagalingam, S.; Cheng, K.H.; Lee, H.J.; Mineva, N.; Thiagalingam, A.; Ponte, J.F. Histone deacetylases: Unique players in shaping the epigenetic histone code. Ann. N. Y. Acad. Sci. 2003, 983, 84–100. [Google Scholar] [CrossRef]
  81. De Ruijter, A.J.; van Gennip, A.H.; Caron, H.N.; Kemp, S.; van Kuilenburg, A.B. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem. J. 2003, 370, 737–749. [Google Scholar] [CrossRef]
  82. Bertos, N.R.; Gilquin, B.; Chan, G.K.; Yen, T.J.; Khochbin, S.; Yang, X.J. Role of the tetradecapeptide repeat domain of human histone deacetylase 6 in cytoplasmic retention. J. Biol. Chem. 2004, 279, 48246–48254. [Google Scholar] [CrossRef] [Green Version]
  83. Li, Y.; Shin, D.; Kwon, S.H. Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes. FEBS J. 2013, 280, 775–793. [Google Scholar] [CrossRef]
  84. Zheng, K.; Jiang, Y.; He, Z.; Kitazato, K.; Wang, Y. Cellular defence or viral assist: The dilemma of HDAC6. J. Gen. Virol. 2017, 98, 322–337. [Google Scholar] [CrossRef] [PubMed]
  85. Mortenson, J.B.; Heppler, L.N.; Banks, C.J.; Weerasekara, V.K.; Whited, M.D.; Piccolo, S.R.; Johnson, W.E.; Thompson, J.W.; Andersen, J.L. Histone deacetylase 6 (HDAC6) promotes the pro-survival activity of 14-3-3zeta via deacetylation of lysines within the 14-3-3zeta binding pocket. J. Biol. Chem. 2015, 290, 12487–12496. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Zhang, L.; Liu, S.; Liu, N.; Zhang, Y.; Liu, M.; Li, D.; Seto, E.; Yao, T.P.; Shui, W.; Zhou, J. Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity. Protein Cell 2015, 6, 42–54. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Wu, J.Y.; Xiang, S.; Zhang, M.; Fang, B.; Huang, H.; Kwon, O.K.; Zhao, Y.; Yang, Z.; Bai, W.; Bepler, G.; et al. Histone deacetylase 6 (HDAC6) deacetylates extracellular signal-regulated kinase 1 (ERK1) and thereby stimulates ERK1 activity. J. Biol. Chem. 2018, 293, 1976–1993. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Beier, U.H.; Wang, L.; Han, R.; Akimova, T.; Liu, Y.; Hancock, W.W. Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Sci. Signal. 2012, 5, ra45. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Salian-Mehta, S.; Xu, M.; McKinsey, T.A.; Tobet, S.; Wierman, M.E. Novel Interaction of Class IIb Histone Deacetylase 6 (HDAC6) with Class IIa HDAC9 Controls Gonadotropin Releasing Hormone (GnRH) Neuronal Cell Survival and Movement. J. Biol. Chem. 2015, 290, 14045–14056. [Google Scholar] [CrossRef] [Green Version]
  90. Gao, L.; Cueto, M.A.; Asselbergs, F.; Atadja, P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 2002, 277, 25748–25755. [Google Scholar] [CrossRef] [Green Version]
  91. Medler, T.R.; Craig, J.M.; Fiorillo, A.A.; Feeney, Y.B.; Harrell, J.C.; Clevenger, C.V. HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth. Mol. Cancer Res. 2016, 14, 994–1008. [Google Scholar] [CrossRef] [Green Version]
  92. Chang, Y.W.; Tseng, C.F.; Wang, M.Y.; Chang, W.C.; Lee, C.C.; Chen, L.T.; Hung, M.C.; Su, J.L. Deacetylation of HSPA5 by HDAC6 leads to GP78-mediated HSPA5 ubiquitination at K447 and suppresses metastasis of breast cancer. Oncogene 2016, 35, 1517–1528. [Google Scholar] [CrossRef]
  93. Yang, M.H.; Laurent, G.; Bause, A.S.; Spang, R.; German, N.; Haigis, M.C.; Haigis, K.M. HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS. Mol. Cancer Res. 2013, 11, 1072–1077. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Liu, K.P.; Zhou, D.; Ouyang, D.Y.; Xu, L.H.; Wang, Y.; Wang, L.X.; Pan, H.; He, X.H. LC3B-II deacetylation by histone deacetylase 6 is involved in serum-starvation-induced autophagic degradation. Biochem. Biophys. Res. Commun. 2013, 441, 970–975. [Google Scholar] [CrossRef] [PubMed]
  95. Zhang, M.; Xiang, S.; Joo, H.Y.; Wang, L.; Williams, K.A.; Liu, W.; Hu, C.; Tong, D.; Haakenson, J.; Wang, C.; et al. HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSalpha. Mol. Cell 2014, 55, 31–46. [Google Scholar] [CrossRef] [Green Version]
  96. Perkins, A.; Nelson, K.J.; Parsonage, D.; Poole, L.B.; Karplus, P.A. Peroxiredoxins: Guardians against oxidative stress and modulators of peroxide signaling. Trends Biochem. Sci. 2015, 40, 435–445. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Parmigiani, R.B.; Xu, W.S.; Venta-Perez, G.; Erdjument-Bromage, H.; Yaneva, M.; Tempst, P.; Marks, P.A. HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. Proc. Natl. Acad. Sci. USA 2008, 105, 9633–9638. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Moreno-Gonzalo, O.; Mayor, F., Jr.; Sanchez-Madrid, F. HDAC6 at Crossroads of Infection and Innate Immunity. Trends Immunol. 2018, 39, 591–595. [Google Scholar] [CrossRef]
  99. Nakka, K.K.; Chaudhary, N.; Joshi, S.; Bhat, J.; Singh, K.; Chatterjee, S.; Malhotra, R.; De, A.; Santra, M.K.; Dilworth, F.J.; et al. Nuclear matrix-associated protein SMAR1 regulates alternative splicing via HDAC6-mediated deacetylation of Sam68. Proc. Natl. Acad. Sci. USA 2015, 112, E3374–E3383. [Google Scholar] [CrossRef] [Green Version]
  100. Huo, L.; Li, D.; Sun, X.; Shi, X.; Karna, P.; Yang, W.; Liu, M.; Qiao, W.; Aneja, R.; Zhou, J. Regulation of Tat acetylation and transactivation activity by the microtubule-associated deacetylase HDAC6. J. Biol. Chem. 2011, 286, 9280–9286. [Google Scholar] [CrossRef] [Green Version]
  101. Matsuyama, A.; Shimazu, T.; Sumida, Y.; Saito, A.; Yoshimatsu, Y.; Seigneurin-Berny, D.; Osada, H.; Komatsu, Y.; Nishino, N.; Khochbin, S.; et al. In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J. 2002, 21, 6820–6831. [Google Scholar] [CrossRef] [Green Version]
  102. Haakenson, J.; Zhang, X. HDAC6 and ovarian cancer. Int. J. Mol. Sci. 2013, 14, 9514–9535. [Google Scholar] [CrossRef] [Green Version]
  103. Fan, S.J.; Huang, F.I.; Liou, J.P.; Yang, C.R. The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer’s disease model. Cell Death Dis. 2018, 9, 655. [Google Scholar] [CrossRef] [PubMed]
  104. Lee, S.W.; Yang, J.; Kim, S.Y.; Jeong, H.K.; Lee, J.; Kim, W.J.; Lee, E.J.; Kim, H.S. MicroRNA-26a induced by hypoxia targets HDAC6 in myogenic differentiation of embryonic stem cells. Nucleic Acids Res. 2015, 43, 2057–2073. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Lafarga, V.; Aymerich, I.; Tapia, O.; Mayor, F., Jr.; Penela, P. A novel GRK2/HDAC6 interaction modulates cell spreading and motility. EMBO J. 2012, 31, 856–869. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Williams, K.A.; Zhang, M.; Xiang, S.; Hu, C.; Wu, J.Y.; Zhang, S.; Ryan, M.; Cox, A.D.; Der, C.J.; Fang, B.; et al. Extracellular signal-regulated kinase (ERK) phosphorylates histone deacetylase 6 (HDAC6) at serine 1035 to stimulate cell migration. J. Biol. Chem. 2013, 288, 33156–33170. [Google Scholar] [CrossRef] [Green Version]
  107. Di Fulvio, S.; Azakir, B.A.; Therrien, C.; Sinnreich, M. Dysferlin interacts with histone deacetylase 6 and increases alpha-tubulin acetylation. PLoS ONE 2011, 6, e28563. [Google Scholar] [CrossRef] [Green Version]
  108. Tala, S.X.; Chen, J.; Zhang, L.; Liu, N.; Zhou, J.; Li, D.; Liu, M. Microtubule stabilization by Mdp3 is partially attributed to its modulation of HDAC6 in addition to its association with tubulin and microtubules. PLoS ONE 2014, 9, e90932. [Google Scholar] [CrossRef]
  109. Yan, J.; Seibenhener, M.L.; Calderilla-Barbosa, L.; Diaz-Meco, M.T.; Moscat, J.; Jiang, J.; Wooten, M.W.; Wooten, M.C. SQSTM1/p62 interacts with HDAC6 and regulates deacetylase activity. PLoS ONE 2013, 8, e76016. [Google Scholar] [CrossRef] [Green Version]
  110. Salemi, L.M.; Almawi, A.W.; Lefebvre, K.J.; Schild-Poulter, C. Aggresome formation is regulated by RanBPM through an interaction with HDAC6. Biol. Open 2014, 3, 418–430. [Google Scholar] [CrossRef] [Green Version]
  111. Perez, M.; Santa-Maria, I.; Gomez de Barreda, E.; Zhu, X.; Cuadros, R.; Cabrero, J.R.; Sanchez-Madrid, F.; Dawson, H.N.; Vitek, M.P.; Perry, G.; et al. Tau--an inhibitor of deacetylase HDAC6 function. J. Neurochem. 2009, 109, 1756–1766. [Google Scholar] [CrossRef]
