Histone deacetylase (HDAC) 6 is a zinc-dependent enzyme of HDAC class IIb. HDAC6 is unique within the HDAC family due to a particular structure giving it unique biological functions implicated in all major cell pathways. This isoenzyme is mainly active in the cytoplasm and possesses two functional catalytic sites and an ubiquitin-binding domain. The deacetylase functions of HDAC6 targets multiple substrates including essentially α-tubulin and heat shock protein (HSP)90α which are key factors in cell regulatory networks through the regulation of the microtubule network and many protein functions, respectively. Accordingly, several studies have highlighted the role of HDAC6 in various pathological conditions. For instance HDAC6 overexpression frequently correlates with tumorigenesis and favor cell survival and metastasis. Therefore, HDAC6 represents an interesting potential therapeutic target.
Carcinogenesis is a multistep process whereby normal cells are transformed into malignant cells. The process is characterized by major biological changes shared by most neoplastic cells called hallmarks of cancer. These transformational events relies on multiple alterations at genetic and epigenetic levels leading to abnormal cell growth [DOI: 10.2174/1568026615666150825141330].
Over the past years protein lysine acetylation has emerged as a key post-translational modification in the coordination of tightly regulated biological functions and alterations of the acetylome profiles are associated with various pathological conditions such as cancer.
The acetylation status of lysine residues within histone and non-histone proteins is finely tuned by the concert action of histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyzing the addition and removal of the acetyl groups, respectively. Recently, there was a particular focus on HDAC6 coming from its unique properties to control multiple cellular pathways linked to cell growth, survival, and migration. Accordingly, the use of HDAC6 inhibitors alone or in combination with additional chemotherapeutic agents appear as a promising strategy to treat various cancers.
|Substrates||Localization of the Substrate||Deacetylated Lysine(s)||Function of the Deacetylated Substrate||Interaction Domains of HDAC6||Reference|
|Post-Translational Modification||Enzyme||Target Site||Consequences||Reference|
|14-3-3ζ||Cytoplasm and nucleus|
|Phosphorylation||GSK3β||Ser-22||Increased deacetylation activity of α-tubulin|||
|CYLD||Deubiquitinase||49, 120||NDRegulation of protein binding Bad and AS160||ND||ND||DD1/DD2[11||Cell proliferation, ciliogenesis10]|
|[||10||9||]||65||19 (HDAC1)||10 (lung cancer)||CI50 = 8.2 µM (cervical cancer)||||β-catenin||Cytoplasm and nucleus||49||Epidermal growth factor-induced nuclear localization and decreased expression of c-Myc||ERK1ND||Ser-1035|
|Regulation of cellular motility||[||10||9]|
|Dysferlin||Skeletal muscle membrane repair, myogenesis, cell adhesion, intercellular calcium signaling|
|Domain C2||ND||Myogenesis||[||NQN-1 (2-benzyl-amino-naphthoquinone)34||ND33||5540]||Values non available (HDAC1, 2, 3, 4, 5, 7, 8, 9, 10, 11)||4 (chronic myeloid leukemia)||CI50 = 0.8 µM (leukemia)||||Cortactin *||Cytoplasm||87, 124, 161, 189, 198, 235, 272, 309, 319||Regulation of cell migration and actin filament binding||DD1 and DD2||GRK2||ND||Increased deacetylation activity of α-tubulin|||
|Mdp3||Stabilization factor of microtubules||Amino-terminal region||ND||Cell motility||||DNAJA1||Cytoplasm||ND||Protein folding||ND|||
|Aurora||ND||Increased deacetylation activity of α-tubulin||[||ERK1||Cytoplasm and nucleus||72||Proliferation, mobility, and cell survival||ND|||
|Paxillin||Focal adhesion||Region rich in proline||ND||Polarization and cell migration||||PKCζ||ND||Increased deacetylation activity of α-tubulin||||Foxp3 *|
|CK2||Nucleus||ND||ND||ND||Ser-458||Improved formation and elimination of aggresomes||[|
|EGFR||Tyr-570||Inhibition of deacetylation activity|||
|Acetylation||p300||Lys-16||Inhibition of deacetylation activity|||
|Protein Inhibiting HDAC6 by Direct Interaction||Protein Function||Protein Region Required for Interaction with HDAC6||HDAC6 Domain Interacting with the Protein||Cellular Impact||References|
. 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 , its involvement in oncogenic cell transformation, tumor development, and cancer immunity regulation makes a strong therapeutic candidate .