  112. Schofield, A.V.; Gamell, C.; Bernard, O. Tubulin polymerization promoting protein 1 (TPPP1) increases beta-catenin expression through inhibition of HDAC6 activity in U2OS osteosarcoma cells. Biochem. Biophys. Res. Commun. 2013, 436, 571–577. [Google Scholar] [CrossRef]
  113. Li, T.; Zhang, C.; Hassan, S.; Liu, X.; Song, F.; Chen, K.; Zhang, W.; Yang, J. Histone deacetylase 6 in cancer. J. Hematol. Oncol. 2018, 11, 111. [Google Scholar] [CrossRef] [PubMed]
  114. Maharaj, K.; Powers, J.J.; Achille, A.; Deng, S.; Fonseca, R.; Pabon-Saldana, M.; Quayle, S.N.; Jones, S.S.; Villagra, A.; Sotomayor, E.M.; et al. Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia. Blood Adv. 2018, 2, 3012–3024. [Google Scholar] [CrossRef] [PubMed]
  115. Li, A.; Chen, P.; Leng, Y.; Kang, J. Histone deacetylase 6 regulates the immunosuppressive properties of cancer-associated fibroblasts in breast cancer through the STAT3-COX2-dependent pathway. Oncogene 2018, 37, 5952–5966. [Google Scholar] [CrossRef] [PubMed]
  116. Qian, H.; Chen, Y.; Nian, Z.; Su, L.; Yu, H.; Chen, F.J.; Zhang, X.; Xu, W.; Zhou, L.; Liu, J.; et al. HDAC6-mediated acetylation of lipid droplet-binding protein CIDEC regulates fat-induced lipid storage. J. Clin. Invest. 2017, 127, 1353–1369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Bamodu, O.A.; Kuo, K.T.; Yuan, L.P.; Cheng, W.H.; Lee, W.H.; Ho, Y.S.; Chao, T.Y.; Yeh, C.T. HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1. Exp. Cell Res. 2018, 370, 519–530. [Google Scholar] [CrossRef]
  118. Cosenza, M.; Pozzi, S. The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease. Int. J. Mol. Sci. 2018, 19, 2337. [Google Scholar] [CrossRef] [Green Version]
  119. Dehmel, F.; Weinbrenner, S.; Julius, H.; Ciossek, T.; Maier, T.; Stengel, T.; Fettis, K.; Burkhardt, C.; Wieland, H.; Beckers, T. Trithiocarbonates as a novel class of HDAC inhibitors: SAR studies, isoenzyme selectivity, and pharmacological profiles. J. Med. Chem. 2008, 51, 3985–4001. [Google Scholar] [CrossRef]
  120. Inks, E.S.; Josey, B.J.; Jesinkey, S.R.; Chou, C.J. A novel class of small molecule inhibitors of HDAC6. ACS Chem. Biol. 2012, 7, 331–339. [Google Scholar] [CrossRef] [Green Version]
  121. Schafer, S.; Saunders, L.; Eliseeva, E.; Velena, A.; Jung, M.; Schwienhorst, A.; Strasser, A.; Dickmanns, A.; Ficner, R.; Schlimme, S.; et al. Phenylalanine-containing hydroxamic acids as selective inhibitors of class IIb histone deacetylases (HDACs). Bioorg. Med. Chem. 2008, 16, 2011–2033. [Google Scholar] [CrossRef]
  122. Schafer, S.; Saunders, L.; Schlimme, S.; Valkov, V.; Wagner, J.M.; Kratz, F.; Sippl, W.; Verdin, E.; Jung, M. Pyridylalanine-containing hydroxamic acids as selective HDAC6 inhibitors. ChemMedChem 2009, 4, 283–290. [Google Scholar] [CrossRef]
  123. Jochems, J.; Boulden, J.; Lee, B.G.; Blendy, J.A.; Jarpe, M.; Mazitschek, R.; Van Duzer, J.H.; Jones, S.; Berton, O. Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability. Neuropsychopharmacology 2014, 39, 389–400. [Google Scholar] [CrossRef] [PubMed]
  124. Porter, N.J.; Mahendran, A.; Breslow, R.; Christianson, D.W. Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors. Proc. Natl. Acad. Sci. USA 2017, 114, 13459–13464. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Krukowski, K.; Ma, J.; Golonzhka, O.; Laumet, G.O.; Gutti, T.; van Duzer, J.H.; Mazitschek, R.; Jarpe, M.B.; Heijnen, C.J.; Kavelaars, A. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy. Pain 2017, 158, 1126–1137. [Google Scholar] [CrossRef] [PubMed]
  126. Strebl, M.G.; Campbell, A.J.; Zhao, W.N.; Schroeder, F.A.; Riley, M.M.; Chindavong, P.S.; Morin, T.M.; Haggarty, S.J.; Wagner, F.F.; Ritter, T.; et al. HDAC6 Brain Mapping with [(18)F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination. ACS Cent. Sci. 2017, 3, 1006–1014. [Google Scholar] [CrossRef] [Green Version]
  127. Wagner, F.F.; Olson, D.E.; Gale, J.P.; Kaya, T.; Weiwer, M.; Aidoud, N.; Thomas, M.; Davoine, E.L.; Lemercier, B.C.; Zhang, Y.L.; et al. Potent and selective inhibition of histone deacetylase 6 (HDAC6) does not require a surface-binding motif. J. Med. Chem. 2013, 56, 1772–1776. [Google Scholar] [CrossRef]
  128. Kozikowski, A.P.; Tapadar, S.; Luchini, D.N.; Kim, K.H.; Billadeau, D.D. Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: A new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6. J. Med. Chem. 2008, 51, 4370–4373. [Google Scholar] [CrossRef] [Green Version]
  129. Sixto-Lopez, Y.; Bello, M.; Rodriguez-Fonseca, R.A.; Rosales-Hernandez, M.C.; Martinez-Archundia, M.; Gomez-Vidal, J.A.; Correa-Basurto, J. Searching the conformational complexity and binding properties of HDAC6 through docking and molecular dynamic simulations. J. Biomol. Struct. Dyn. 2017, 35, 2794–2814. [Google Scholar] [CrossRef]
  130. Huang, P.; Almeciga-Pinto, I.; Jarpe, M.; van Duzer, J.H.; Mazitschek, R.; Yang, M.; Jones, S.S.; Quayle, S.N. Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models. Oncotarget 2017, 8, 2694–2707. [Google Scholar] [CrossRef] [Green Version]
  131. Olsen, C.A.; Ghadiri, M.R. Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic alpha3beta-tetrapeptides. J. Med. Chem. 2009, 52, 7836–7846. [Google Scholar] [CrossRef] [Green Version]
  132. Chen, Y.; Lopez-Sanchez, M.; Savoy, D.N.; Billadeau, D.D.; Dow, G.S.; Kozikowski, A.P. A series of potent and selective, triazolylphenyl-based histone deacetylases inhibitors with activity against pancreatic cancer cells and Plasmodium falciparum. J. Med. Chem. 2008, 51, 3437–3448. [Google Scholar] [CrossRef]
  133. Diedrich, D.; Hamacher, A.; Gertzen, C.G.; Alves Avelar, L.A.; Reiss, G.J.; Kurz, T.; Gohlke, H.; Kassack, M.U.; Hansen, F.K. Rational design and diversity-oriented synthesis of peptoid-based selective HDAC6 inhibitors. Chem. Commun. (Camb.) 2016, 52, 3219–3222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Lin, X.; Chen, W.; Qiu, Z.; Guo, L.; Zhu, W.; Li, W.; Wang, Z.; Zhang, W.; Zhang, Z.; Rong, Y.; et al. Design and synthesis of orally bioavailable aminopyrrolidinone histone deacetylase 6 inhibitors. J. Med. Chem. 2015, 58, 2809–2820. [Google Scholar] [CrossRef] [PubMed]
  135. Blackburn, C.; Barrett, C.; Chin, J.; Garcia, K.; Gigstad, K.; Gould, A.; Gutierrez, J.; Harrison, S.; Hoar, K.; Lynch, C.; et al. Potent histone deacetylase inhibitors derived from 4-(aminomethyl)-N-hydroxybenzamide with high selectivity for the HDAC6 isoform. J. Med. Chem. 2013, 56, 7201–7211. [Google Scholar] [CrossRef]
  136. Seidel, C.; Schnekenburger, M.; Mazumder, A.; Teiten, M.H.; Kirsch, G.; Dicato, M.; Diederich, M. 4-Hydroxybenzoic acid derivatives as HDAC6-specific inhibitors modulating microtubular structure and HSP90alpha chaperone activity against prostate cancer. Biochem. Pharmacol. 2016, 99, 31–52. [Google Scholar] [CrossRef] [PubMed]
  137. Tang, G.; Wong, J.C.; Zhang, W.; Wang, Z.; Zhang, N.; Peng, Z.; Zhang, Z.; Rong, Y.; Li, S.; Zhang, M.; et al. Identification of a novel aminotetralin class of HDAC6 and HDAC8 selective inhibitors. J. Med. Chem. 2014, 57, 8026–8034. [Google Scholar] [CrossRef] [PubMed]
  138. Wang, X.X.; Wan, R.Z.; Liu, Z.P. Recent advances in the discovery of potent and selective HDAC6 inhibitors. Eur. J. Med. Chem. 2018, 143, 1406–1418. [Google Scholar] [CrossRef] [PubMed]
  139. Liang, T.; Hou, X.; Zhou, Y.; Yang, X.; Fang, H. Design, Synthesis, and Biological Evaluation of 2,4-Imidazolinedione Derivatives as HDAC6 Isoform-Selective Inhibitors. ACS Med. Chem. Lett. 2019, 10, 1122–1127. [Google Scholar] [CrossRef]
  140. Kozikowski, A.P.; Chen, Y.; Gaysin, A.; Chen, B.; D’Annibale, M.A.; Suto, C.M.; Langley, B.C. Functional differences in epigenetic modulators-superiority of mercaptoacetamide-based histone deacetylase inhibitors relative to hydroxamates in cortical neuron neuroprotection studies. J. Med. Chem. 2007, 50, 3054–3061. [Google Scholar] [CrossRef]
  141. Lee, H.Y.; Nepali, K.; Huang, F.I.; Chang, C.Y.; Lai, M.J.; Li, Y.H.; Huang, H.L.; Yang, C.R.; Liou, J.P. (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo. J. Med. Chem. 2018, 61, 905–917. [Google Scholar] [CrossRef]
  142. Shen, S.; Hadley, M.; Ustinova, K.; Pavlicek, J.; Knox, T.; Noonepalle, S.; Tavares, M.T.; Zimprich, C.A.; Zhang, G.; Robers, M.B.; et al. Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models. J. Med. Chem. 2019, 62, 8557–8577. [Google Scholar] [CrossRef]
  143. Vogerl, K.; Ong, N.; Senger, J.; Herp, D.; Schmidtkunz, K.; Marek, M.; Muller, M.; Bartel, K.; Shaik, T.B.; Porter, N.J.; et al. Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors. J. Med. Chem. 2019, 62, 1138–1166. [Google Scholar] [CrossRef] [PubMed]
  144. Porter, N.J.; Osko, J.D.; Diedrich, D.; Kurz, T.; Hooker, J.M.; Hansen, F.K.; Christianson, D.W. Histone Deacetylase 6-Selective Inhibitors and the Influence of Capping Groups on Hydroxamate-Zinc Denticity. J. Med. Chem. 2018, 61, 8054–8060. [Google Scholar] [CrossRef] [PubMed]
  145. Duan, W.; Li, J.; Inks, E.S.; Chou, C.J.; Jia, Y.; Chu, X.; Li, X.; Xu, W.; Zhang, Y. Design, synthesis, and antitumor evaluation of novel histone deacetylase inhibitors equipped with a phenylsulfonylfuroxan module as a nitric oxide donor. J. Med. Chem. 2015, 58, 4325–4338. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Cho, M.; Choi, E.; Yang, J.S.; Lee, C.; Seo, J.J.; Kim, B.S.; Oh, S.J.; Kim, H.M.; Lee, K.; Park, S.K.; et al. Discovery of pyridone-based histone deacetylase inhibitors: Approaches for metabolic stability. ChemMedChem 2013, 8, 272–279. [Google Scholar] [CrossRef] [PubMed]
  147. Liu, Y.M.; Lee, H.Y.; Lai, M.J.; Pan, S.L.; Huang, H.L.; Kuo, F.C.; Chen, M.C.; Liou, J.P. Pyrimidinedione-mediated selective histone deacetylase 6 inhibitors with antitumor activity in colorectal cancer HCT116 cells. Org. Biomol. Chem. 2015, 13, 10226–10235. [Google Scholar] [CrossRef]
  148. Yu, C.W.; Chang, P.T.; Hsin, L.W.; Chern, J.W. Quinazolin-4-one derivatives as selective histone deacetylase-6 inhibitors for the treatment of Alzheimer’s disease. J. Med. Chem. 2013, 56, 6775–6791. [Google Scholar] [CrossRef]
  149. Heltweg, B.; Dequiedt, F.; Marshall, B.L.; Brauch, C.; Yoshida, M.; Nishino, N.; Verdin, E.; Jung, M. Subtype selective substrates for histone deacetylases. J. Med. Chem. 2004, 47, 5235–5243. [Google Scholar] [CrossRef] [Green Version]
  150. Hideshima, T.; Qi, J.; Paranal, R.M.; Tang, W.; Greenberg, E.; West, N.; Colling, M.E.; Estiu, G.; Mazitschek, R.; Perry, J.A.; et al. Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma. Proc. Natl. Acad. Sci. USA 2016, 113, 13162–13167. [Google Scholar] [CrossRef] [Green Version]
  151. Sellmer, A.; Stangl, H.; Beyer, M.; Grunstein, E.; Leonhardt, M.; Pongratz, H.; Eichhorn, E.; Elz, S.; Striegl, B.; Jenei-Lanzl, Z.; et al. Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors. J. Med. Chem. 2018, 61, 3454–3477. [Google Scholar] [CrossRef]
  152. Lee, H.Y.; Tsai, A.C.; Chen, M.C.; Shen, P.J.; Cheng, Y.C.; Kuo, C.C.; Pan, S.L.; Liu, Y.M.; Liu, J.F.; Yeh, T.K.; et al. Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells. J. Med. Chem. 2014, 57, 4009–4022. [Google Scholar] [CrossRef]
  153. Mackwitz, M.K.W.; Hamacher, A.; Osko, J.D.; Held, J.; Scholer, A.; Christianson, D.W.; Kassack, M.U.; Hansen, F.K. Multicomponent Synthesis and Binding Mode of Imidazo[1,2 -a]pyridine-Capped Selective HDAC6 Inhibitors. Org. Lett. 2018, 20, 3255–3258. [Google Scholar] [CrossRef] [PubMed]
  154. Lee, J.H.; Yao, Y.; Mahendran, A.; Ngo, L.; Venta-Perez, G.; Choy, M.L.; Breslow, R.; Marks, P.A. Creation of a histone deacetylase 6 inhibitor and its biological effects [corrected]. Proc. Natl. Acad. Sci. USA 2015, 112, 12005–12010. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Lee, J.H.; Mahendran, A.; Yao, Y.; Ngo, L.; Venta-Perez, G.; Choy, M.L.; Kim, N.; Ham, W.S.; Breslow, R.; Marks, P.A. Development of a histone deacetylase 6 inhibitor and its biological effects. Proc. Natl. Acad. Sci. USA 2013, 110, 15704–15709. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Hai, Y.; Christianson, D.W. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 2016, 12, 741–747. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Yang, Z.; Wang, T.; Wang, F.; Niu, T.; Liu, Z.; Chen, X.; Long, C.; Tang, M.; Cao, D.; Wang, X.; et al. Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer. J. Med. Chem. 2016, 59, 1455–1470. [Google Scholar] [CrossRef] [PubMed]
  158. Bergman, J.A.; Woan, K.; Perez-Villarroel, P.; Villagra, A.; Sotomayor, E.M.; Kozikowski, A.P. Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth. J. Med. Chem. 2012, 55, 9891–9899. [Google Scholar] [CrossRef]
  159. Senger, J.; Melesina, J.; Marek, M.; Romier, C.; Oehme, I.; Witt, O.; Sippl, W.; Jung, M. Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors. J. Med. Chem. 2016, 59, 1545–1555. [Google Scholar] [CrossRef]
  160. Santo, L.; Hideshima, T.; Kung, A.L.; Tseng, J.C.; Tamang, D.; Yang, M.; Jarpe, M.; van Duzer, J.H.; Mazitschek, R.; Ogier, W.C.; et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012, 119, 2579–2589. [Google Scholar] [CrossRef]
  161. Wang, F.; Zhong, B.W.; Zhao, Z.R. ACY 1215, a histone deacetylase 6 inhibitor, inhibits cancer cell growth in melanoma. J. Biol. Regul. Homeost. Agents 2018, 32, 851–858. [Google Scholar]
  162. Zhang, I.; Beus, M.; Stochaj, U.; Le, P.U.; Zorc, B.; Rajic, Z.; Petrecca, K.; Maysinger, D. Inhibition of glioblastoma cell proliferation, invasion, and mechanism of action of a novel hydroxamic acid hybrid molecule. Cell Death Discov 2018, 4, 41. [Google Scholar] [CrossRef]
  163. Dong, J.; Zheng, N.; Wang, X.; Tang, C.; Yan, P.; Zhou, H.B.; Huang, J. A novel HDAC6 inhibitor exerts an anti-cancer effect by triggering cell cycle arrest and apoptosis in gastric cancer. Eur. J. Pharmacol. 2018, 828, 67–79. [Google Scholar] [CrossRef] [PubMed]
  164. Butler, K.V.; Kalin, J.; Brochier, C.; Vistoli, G.; Langley, B.; Kozikowski, A.P. Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J. Am. Chem. Soc. 2010, 132, 10842–10846. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Aldana-Masangkay, G.I.; Rodriguez-Gonzalez, A.; Lin, T.; Ikeda, A.K.; Hsieh, Y.T.; Kim, Y.M.; Lomenick, B.; Okemoto, K.; Landaw, E.M.; Wang, D.; et al. Tubacin suppresses proliferation and induces apoptosis of acute lymphoblastic leukemia cells. Leuk. Lymphoma 2011, 52, 1544–1555. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Depetter, Y.; Geurs, S.; De Vreese, R.; Goethals, S.; Vandoorn, E.; Laevens, A.; Steenbrugge, J.; Meyer, E.; de Tullio, P.; Bracke, M.; et al. Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models. Int. J. Cancer 2019, 145, 735–747. [Google Scholar] [CrossRef] [Green Version]
  167. Patil, V.; Sodji, Q.H.; Kornacki, J.R.; Mrksich, M.; Oyelere, A.K. 3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition. J. Med. Chem. 2013, 56, 3492–3506. [Google Scholar] [CrossRef] [Green Version]
  168. Muthyala, R.; Shin, W.S.; Xie, J.; Sham, Y.Y. Discovery of 1-hydroxypyridine-2-thiones as selective histone deacetylase inhibitors and their potential application for treating leukemia. Bioorg. Med. Chem. Lett. 2015, 25, 4320–4324. [Google Scholar] [CrossRef]
  169. Itoh, Y.; Suzuki, T.; Kouketsu, A.; Suzuki, N.; Maeda, S.; Yoshida, M.; Nakagawa, H.; Miyata, N. Design, synthesis, structure--selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhibitors. J. Med. Chem. 2007, 50, 5425–5438. [Google Scholar] [CrossRef]
  170. Segretti, M.C.; Vallerini, G.P.; Brochier, C.; Langley, B.; Wang, L.; Hancock, W.W.; Kozikowski, A.P. Thiol-Based Potent and Selective HDAC6 Inhibitors Promote Tubulin Acetylation and T-Regulatory Cell Suppressive Function. ACS Med. Chem. Lett. 2015, 6, 1156–1161. [Google Scholar] [CrossRef] [Green Version]
  171. Wahhab, A.; Smil, D.; Ajamian, A.; Allan, M.; Chantigny, Y.; Therrien, E.; Nguyen, N.; Manku, S.; Leit, S.; Rahil, J.; et al. Sulfamides as novel histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 336–340. [Google Scholar] [CrossRef]
  172. Choi, E.W.; Song, J.W.; Ha, N.; Choi, Y.I.; Kim, S. CKD-506, a novel HDAC6-selective inhibitor, improves renal outcomes and survival in a mouse model of systemic lupus erythematosus. Sci. Rep. 2018, 8, 17297. [Google Scholar] [CrossRef]