|Cancer Type||Cancers||Expression of HDAC6-Comments||References|
|Class||HDAC6 Inhibitor||Binding Domain||CI50 (nM) of the HDAC6 Activity in Vitro||Selectivity Ratio for HDAC6 Compared to (Other HDACs)||Inhibition of HDAC6 in Cellulo (µM)$||Effect on Cancer Cell Lines or Cancer Type||References|
|Oral squamous cell carcinoma||Overexpressed-Enhanced expression in advanced stages|||
|p62||Transport of misfolded proteins||Between the ZZ domain and the TRAF6 link area||DD2||Aggresome formation|||
|Ovarian carcinoma||Overexpressed-Enhanced expression in advanced stages||||14||13||]|
|Hydroxamates||Hydroxamic acid containing a phenylalanine (4n)||His215, His216, Tyr386, Phe283, and Tyr255 of DD1 and His610, His611, Tyr782, Phe620, and Phe680 of an HDAC6 homology model||1690||14 (HDAC1)||1 (colorectal carcinoma)||IC50: 3 to > 50 µM (various cancer cell lines)||[4948|
|>400 (HDAC1, 2, 7, 8)|
|0.03 (Human PBMCs)|
|HDAC6 Inhibitor||Clinical Trial Identification||Phase of the Clinical Trial||Pathology|
|NCT02935790||Ib||Stage III and IV unresectable melanoma|
|NCT02551185||Ib||Advanced solid tumors|
|NCT02635061||Ib||Non-resectable non-small cell lung cancer|
|ACY-1215||NCT02632071||Ib||Unresectable or metastatic breast cancer|
|RanBPM||Apoptosis, proliferation and cell migration||ND||Aggresome formation|||
|HDAC9||Cytoplasm and nucleus||ND||Modulation of cell survival and arrest of cellular movement||DD2|||
|Breast||Overexpressed-Prediction of a good or bad prognosis||||Tau||Stabilization factor of microtubules||Tubulin binding region||SE14 domain||Aggresome formation||||Transcriptional activation of interleukin 10||ND|
|Hepatocytic carcinoma||TPPP1||Polymerization and acetylation of microtubules||[||16||15]|
|ND||Regulation of microtubule acetylation and β-catenin expression||[||39||38||]||HMGN2||Nucleus||2||Increased transcription of STAT5||ND||[|
|Hydroxamic acid containing a pyridylalanine (5a)||Phe566 of DD2 of an HDAC6 homology model||3970||25 (HDAC1)||ND||IC||50: 104 µM (breast cancer)|||
|ACY-738||ND||1.7||55 (HDAC1), 75 (HDAC2), 128 (HDAC3)||2.5 (neural cells)||ND|||
|ND||7.5||NCT02787369||283 (HDAC1), 343 (HDAC2), 1496 (HDAC3)||2.5 (neural cells)||ND||||Overexpressed-Enhanced expression in advanced stages||[2827|
|Relapsed chronic lymphocytic leukemia||ACY-1083||His573 and His574 of DD2||3||260 (HDAC1)||0.03 (neuroblastoma)||ND||[52|
|NCT02091063||51||]||[||53||52||]||Ib/II||Relapsed or refractory lymphoid malignancies||Under-expressed-HDAC6 suggested as a tumor suppressor||||1716]|
|Bavarostat||Ser568 of DD2||60||>10000 (HDAC1, 2, 3), 188 (HDAC4), 317 (HDAC5), 78 (HDAC7), 142 (HDAC8), 87 (HDAC9), >17 (HDAC10), 167 (HDAC11)||Hematological||Chronic lymphocytic leukemia||Overexpressed-Observation on patient samples, cell lines and a transgenic mouse model||||HSC70||Cytoplasm||ND||Protein folding||ND|||