  173. Schnekenburger, M.; Florean, C.; Dicato, M.; Diederich, M. Epigenetic alterations as a universal feature of cancer hallmarks and a promising target for personalized treatments. Curr. Top. Med. Chem. 2016, 16, 745–776. [Google Scholar] [CrossRef] [PubMed]
  174. Batchu, S.N.; Brijmohan, A.S.; Advani, A. The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease. Clin. Sci. (Lond.) 2016, 130, 987–1003. [Google Scholar] [CrossRef] [PubMed]
  175. Rosik, L.; Niegisch, G.; Fischer, U.; Jung, M.; Schulz, W.A.; Hoffmann, M.J. Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells. Cancer Biol. Ther. 2014, 15, 742–757. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Hsieh, Y.L.; Tu, H.J.; Pan, S.L.; Liou, J.P.; Yang, C.R. Anti-metastatic activity of MPT0G211, a novel HDAC6 inhibitor, in human breast cancer cells in vitro and in vivo. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 992–1003. [Google Scholar] [CrossRef]
  177. Shan, B.; Yao, T.P.; Nguyen, H.T.; Zhuo, Y.; Levy, D.R.; Klingsberg, R.C.; Tao, H.; Palmer, M.L.; Holder, K.N.; Lasky, J.A. Requirement of HDAC6 for transforming growth factor-beta1-induced epithelial-mesenchymal transition. J. Biol. Chem. 2008, 283, 21065–21073. [Google Scholar] [CrossRef] [Green Version]
  178. Kaluza, D.; Kroll, J.; Gesierich, S.; Yao, T.P.; Boon, R.A.; Hergenreider, E.; Tjwa, M.; Rossig, L.; Seto, E.; Augustin, H.G.; et al. Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin. EMBO J. 2011, 30, 4142–4156. [Google Scholar] [CrossRef]
  179. Morel, D.; Jeffery, D.; Aspeslagh, S.; Almouzni, G.; Postel-Vinay, S. Combining epigenetic drugs with other therapies for solid tumours—Past lessons and future promise. Nat. Rev. Clin. Oncol. 2020, 17, 91–107. [Google Scholar] [CrossRef]
  180. Valdespino, V.; Valdespino, P.M. Potential of epigenetic therapies in the management of solid tumors. Cancer Manag. Res. 2015, 7, 241–251. [Google Scholar] [CrossRef] [Green Version]
  181. Grassadonia, A.; Cioffi, P.; Simiele, F.; Iezzi, L.; Zilli, M.; Natoli, C. Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies. Cancers 2013, 5, 919–942. [Google Scholar] [CrossRef] [Green Version]
  182. Wang, E.C.; Min, Y.; Palm, R.C.; Fiordalisi, J.J.; Wagner, K.T.; Hyder, N.; Cox, A.D.; Caster, J.M.; Tian, X.; Wang, A.Z. Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors. Biomaterials 2015, 51, 208–215. [Google Scholar] [CrossRef] [Green Version]
  183. Brindisi, M.; Saraswati, A.P.; Brogi, S.; Gemma, S.; Butini, S.; Campiani, G. Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases. J. Med. Chem. 2020, 63, 23–39. [Google Scholar] [CrossRef] [PubMed]
  184. Hackanson, B.; Rimmele, L.; Benkisser, M.; Abdelkarim, M.; Fliegauf, M.; Jung, M.; Lubbert, M. HDAC6 as a target for antileukemic drugs in acute myeloid leukemia. Leuk. Res. 2012, 36, 1055–1062. [Google Scholar] [CrossRef] [PubMed]
  185. Liu, Y.; Peng, L.; Seto, E.; Huang, S.; Qiu, Y. Modulation of histone deacetylase 6 (HDAC6) nuclear import and tubulin deacetylase activity through acetylation. J. Biol. Chem. 2012, 287, 29168–29174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Kramer, O.H.; Mahboobi, S.; Sellmer, A. Drugging the HDAC6-HSP90 interplay in malignant cells. Trends Pharmacol. Sci. 2014, 35, 501–509. [Google Scholar] [CrossRef] [PubMed]
  187. Ryu, H.W.; Shin, D.H.; Lee, D.H.; Choi, J.; Han, G.; Lee, K.Y.; Kwon, S.H. HDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis. Cancer Lett. 2017, 391, 162–171. [Google Scholar] [CrossRef]
  188. Bali, P.; Pranpat, M.; Bradner, J.; Balasis, M.; Fiskus, W.; Guo, F.; Rocha, K.; Kumaraswamy, S.; Boyapalle, S.; Atadja, P.; et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: A novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 2005, 280, 26729–26734. [Google Scholar] [CrossRef] [Green Version]
  189. Rao, R.; Fiskus, W.; Yang, Y.; Lee, P.; Joshi, R.; Fernandez, P.; Mandawat, A.; Atadja, P.; Bradner, J.E.; Bhalla, K. HDAC6 inhibition enhances 17-AAG--mediated abrogation of hsp90 chaperone function in human leukemia cells. Blood 2008, 112, 1886–1893. [Google Scholar] [CrossRef] [Green Version]
  190. Chen, P.B.; Hung, J.H.; Hickman, T.L.; Coles, A.H.; Carey, J.F.; Weng, Z.; Chu, F.; Fazzio, T.G. Hdac6 regulates Tip60-p400 function in stem cells. Elife 2013, 2, e01557. [Google Scholar] [CrossRef]
  191. Kuo, Y.H.; Qi, J.; Cook, G.J. Regain control of p53: Targeting leukemia stem cells by isoform-specific HDAC inhibition. Exp. Hematol. 2016, 44, 315–321. [Google Scholar] [CrossRef] [Green Version]
  192. Lernoux, M.; Schnekenburger, M.; Dicato, M.; Diederich, M. Epigenetic mechanisms underlying the therapeutic effects of HDAC inhibitors in chronic myeloid leukemia. Biochem. Pharmacol. 2019. [Google Scholar] [CrossRef]
  193. Li, L.; Wang, L.; Li, L.; Wang, Z.; Ho, Y.; McDonald, T.; Holyoake, T.L.; Chen, W.; Bhatia, R. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 2012, 21, 266–281. [Google Scholar] [CrossRef] [Green Version]
  194. Fiskus, W.; Pranpat, M.; Balasis, M.; Bali, P.; Estrella, V.; Kumaraswamy, S.; Rao, R.; Rocha, K.; Herger, B.; Lee, F.; et al. Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate-sensitive or imatinib mesylate-resistant chronic myelogenous leukemia cells. Clin. Cancer Res. 2006, 12, 5869–5878. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  195. Nimmanapalli, R.; Fuino, L.; Bali, P.; Gasparetto, M.; Glozak, M.; Tao, J.; Moscinski, L.; Smith, C.; Wu, J.; Jove, R.; et al. Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res. 2003, 63, 5126–5135. [Google Scholar] [PubMed]
  196. Nguyen, T.; Dai, Y.; Attkisson, E.; Kramer, L.; Jordan, N.; Nguyen, N.; Kolluri, N.; Muschen, M.; Grant, S. HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo. Clin. Cancer Res. 2011, 17, 3219–3232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Jin, Y.; Yao, Y.; Chen, L.; Zhu, X.; Jin, B.; Shen, Y.; Li, J.; Du, X.; Lu, Y.; Jiang, S.; et al. Depletion of gamma-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib. Theranostics 2016, 6, 1947–1962. [Google Scholar] [CrossRef] [Green Version]
  198. Zhang, B.; Strauss, A.C.; Chu, S.; Li, M.; Ho, Y.; Shiang, K.D.; Snyder, D.S.; Huettner, C.S.; Shultz, L.; Holyoake, T.; et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 2010, 17, 427–442. [Google Scholar] [CrossRef] [Green Version]
  199. Zhang, H.; Li, S. Concise Review: Exploiting Unique Biological Features of Leukemia Stem Cells for Therapeutic Benefit. Stem Cells Transl. Med. 2019, 8, 768–774. [Google Scholar] [CrossRef] [Green Version]
  200. Rossari, F.; Minutolo, F.; Orciuolo, E. Past, present, and future of Bcr-Abl inhibitors: From chemical development to clinical efficacy. J. Hematol. Oncol. 2018, 11, 84. [Google Scholar] [CrossRef] [Green Version]
  201. Yang, H.; Lv, W.; He, M.; Deng, H.; Li, H.; Wu, W.; Rao, Y. Plasticity in designing PROTACs for selective and potent degradation of HDAC6. Chem. Commun. (Camb.) 2019, 55, 14848–14851. [Google Scholar] [CrossRef]
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Figure 1. Progression of chronic myeloid leukemia. Chronic myeloid leukemia (CML) is characterized by an excessive proliferation of non-functional leukocytes (dotted lines) or blasts in the bone marrow and then in the blood. The chronic phase remains generally asymptomatic, during which 5% blasts are found in the bloodstream. After 5 to 6 years without treatment, the pathology progresses towards the accelerated phase (5% to 20% blasts) and symptoms including fatigue and loss of appetite and weight begin to appear. Without treatment, the accelerated phase progresses in 6 to 9 months to the blast phase (more than 20% blasts), causing rapid deterioration of the general condition of the patient and death after only a few months without management. Symptoms and resistance to therapy increase during the course of chronic myeloid leukemia, while the probability of survival decreases.