|10 (neural progenitor cells derived from induced pluripotent stem cells)||ND||[||54||53||]|
|BRD9757||ND||30||21 (HDAC1), 60 (HDAC2), 23 (HDAC3), 727 (HDAC4), 611 (HDAC5), 420 (HDAC7), 36 (HDAC8), >1000 (HDAC9)||10 (cervical cancer)||ND||||Acute myeloid leukemia||Overexpressed||[4241|
|]||Cay10603||His499 of DD2 of an HDAC6 homology model||0.002||ND||<1 to 1 µM (several pancreatic cancer cell lines)||ND||[5655|
|NCT01997840||Ib/II||Recurrent and refractory multiple myeloma||]||[|
|NCT01583283||I/II||Multiple myeloma recurrent or recurrent and refractory||57||56||]|
|NCT02189343||Ib||Recurrent and refractory multiple myeloma||HSPA5|
|Cytoplasm||353||NCT01323751Ubiquitination of HSPA5 mediated by GP78||ND|||
|Acute lymphoblastic leukemia||Overexpressed-Enhanced expression in advanced stages|
|[||28||Citarinostat (ACY-241)27]||ND||2.6||14 (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)||||I/II||Multiple myeloma recurrent or recurrent and refractory||HSP90α||Cytoplasm|
|α3β-cyclic tetrapeptide (23)||294||Degradation and elimination of misfolded proteins and regulation of glucocorticoid receptors||DD1, DD2 et BUZ||ND||39|
|Chronic lymphocytic leukemia||Overexpressed-Correlated with longer survival||[2827||3 (HDAC1), 4 (HDAC3), 6 (HDAC8)||2 (acute lymphoblastic leukemia)||IC||50: 9 to > 20 µM (various cancer cell lines)|||
|K-RAS *||Cytoplasm||104||Cell proliferation||ND|||
|NCT02856568||T-cell cutaneous lymphoma|
|Ib||Overexpressed-Correlated with longer survival||Compound containing a phenylisoxazole group as a surface recognition group (7)||His499 of HDAC7||0.002||>100000 (HDAC1), >100000 (HDAC2), 210 (HDAC3), >3000000 (HDAC8), 45350 (HDAC10)||ND||IC50: 0.1 to 1 µM (various prostate cancer cell lines)||[5655||Ku70||Cytoplasm||539, 542||Suppression of apoptosis|
|]||Chronic myeloid leukemia||ND||Overexpressed-Increased expression in CD34+||[||98]|
|Compound containing a triazolylphenyl group (6b)||ND||1.9||52 (HDAC1), 155 (HDAC2), 7 (HDAC3), 420 (HDAC8), 59 (HDAC10)||ND||IC50: <0.5 to 22 µM (several prostate cancer lines)||||LC3B-II*||Cytoplasm||ND||Regulation of autophagy||ND|||
|Compound containing a peptoid (2i)||Tyr301 of DD2 of an HDAC6 homology model||1.59||126 (HDAC2), >6000 (HDAC4), 40 (HDAC11)||N||IC50: 0.34 to 2.7 µM (various cancer cell lines)||[||MSH2||Cytoplasm and nucleus||845, 847, 871, 892||Reduced cellular sensitivity to DNA damaging agents and reduced DNA mismatch repair activities by downregulation of MSH2||DD1|||
|61||60||]||Mantle cell lymphoma||Overexpressed||||MYH9||Cytoplasm||ND|