Figure 1. Progression of chronic myeloid leukemia. Chronic myeloid leukemia (CML) is characterized by an excessive proliferation of non-functional leukocytes (dotted lines) or blasts in the bone marrow and then in the blood. The chronic phase remains generally asymptomatic, during which 5% blasts are found in the bloodstream. After 5 to 6 years without treatment, the pathology progresses towards the accelerated phase (5% to 20% blasts) and symptoms including fatigue and loss of appetite and weight begin to appear. Without treatment, the accelerated phase progresses in 6 to 9 months to the blast phase (more than 20% blasts), causing rapid deterioration of the general condition of the patient and death after only a few months without management. Symptoms and resistance to therapy increase during the course of chronic myeloid leukemia, while the probability of survival decreases.
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Figure 2. Breakpoints in the Abelson (ABL)1 and breakpoint cluster region (BCR) genes result in the formation of different transcripts encoding the BCR-ABL chimeric protein: (A) Structure of the Abelson (ABL)1 and breakpoint cluster region (BCR) genes composed of 11 and 23 exons, respectively; (B) Diagram of ABL transcripts (1130 amino acids), BCR (1271 amino acids), and BCR-ABL hybrids. The hybrid mRNA eXaY is produced after cleavage occurs after exon X of BCR and before exon Y of ABL; (C) ABL protein (145 kDa) has tyrosine kinase activity and predominantly nuclear localization. It comprises a long lipid chain, myristate (Myr), conferring a capacity for self-inhibition, SH2 and SH3 domains of Src homology, allowing interactions with proline-rich regions and with phosphorylated tyrosines, respectively, a tyrosine kinase (TK) domain, and finally an actin-binding domain (ABD) binding domain to DNA and β-actin. ABL is involved in cytoskeletal dynamics (adhesion, polarity, cell migration, and cellular protrusions), proliferation and cell survival, membrane transport (endocytosis, macropinocytosis, phagocytosis, and caveolae formation) by phosphorylating receptors such as epidermal growth factor receptor, platelet-derived growth factor beta receptor and muscle specific tyrosine kinase receptor [8], and finally in autophagy [9,10]. ABL protein is involved in neurodegenerative diseases and neuroinflammation [9,10]. The BCR protein (160 kDa) has serine/threonine kinase activity and is localized in the cytoplasm [11]. BCR comprises an oligomerization domain (OLI). Mutations in this domain cause a decrease in the tyrosine kinase activity of the BCR-ABL protein and prevent the interaction of BCR and BCR-ABL proteins. It also has a domain of homology to the protein DBL [guanosine diphosphate exchange factor (GDP) in guanosine triphosphate (GTP)], a domain of pleckstrin homology (PH), a C2 domain for binding of calcium-dependent phospholipids, and finally a GTPase (GTPase activating protein) domain (GTPase hydrolysis in GDP and phosphate ion) for binding to Rac proteins.
Figure 2. Breakpoints in the Abelson (ABL)1 and breakpoint cluster region (BCR) genes result in the formation of different transcripts encoding the BCR-ABL chimeric protein: (A) Structure of the Abelson (ABL)1 and breakpoint cluster region (BCR) genes composed of 11 and 23 exons, respectively; (B) Diagram of ABL transcripts (1130 amino acids), BCR (1271 amino acids), and BCR-ABL hybrids. The hybrid mRNA eXaY is produced after cleavage occurs after exon X of BCR and before exon Y of ABL; (C) ABL protein (145 kDa) has tyrosine kinase activity and predominantly nuclear localization. It comprises a long lipid chain, myristate (Myr), conferring a capacity for self-inhibition, SH2 and SH3 domains of Src homology, allowing interactions with proline-rich regions and with phosphorylated tyrosines, respectively, a tyrosine kinase (TK) domain, and finally an actin-binding domain (ABD) binding domain to DNA and β-actin. ABL is involved in cytoskeletal dynamics (adhesion, polarity, cell migration, and cellular protrusions), proliferation and cell survival, membrane transport (endocytosis, macropinocytosis, phagocytosis, and caveolae formation) by phosphorylating receptors such as epidermal growth factor receptor, platelet-derived growth factor beta receptor and muscle specific tyrosine kinase receptor [8], and finally in autophagy [9,10]. ABL protein is involved in neurodegenerative diseases and neuroinflammation [9,10]. The BCR protein (160 kDa) has serine/threonine kinase activity and is localized in the cytoplasm [11]. BCR comprises an oligomerization domain (OLI). Mutations in this domain cause a decrease in the tyrosine kinase activity of the BCR-ABL protein and prevent the interaction of BCR and BCR-ABL proteins. It also has a domain of homology to the protein DBL [guanosine diphosphate exchange factor (GDP) in guanosine triphosphate (GTP)], a domain of pleckstrin homology (PH), a C2 domain for binding of calcium-dependent phospholipids, and finally a GTPase (GTPase activating protein) domain (GTPase hydrolysis in GDP and phosphate ion) for binding to Rac proteins.
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Figure 3. BCR-ABL-dependent and -independent imatinib resistances. BCR-ABL-dependent (purple) and -independent (blue) resistances can be explained by BCR-ABL duplication and mutation mechanisms, co-medication, interindividual variety, decreased import proteins, increased export proteins, binding of imatinib to plasma proteins, and the presence of imatinib-insensitive leukemic stem cells (LSCs). CYP3A4: cytochrome 3A4.
Figure 3. BCR-ABL-dependent and -independent imatinib resistances. BCR-ABL-dependent (purple) and -independent (blue) resistances can be explained by BCR-ABL duplication and mutation mechanisms, co-medication, interindividual variety, decreased import proteins, increased export proteins, binding of imatinib to plasma proteins, and the presence of imatinib-insensitive leukemic stem cells (LSCs). CYP3A4: cytochrome 3A4.
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Figure 4. Protein structure of histone deacetylase 6 (HDAC6). The HDAC6 protein consists of 1215 amino acids. It has a nuclear localization sequence (NLS), a nuclear export sequence (NES), two functional active catalytic (SC) sites, a cytoplasmic retention signal of eight consecutive serine-glutamic acid tetradecapeptides (SE14), and a ubiquitin-binding domain (BUZ) at the C-terminal.
Figure 4. Protein structure of histone deacetylase 6 (HDAC6). The HDAC6 protein consists of 1215 amino acids. It has a nuclear localization sequence (NLS), a nuclear export sequence (NES), two functional active catalytic (SC) sites, a cytoplasmic retention signal of eight consecutive serine-glutamic acid tetradecapeptides (SE14), and a ubiquitin-binding domain (BUZ) at the C-terminal.
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Figure 5. The HDAC6 protein is involved in many cellular processes. HDAC6 is involved in F-actin polymerization (A), microtubule dynamics (B), anti-apoptotic activity (C), proteasome-dependent and -independent degradation (D), transcriptional activation of chaperone proteins (E), and autophagy (F). Ac: acetylated; HAT: histone acetyltransferase; HDAC: histone deacetylase; HSF: heat shock factor; HSP: heat shock protein; MTOC: microtubule organizing center; SIRT: sirtuin; VCP: valosin-containing protein/ATPase.
Figure 5. The HDAC6 protein is involved in many cellular processes. HDAC6 is involved in F-actin polymerization (A), microtubule dynamics (B), anti-apoptotic activity (C), proteasome-dependent and -independent degradation (D), transcriptional activation of chaperone proteins (E), and autophagy (F). Ac: acetylated; HAT: histone acetyltransferase; HDAC: histone deacetylase; HSF: heat shock factor; HSP: heat shock protein; MTOC: microtubule organizing center; SIRT: sirtuin; VCP: valosin-containing protein/ATPase.
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Figure 6. Role of HDAC6 in chronic myeloid leukemia. (A) HDAC6 is implicated in proteasome-dependent protein degradation by its interaction with HSP90α, a chaperone protein which, when deacetylated by HDAC6, is involved in the stabilization of BCR-ABL. In its acetylated (Ac) form, HSP90α loses its chaperone function, which leads to ubiquitination (Ub) and subsequent degradation of BCR-ABL by the proteasome. (B) Imatinib-insensitive chronic myeloid leukemia (CML) leukemic stem cells (LSCs) overexpress HDAC6 compared to CML cells.
Figure 6. Role of HDAC6 in chronic myeloid leukemia. (A) HDAC6 is implicated in proteasome-dependent protein degradation by its interaction with HSP90α, a chaperone protein which, when deacetylated by HDAC6, is involved in the stabilization of BCR-ABL. In its acetylated (Ac) form, HSP90α loses its chaperone function, which leads to ubiquitination (Ub) and subsequent degradation of BCR-ABL by the proteasome. (B) Imatinib-insensitive chronic myeloid leukemia (CML) leukemic stem cells (LSCs) overexpress HDAC6 compared to CML cells.
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Table
Table 1. Human BCR-ABL transcripts and proteins. The name and composition of the various human BCR-ABL hybrid transcripts identified in patients are described. The size of the corresponding proteins, their frequency of detection, and the cell lines expressing them are also indicated.
Table 1. Human BCR-ABL transcripts and proteins. The name and composition of the various human BCR-ABL hybrid transcripts identified in patients are described. The size of the corresponding proteins, their frequency of detection, and the cell lines expressing them are also indicated.