|3-aminopyrrolidinone derivative (33)||ND||17||4359 (HDAC1), 11 (HDAC8)||0.3 (multiple myeloma)||Good oral bioavailability||||Regulation of binding to actin filaments||ND|||
|PrxI||Cytoplasm and nucleus|
|Diffuse large B cell lymphoma||Overexpressed|
|[||46||4-aminomethylaryl acid derivative (1a)45]||ND||19||305 (HDAC1), 842 (HDAC2), 237 (HDAC3), 790 (HDAC4), 174 (HDAC5), 242 (HDAC7), 36 (HDAC8), 195 (HDAC0)||0.46 (cervical cancer)||ND||197||Antioxidant activity||ND|||
|[||63||62||]||Peripheral T-cell lymphoma||Overexpressed|||
|4-hydroxybenzoic acid derivative (7b)||ND||200||>50000 (HDAC1, 2, 8), >500000 (HDAC3, 10, 11)||50 (prostate cancer)||IC50: 41 to 130 (several prostate and breast cancer cell lines)||||PrxII||Cytoplasm and nucleus||196||Antioxidant activity||ND||[22|
|4-hydroxybenzoic acid derivative (13a)||21||ND||]||[||200002322]|
|25 (HDAC1), >5000 (HDAC2, 3, 4, 8, 10), >2500 (HDAC11)||50 (prostate cancer)||IC||50||: 19 to 127 (several prostate and breast cancer cell lines)||[||64||63]||RIG-I||Cytoplasm||858, 909||Recognition of viral RNA||ND|||
|Aminoteraline derivative (32)||Phe620 and Phe680 of an HDAC6 homology model||50||126 (HDAC1), 2 (HDAC8)||2 (neuroblastoma)||IC50 = 5.4 µM (neuroblastoma)|||
|Benzothiophene derivative (39)||ND||14||ND||Same effect as tubastatin A||Does not target NF-κB and AP-1 at the transcriptional level||||Nucleus||129||Anti-apoptotic function||DD2|
|2,4-imidazolinedione derivative (10c)||[||ND||9||8]|
|4.4||218 (HDAC1), 63 (HDAC2), 53 (HDAC3), > 20000 (HDAC4, 7, 8, 9, 11), 3386 (HDAC5), 37 (HDAC10)||1.6 (acute myeloid leukemia)||IC||50||: 0.2 to 0.8 µM (various cancer cell lines)||[||6766]||Tat||Cytoplasm||28||Suppression of HIV transactivation||DD2 and BUZ|||
|α-tubulin *||Cytoplasm||40||Formation of immune synapses, viral infection, cell migration and chemotaxis||DD1 or DD2|||
|Benzamides||Trithiocarbonate derivative (12ac)|
|Unresectable or metastatic cholangiocarcinoma|
|Ovarian cancer, primary peritoneal cancer or platinum-resistant fallopian tubes|
|Mercaptoacetamide derivative (2)|
|34 (HDAC1), 77 (HDAC2), 64 (HDAC8), 112 (HDAC10)|
|ND||At 10 µM protects cortical neurons from oxidative stress inducing death||[||68||67||]|
|N-Hydroxycarbonylbenylamino quinoline derivative (13)||ND||0.291||32817 (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)|||
|Isoxazole-3-hydroxamate derivative (SS-208)||His463, Pro464, Phe583, and Leu712 of DD2||12||116 (HDAC1), 1625 (HDAC4), 576 (HDAC5), 695 (HDAC7), 103 (HDAC8), 3183 (HDAC9), 427 (HDAC11)||5 (melanoma)||ND|||
|Phenothiazine derivative (7i)||Phe620 and Phe680 of DD2||5||538 (HDAC1)||0.1 (acute myeloid leukemia)||ND|||
|Phenylhydroxamate derivative (2)||Phe464 and His614 of DD2||3||27 (HDAC1)||ND||CI50: 0.65 to 2.77 (ovarian cancer and squamous cell carcinoma of the tongue)|||