BCR-ABL mRNASize of the Corresponding Protein (kDa)Examples of CML Cell LinesReferences
Hybrid mRNA NameComposition
BCR Exons $ABL Exons £
e13a2 or b2a21–132–11210MEG-01, KBM-7, KYO-1, CML-T1, KCL-22[12,13,14,15]
e14a2 or b3a21–142–11210K-562, KBM-5, LAMA-84, EM-3, TK-6, EM-2[12,13,15,16]
e13a3 or b2a31–133–11210NA[17]
e14a3 or b3a31–143–11210NA[17]
e18a21–182–11225AR-230[13,18]
e19a21–192–11230AR-230[13,17]
e1a212–11190SUP-B15 *, Z-33 *, SD-1 *, TOM-1 *, Z-119 *[13,14]
e6a21–62–11185NA[19]
$ Of the 23 exons that compose the BCR gene. £ Of the 11 exons that compose the ABL gene. * Acute lymphocytic leukemia cell lines. ABL: Abelson; BCR: breakpoint cluster region; NA: not applicable.
Table
Table 2. BCR-ABL substrates.
Table 2. BCR-ABL substrates.
SubstratesPhosphorylation siteFunctionReferences
Abi 1 and 2NDProliferation[21]
BAP-1Serine and tyrosine residuesProliferation[22,23]
CblTyr-674Unknown[22,24,25]
CK2NDCell cycle, apoptosis, transcription, viral infection[26,27,28]
CrkTyr-221Migration and cellular adhesion[22,29]
CrkLTyr-207Migration and cellular adhesion[22,29]
Dok1Tyr-361Negative regulation of signaling pathways mediated by tyrosine kinase proteins[8,22,30]
FesNDMyeloid differentiation[22,31]
GAP-associated proteinsNDRas activation[22]
GCKRNDSAPK activation[24,32]
Grb2Tyr-209Ras activation[24,33,34]
LASP1Tyr-171Interaction with the cytoskeleton, migration and cell survival[35,36]
LynNDCell survival[37]
PaxillinNDFocal adhesion, signaling and cell migration[22,38]
PLCγTyr-69/Tyr-74Actin rearrangement and cell migration[22,39]
PI3-K p85NDProliferation, survival and cellular motility[22,40]
PKDTyr-463Proliferation, migration and cell survival, angiogenesis, regulation of gene expression[22,41]
P27Kip1Tyr-88Cell proliferation[42]
p73NDActivation of transcription[22]
Rad9Tyr-28DNA damage repair[22]
Rad51Tyr-54DNA damage repair[22]
Ras-GAPNDApoptosis, proliferation and cell migration[22,43]
RNA-polymerase IIC-terminalTranscription[22]
RAFT1NDCell proliferation, autophagy, cytoskeletal reorganization[22,44]
ShcTyr-427Migration, angiogenesis[22,25,45]
SHIP1, SHIP2Tyr-986 et Tyr-1135 (SHIP2)Signal transduction, macrophage programming, phagocytosis, migration[24,25,46]
STAT5Tyr-694Signal transduction, transcription activation[47]
SypNDUnknown[22]
TalinNDSignal transmission between the extracellular matrix and the cytoskeleton[22,48]
TERTNDGenomic integrity[22,49]
VAV p95NDHematopoietic differentiation[22]
Abi: Abelson interactor; BAP-1: breakpoint cluster region-associated protein 1; Cbl: Casitas-B-lineage protein; CK: casein kinase; CrkL: Crk like protein; Dok: docking protein; GAP: guanosine triphosphate (GTP)ase-activating proteins; GCKR: germinal-center kinase related protein; Grb2: growth factor receptor-bound protein 2; LASP1: LIM and Src homology (SH)3 protein 1; ND: not determined; PLCγ: phospholipase C-γ; PI3-K: phosphatidylinositol 3-kinase; PKD: protein kinase D; RAFT1: rapamycin and FK506-binding protein (FKBP)-target 1; Ras-GAP: RAS GTPase activating proteins; Shc: Src homology 2 domain containing; SHIP: SH2-containing inositol polyphosphate 5-phosphatase; Syp: SH2-containing phosphotyrosine phosphatase; TERT: telomerase reverse transcriptase; Tyr: tyrosine.
Table
Table 3. Tyrosine kinase inhibitors approved by the US Food and Drug Administration for the treatment of chronic myeloid leukemia.
Table 3. Tyrosine kinase inhibitors approved by the US Food and Drug Administration for the treatment of chronic myeloid leukemia.
GenerationDrug Name (and Others)Pharmaceutical Company and Marketing Authorization year by FDATargetsDaily Dosage in AdultsReferences
FirstImatinib ° (Gleevec, STI571, CGP57148B)Novartis, 2001BCR-ABL, c-KIT, PDGFR400 mg single dose[58,59]
SecondDasatinib * (Sprycel, BMS-354825)Bristol-Myers Squibb, 2006BCR-ABL, Src family, c-KIT, PDGFR100 mg single dose[58,59,60]
Nilotinib ° (Tasigna, AMN107)Novartis, 2007BCR-ABL, c-KIT, PDGFR300 mg in two doses[58,59,61]
Bosutinib * (Bosulif, SKI-606)Pfizer, 2012BCR-ABL, Src family500 mg single dose[58,59,62]
ThirdPonatinib ° (Iclusig, AP24534)ARIAD Pharmaceuticals, 2012BCR-ABL, FTL3, Src family, RET45 mg single dose[58,59]
° Type II inhibitor binding to the inactive conformation of BCR-ABL. * Type I inhibitor binding to the active and inactive conformation of BCR-ABL. BCR-ABL: breakpoint cluster region-Abelson; FTL3: Fms-like tyrosine kinase 3; PDGFR: platelet-derived growth factor receptor; RET: rearranged during transfection.
Table
Table 4. List of substrates specifically deacetylated by HDAC6.
Table 4. List of substrates specifically deacetylated by HDAC6.
SubstratesLocalization of the SubstrateDeacetylated Lysine(s)Function of the Deacetylated SubstrateInteraction Domains of HDAC6Reference
14-3-3ζCytoplasm and nucleus49, 120Regulation of protein binding Bad and AS160ND[85]
β-cateninCytoplasm and nucleus49Epidermal growth factor-induced nuclear localization and decreased expression of c-MycND[83]
Cortactin *Cytoplasm87, 124, 161, 189, 198, 235, 272, 309, 319Regulation of cell migration and actin filament bindingDD1 and DD2[83]
DNAJA1CytoplasmNDProtein foldingND[86]
ERK1Cytoplasm and nucleus72Proliferation, mobility, and cell survival [87]
Foxp3 *NucleusNDNDND[88]
HDAC9Cytoplasm and nucleusNDModulation of cell survival and arrest of cellular movementDD2[89]
HDAC11NucleusNDTranscriptional activation of interleukin 10ND[90]
HMGN2Nucleus2Increased transcription of STAT5ND[91]
HSC70CytoplasmNDProtein foldingND[86]
HSPA5Cytoplasm353Ubiquitination of HSPA5 mediated by GP78ND[92]
HSP90αCytoplasm294Degradation and elimination of misfolded proteins and regulation of glucocorticoid receptorsDD1, DD2 et BUZ[83]
K-RAS *Cytoplasm104Cell proliferationND[93]
Ku70Cytoplasm539, 542Suppression of apoptosisND[83]
LC3B-II*CytoplasmNDRegulation of autophagyND[94]
MSH2Cytoplasm and nucleus845, 847, 871, 892Reduced cellular sensitivity to DNA damaging agents and reduced DNA mismatch repair activities by downregulation of MSH2DD1[95]
MYH9CytoplasmNDRegulation of binding to actin filamentsND[86]
PrxICytoplasm and nucleus197Antioxidant activityND[96,97]
PrxIICytoplasm and nucleus196Antioxidant activityND[96,97]
RIG-ICytoplasm858, 909Recognition of viral RNAND[98]
Sam68NucleusNDAlternative splicingND[99]
SurvivinNucleus129Anti-apoptotic functionDD2[83]
TatCytoplasm28Suppression of HIV transactivationDD2 and BUZ[100]
α-tubulin *Cytoplasm40Formation of immune synapses, viral infection, cell migration and chemotaxisDD1 or DD2[83,101]
* Cortactin and LC3B-II are also deacetylated by SIRT1, K-RAS and α-tubulin are also deacetylated by SIRT2, and Foxp3 is also deacetylated by HDAC9 and SIRT1. AS160: Akt substrate of 160 kDa; Bad: Bcl-2 associated agonist of cell death; BUZ: binding-of-ubiquitin zinc; DD: deacetylase domain; DNAJA1: dnaJ homolog subfamily A member 1; ERK1: extracellular signal-regulated kinase 1; Foxp3: forkhead box P3; GP: glycoprotein; HDAC: histone deacetylase; HIV: human immunodeficiency virus; HMGN2: high mobility group nucleosomal binding domain 2; HSC: heat shock cognate; HSP (A): heat shock protein [family A (HSP70) member 5]; LC3B-II: microtubule-associated protein 1 light chain 3; MSH2: MutS protein homolog 2; MYH9: myosin heavy chain 9; ND: non determined; Prx: peroxiredoxin; RIG-I: retinoic acid-inducible gene I protein; Sam: Src-associated substrate in mitosis; STAT: signal transducer and transcriptional activator; Tat: twin-arginine translocation protein.
Table
Table 5. Post-translational modifications regulating the activity of HDAC6.
Table 5. Post-translational modifications regulating the activity of HDAC6.
Post-Translational ModificationEnzymeTarget SiteConsequencesReference
PhosphorylationGSK3βSer-22Increased deacetylation activity of α-tubulin[84]
ERK1Ser-1035Regulation of cellular motility[84]
GRK2NDIncreased deacetylation activity of α-tubulin[105]
AuroraNDIncreased deacetylation activity of α-tubulin[84]
PKCζNDIncreased deacetylation activity of α-tubulin[84]
CK2Ser-458Improved formation and elimination of aggresomes[84]
EGFRTyr-570Inhibition of deacetylation activity[106]
Acetylationp300Lys-16Inhibition of deacetylation activity[84]
CK2: casein kinase 2; EGFR: epidermal growth factor receptor; ERK1: extracellular signal-regulated kinase; GRK2: G protein-coupled receptor kinase 2; GSK3: glycogen synthase kinase 3; Lys: lysine; ND: non determined; PKCζ: protein kinase C isoform ζ; Ser: serine; Thr: threonine.
Table
Table 6. Proteins that interact directly with the HDAC6 protein.
Table 6. Proteins that interact directly with the HDAC6 protein.
Protein Inhibiting HDAC6 by Direct InteractionProtein FunctionProtein Region Required for Interaction with HDAC6HDAC6 Domain Interacting with the ProteinCellular ImpactReferences
CYLDDeubiquitinaseNDDD1/DD2Cell proliferation, ciliogenesis[84]
DysferlinSkeletal muscle membrane repair, myogenesis, cell adhesion, intercellular calcium signalingDomain C2NDMyogenesis[107]
Mdp3Stabilization factor of microtubulesAmino-terminal regionNDCell motility[108]
PaxillinFocal adhesionRegion rich in prolineNDPolarization and cell migration[84]
p62Transport of misfolded proteinsBetween the ZZ domain and the TRAF6 link areaDD2Aggresome formation[109]
RanBPMApoptosis, proliferation and cell migration NDAggresome formation[110]
TauStabilization factor of microtubulesTubulin binding regionSE14 domainAggresome formation[109,111]
TPPP1Polymerization and acetylation of microtubules NDRegulation of microtubule acetylation and β-catenin expression[112]
DD: deacetylase domain; Mdp3: microtubule-associated protein (MAP) 7 domain-containing protein 3; ND: non determined; RanBPM: Ran-binding protein microtubule-organizing center; tau: tubulin-associated unit; TPPP1: tubulin polymerization-promoting protein-1.
Table
Table 7. Deregulation of HDAC6 expression in different types of cancers.
Table 7. Deregulation of HDAC6 expression in different types of cancers.
Cancer TypeCancersExpression of HDAC6-CommentsReferences
Solid tumorsBladderOverexpressed[113]
MelanomaOverexpressed[113]
LungOverexpressed[113]
Oral squamous cell carcinomaOverexpressed-Enhanced expression in advanced stages[68,114]
Ovarian carcinomaOverexpressed-Enhanced expression in advanced stages[68,114]
BreastOverexpressed-Prediction of a good or bad prognosis[68,115]
Hepatocytic carcinomaOverexpressed-Enhanced expression in advanced stages[68]
Under-expressed-HDAC6 suggested as a tumor suppressor[68,116]
HematologicalChronic lymphocytic leukemiaOverexpressed-Observation on patient samples, cell lines and a transgenic mouse model[114]
Acute myeloid leukemiaOverexpressed[68,114]
Acute lymphoblastic leukemiaOverexpressed-Enhanced expression in advanced stages[68]
Chronic lymphocytic leukemiaOverexpressed-Correlated with longer survival[68]
T-cell cutaneous lymphomaOverexpressed-Correlated with longer survival[68]
Chronic myeloid leukemiaOverexpressed-Increased expression in CD34+ cells[117]
Multiple myelomaOverexpressed[118]
Mantle cell lymphomaOverexpressed[118]
Diffuse large B cell lymphomaOverexpressed[118]
Peripheral T-cell lymphomaOverexpressed[118]
CD: cluster of differentiation; HDAC6: histone deacetylase 6.
Table
Table 8. List of HDAC6 inhibitors.
Table 8. List of HDAC6 inhibitors.
ClassHDAC6 InhibitorBinding DomainCI50 (nM) of the HDAC6 Activity in VitroSelectivity Ratio for HDAC6 Compared to (Other HDACs)Inhibition of HDAC6 in Cellulo (µM)$Effect on Cancer Cell Lines or Cancer TypeReferences
BenzamidesTrithiocarbonate derivative (12ac)ND6519 (HDAC1)10 (lung cancer)CI50 = 8.2 µM (cervical cancer)[119]
NQN-1 (2-benzyl-amino-naphthoquinone)ND5540Values non available (HDAC1, 2, 3, 4, 5, 7, 8, 9, 10, 11)4 (chronic myeloid leukemia)CI50 = 0.8 µM (leukemia)[120]
HydroxamatesHydroxamic acid containing a phenylalanine (4n)His215, His216, Tyr386, Phe283, and Tyr255 of DD1 and His610, His611, Tyr782, Phe620, and Phe680 of an HDAC6 homology model169014 (HDAC1)1 (colorectal carcinoma)IC50: 3 to > 50 µM (various cancer cell lines)[121]
Hydroxamic acid containing a pyridylalanine (5a)Phe566 of DD2 of an HDAC6 homology model397025 (HDAC1)NDIC50: 104 µM (breast cancer)[122]
ACY-738ND1.755 (HDAC1), 75 (HDAC2), 128 (HDAC3)2.5 (neural cells)ND[123]
ACY-775ND7.5283 (HDAC1), 343 (HDAC2), 1496 (HDAC3)2.5 (neural cells)ND[123]
ACY-1083His573 and His574 of DD23260 (HDAC1)0.03 (neuroblastoma)ND[124,125]
BavarostatSer568 of DD260>10000 (HDAC1, 2, 3), 188 (HDAC4), 317 (HDAC5), 78 (HDAC7), 142 (HDAC8), 87 (HDAC9), >17 (HDAC10), 167 (HDAC11)10 (neural progenitor cells derived from induced pluripotent stem cells)ND[126]
BRD9757ND3021 (HDAC1), 60 (HDAC2), 23 (HDAC3), 727 (HDAC4), 611 (HDAC5), 420 (HDAC7), 36 (HDAC8), >1000 (HDAC9)10 (cervical cancer)ND[127]
Cay10603His499 of DD2 of an HDAC6 homology model0.002ND<1 to 1 µM (several pancreatic cancer cell lines)ND[128,129]
Citarinostat (ACY-241)ND2.614 (HDAC1), 17 (HDAC2), 18 (HDAC3 and 4), >7000 (HDAC4, 5,9), 2808 (HDAC7), 53 (HDAC8), 0.3 (ovarian cancer)CI50: 4.6 to 6.1 µM (ovarian and breast cancer)[130]
α3β-cyclic tetrapeptide (23)ND393 (HDAC1), 4 (HDAC3), 6 (HDAC8)2 (acute lymphoblastic leukemia)IC50: 9 to > 20 µM (various cancer cell lines)[131]
Compound containing a phenylisoxazole group as a surface recognition group (7)His499 of HDAC70.002>100000 (HDAC1), >100000 (HDAC2), 210 (HDAC3), >3000000 (HDAC8), 45350 (HDAC10)NDIC50: 0.1 to 1 µM (various prostate cancer cell lines)[128]
Compound containing a triazolylphenyl group (6b)ND1.952 (HDAC1), 155 (HDAC2), 7 (HDAC3), 420 (HDAC8), 59 (HDAC10)NDIC50: <0.5 to 22 µM (several prostate cancer lines)[132]
Compound containing a peptoid (2i)Tyr301 of DD2 of an HDAC6 homology model1.59126 (HDAC2), >6000 (HDAC4), 40 (HDAC11)NIC50: 0.34 to 2.7 µM (various cancer cell lines)[133]
3-aminopyrrolidinone derivative (33)ND174359 (HDAC1), 11 (HDAC8)0.3 (multiple myeloma)Good oral bioavailability[134]
4-aminomethylaryl acid derivative (1a)ND19305 (HDAC1), 842 (HDAC2), 237 (HDAC3), 790 (HDAC4), 174 (HDAC5), 242 (HDAC7), 36 (HDAC8), 195 (HDAC0)0.46 (cervical cancer)ND[135]
4-hydroxybenzoic acid derivative (7b)ND200>50000 (HDAC1, 2, 8), >500000 (HDAC3, 10, 11)50 (prostate cancer)IC50: 41 to 130 (several prostate and breast cancer cell lines)[136]
4-hydroxybenzoic acid derivative (13a)ND2000025 (HDAC1), >5000 (HDAC2, 3, 4, 8, 10), >2500 (HDAC11)50 (prostate cancer)IC50: 19 to 127 (several prostate and breast cancer cell lines)[136]
Aminoteraline derivative (32)Phe620 and Phe680 of an HDAC6 homology model50126 (HDAC1), 2 (HDAC8)2 (neuroblastoma)IC50 = 5.4 µM (neuroblastoma)[137]
Benzothiophene derivative (39)ND14NDSame effect as tubastatin ADoes not target NF-κB and AP-1 at the transcriptional level[138]
2,4-imidazolinedione derivative (10c)ND4.4218 (HDAC1), 63 (HDAC2), 53 (HDAC3), > 20000 (HDAC4, 7, 8, 9, 11), 3386 (HDAC5), 37 (HDAC10)1.6 (acute myeloid leukemia)IC50: 0.2 to 0.8 µM (various cancer cell lines)[139]
Mercaptoacetamide derivative (2)ND95.334 (HDAC1), 77 (HDAC2), 64 (HDAC8), 112 (HDAC10)NDAt 10 µM protects cortical neurons from oxidative stress inducing death[140]
N-Hydroxycarbonylbenylamino quinoline derivative (13)ND0.29132817 (HDAC1), 42955 (HDAC2), 26632 (HDAC3), 15250 (HDAC4), 10694 (HDAC5), 2436 (HDAC7), 4089 (HDAC8), 5258 (HDAC9), 33646 (HDAC10), 1292 (HDAC11)0.1 (multiple myeloma)IC50: 9.1 to 40.6 µM (multiple myeloma)[141]
Isoxazole-3-hydroxamate derivative (SS-208)His463, Pro464, Phe583, and Leu712 of DD212116 (HDAC1), 1625 (HDAC4), 576 (HDAC5), 695 (HDAC7), 103 (HDAC8), 3183 (HDAC9), 427 (HDAC11)5 (melanoma)ND[142]
Phenothiazine derivative (7i)Phe620 and Phe680 of DD25538 (HDAC1)0.1 (acute myeloid leukemia)ND[143]
Phenylhydroxamate derivative (2)Phe464 and His614 of DD2327 (HDAC1)NDCI50: 0.65 to 2.77 (ovarian cancer and squamous cell carcinoma of the tongue)[133,144]
Phenylsulfonylfuroxan derivative (5c)ND7.433 (HDAC1), 51 (HDAC2), 45 (HDAC3), 4 (HDAC4), 46 (HDAC8), 82 (HDAC11)0.013 (acute myeloid leukemia)IC50: 0.4 to 5.8 µM (various cancer cell lines)[145]
Pyridone derivative (11e)Phe155 and Phe210 of HDAC22.468 (HDAC1), 52 (HDAC2), 127 (HDAC3), 2329 (HDAC4), 785 (HDAC5), 1512 (HDAC7), 77 (HDAC8), 2268 (HDAC9), 21 (HDAC10), 22 (HDAC11)NDIC50: 0.14 to 0.38 µM (various cancer cell lines)[146]
Pyrimidinedione derivative (6)ND12.4138 (HDAC1), 444 (HDAC2)NDInduces arrest of the cell cycle in subG1 phase and death by apoptosis (colon cancer)[138,147]
Quinazolin-4-one derivative (3f)ND2965 (HDAC1), 222 (HDAC2), 60 (HDAC18), 141 (HDAC11)Increases acetylation levels of α-tubulin and histone H3 at 10 μMND[148]
Sulfone derivative (36)ND8138 (HDAC8), 300 (HDAC11)0.01 (unspecified)ND[138]
Trichostatine A derivatives (M344, 16b)ND883 (HDAC1)NDND[149]
Tubacin derivative (WT-161)Phe200, Phe201, Leu270, Arg194 of HDAC70.4129 (HDAC3)0.3 (multiple myeloma)IC50 = 3.6 µM (multiple myeloma)SangtingTaoCI50: 1.5 to 4.7 µM (multiple myeloma cell lines)[150]
Tubastatin A derivative (Marbostat-100)Asp649, His651 et Asp742 of DD20.71106 (HDAC2), 247 (HDAC8)0.05 (acute monocytic leukemia)Non-cytotoxic[151]
Indolylsulfonylcinnamic hydroxamate (12)ND5.260 (HDAC1), 223 (HDAC2)0.1 (colon cancer)IC50: 0.4 to 2.5 µM (multiple cancer cell lines)[152]
MAIP-032DD25838 (HDAC1)NDCI50: 3.87 µM (squamous cell carcinoma line of the tongue)[153]
MPT0G211ND0.291ND0.1 (neuroblastoma)ND[103]
N-hydroxy-4-[(N(2-hydroxyethyl)-2-phenylacetamido)methyl)-benzamide)] (HPB)His573 and His574 of DD23137 (HDAC1)8 (prostate cancer)ND[124,154]
N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB)Binding to zinc ion only via its OH group but does not displace the zinc-bound water molecule5652 (HDAC1)16 (prostate cancer, adenocarcinoma, glioblastoma)Increases the effect on cell viability in combination with etoposide, dexamethasone or SAHA[155,156]
N-hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)-amino)phenoxy)butanamide (23bb)Tyr298 and Glu255 of an HDAC6 homology model1725 (HDAC1), 200 (HDAC8)0.051 (cervical cancer)IC50: 14 to 104 nM (various cancer cell lines)[157]
Nexturastat ADD2 of an HDAC6 homology model5604 (HDAC1)0.01 (murine melanoma)IC50 = 14.3 µM (melanoma)[129,158]
Oxazole hydroxamate (4g)Phe620, Phe680, Leu749, and Tyr782 of DD2 of an HDAC6 homology model59237 (HDAC1, 8)10 (cervical cancer)IC50 = 10.2 µM (acute myeloid leukemia)[159]
Ricolinostat (ACY-1215)DD2 of an HDAC6 homology model4.712 (HDAC1), 10 (HDAC2), 11 (HDAC3), 1490 (HDAC4), 1064 (HDAC5), 298 (HDAC7), 21 (HDAC8), >2000 (HDAC9, 11)0.62 (multiple myeloma)CI50: 2 to 8 µM (multiple myeloma cell lines)[129,160,161]
SahaquineNDNDND0.1 (glioblastoma)CI50: 10 µM (glioblastoma)[162]
TC24Ser568, His610, Phe679 and Tyr782 of HDAC6NDND1 et 10 (gastric cancer)CI50: 10.2 to 17.2 µM (several gastric cancer cell lines)[163]
Tetrahydroisoquinoline (5a)ND361250 (HDAC1), >1000 (HDAC2, 4, 5, 7, 10, 11), 1278 (HDAC3), 58 (HDAC8)0.21 (cervical cancer)ND[135]
ThiazoleND52NDNDND[135]
TubacinDD2 of an HDAC6 homology model4350 (HDAC1)5 (prostate cancer)SangtingTao2.5 (acute lymphoblastic leukemia)IC50: 1.2 to 2 µM (acute lymphoblastic leukemia)[129,164,165]
Tubastatin AHis610, His611, Phe679, Phe680 and Tyr782 of HDAC6151093 (HDAC1)2.5 (unspecified)ND[163,164]
Tubathian AND1.95790 (HDAC1)0.1 (ovarian cancer)ND[166]
Other3-hydroxypyridine-2-thione (3-HPT)Tyr306 of HDAC86815 (HDAC8)NDInactive against two prostate cancer cell lines and one acute T cell leukemia cell line[167]
1-hydroxypyridine-2-thione (1HPT)-6-carboxylic acidDD150287 (HDAC1), 4733 (HDAC2), 473 (HDAC4), 233 (HDAC5), 1933 (HDAC7), 22 (HDAC8), 313 (HDAC9)NDCI50: 18 to 75 µM (leukemia)[168]
Adamantylamino derivative (20a)ND8246 (HDAC1), 51 (HDAC4)NDND[169]
Mercaptoacetamide derivative (2b)ND1.33615 (HDAC1)10 (primary rat cortical culture)ND[170]
Sulfamide derivative (13e)ND440>23 (HDAC1)1 (bladder cancer)ND[171]
Undefined structureCKD-506ND5>400 (HDAC1, 2, 7, 8)0.03 (Human PBMCs)ND[172]
Arg: arginine; Asp: aspartic acid; CI50: concentration inhibiting 50% of cell viability; DD: deacetylase domain; Glu: glutamic acid; HDAC: histone deacetylase; His: histidine; IC50: concentration inhibiting 50% of cell growth; Leu: leucine; ND: non determined; PBMC: peripheral blood mononuclear cell; Phe: phenylalanine; Pro: proline; Ser: serine; Tyr: tyrosine.
Table
Table 9. HDAC6 Inhibitors in Clinical Trials in Cancer. Clinical studies include four phases. Phase I is performed on healthy volunteers to determine the maximum tolerated dose in humans. Phase II is performed on a limited patient population to determine the optimal dosage. Phase III is performed on several thousand patients and will demonstrate the therapeutic value of the drug and assess its benefit/risk. Phase IV is performed once the drug is marketed and allows to better characterize its adverse effects.
Table 9. HDAC6 Inhibitors in Clinical Trials in Cancer. Clinical studies include four phases. Phase I is performed on healthy volunteers to determine the maximum tolerated dose in humans. Phase II is performed on a limited patient population to determine the optimal dosage. Phase III is performed on several thousand patients and will demonstrate the therapeutic value of the drug and assess its benefit/risk. Phase IV is performed once the drug is marketed and allows to better characterize its adverse effects.
HDAC6 InhibitorClinical Trial IdentificationPhase of the Clinical TrialPathology
ACY-241NCT02400242Ia/IbMultiple myeloma
NCT02935790IbStage III and IV unresectable melanoma
NCT02551185IbAdvanced solid tumors
NCT02635061IbNon-resectable non-small cell lung cancer
ACY-1215NCT02632071IbUnresectable or metastatic breast cancer
NCT02787369IbRelapsed chronic lymphocytic leukemia
NCT02091063Ib/IIRelapsed or refractory lymphoid malignancies
NCT01997840Ib/IIRecurrent and refractory multiple myeloma
NCT01583283I/IIMultiple myeloma recurrent or recurrent and refractory
NCT02189343IbRecurrent and refractory multiple myeloma
NCT01323751I/IIMultiple myeloma recurrent or recurrent and refractory
NCT02856568IbUnresectable or metastatic cholangiocarcinoma
NCT02661815IbOvarian cancer, primary peritoneal cancer or platinum-resistant fallopian tubes

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Losson, H.; Schnekenburger, M.; Dicato, M.; Diederich, M. HDAC6—An Emerging Target Against Chronic Myeloid Leukemia? Cancers 2020, 12, 318. https://doi.org/10.3390/cancers12020318

AMA Style

Losson H, Schnekenburger M, Dicato M, Diederich M. HDAC6—An Emerging Target Against Chronic Myeloid Leukemia? Cancers. 2020; 12(2):318. https://doi.org/10.3390/cancers12020318

Chicago/Turabian Style

Losson, Hélène, Michael Schnekenburger, Mario Dicato, and Marc Diederich. 2020. "HDAC6—An Emerging Target Against Chronic Myeloid Leukemia?" Cancers 12, no. 2: 318. https://doi.org/10.3390/cancers12020318

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