|Phenylsulfonylfuroxan derivative (5c)||ND||7.4||33 (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)|||
|Pyridone derivative (11e)||Phe155 and Phe210 of HDAC2||2.46||8 (HDAC1), 52 (HDAC2), 127 (HDAC3), 2329 (HDAC4), 785 (HDAC5), 1512 (HDAC7), 77 (HDAC8), 2268 (HDAC9), 21 (HDAC10), 22 (HDAC11)||ND||IC50: 0.14 to 0.38 µM (various cancer cell lines)|||
|Pyrimidinedione derivative (6)||ND||12.4||138 (HDAC1), 444 (HDAC2)||ND||Induces arrest of the cell cycle in subG1 phase and death by apoptosis (colon cancer)|||
|Quinazolin-4-one derivative (3f)||ND||29||65 (HDAC1), 222 (HDAC2), 60 (HDAC18), 141 (HDAC11)||Increases acetylation levels of α-tubulin and histone H3 at 10 μM||ND|||
|Sulfone derivative (36)||ND||8||138 (HDAC8), 300 (HDAC11)||0.01 (unspecified)||ND|||
|Trichostatine A derivatives (M344, 16b)||ND||88||3 (HDAC1)||ND||ND|||
|Tubacin derivative (WT-161)||Phe200, Phe201, Leu270, Arg194 of HDAC7||0.4||129 (HDAC3)||0.3 (multiple myeloma)||IC50 = 3.6 µM (multiple myeloma)SangtingTaoCI50: 1.5 to 4.7 µM (multiple myeloma cell lines)|||
|Tubastatin A derivative (Marbostat-100)||Asp649, His651 et Asp742 of DD2||0.7||1106 (HDAC2), 247 (HDAC8)||0.05 (acute monocytic leukemia)||Non-cytotoxic|||
|Indolylsulfonylcinnamic hydroxamate (12)||ND||5.2||60 (HDAC1), 223 (HDAC2)||0.1 (colon cancer)||IC50: 0.4 to 2.5 µM (multiple cancer cell lines)|||
|MAIP-032||DD2||58||38 (HDAC1)||ND||CI50: 3.87 µM (squamous cell carcinoma line of the tongue)|||
|N-hydroxy-4-[(N(2-hydroxyethyl)-2-phenylacetamido)methyl)-benzamide)] (HPB)||His573 and His574 of DD2||31||37 (HDAC1)||8 (prostate cancer)||ND|||
|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 molecule||56||52 (HDAC1)||16 (prostate cancer, adenocarcinoma, glioblastoma)||Increases the effect on cell viability in combination with etoposide, dexamethasone or SAHA|||
|N-hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)-amino)phenoxy)butanamide (23bb)||Tyr298 and Glu255 of an HDAC6 homology model||17||25 (HDAC1), 200 (HDAC8)||0.051 (cervical cancer)||IC50: 14 to 104 nM (various cancer cell lines)|||
|Nexturastat A||DD2 of an HDAC6 homology model||5||604 (HDAC1)||0.01 (murine melanoma)||IC50 = 14.3 µM (melanoma)|||
|Oxazole hydroxamate (4g)||Phe620, Phe680, Leu749, and Tyr782 of DD2 of an HDAC6 homology model||59||237 (HDAC1, 8)||10 (cervical cancer)||IC50 = 10.2 µM (acute myeloid leukemia)|||
|Ricolinostat (ACY-1215)||DD2 of an HDAC6 homology model||4.7||12 (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)|||
|Sahaquine||ND||ND||ND||0.1 (glioblastoma)||CI50: 10 µM (glioblastoma)|||
|TC24||Ser568, His610, Phe679 and Tyr782 of HDAC6||ND||ND||1 et 10 (gastric cancer)||CI50: 10.2 to 17.2 µM (several gastric cancer cell lines)|||
|Tetrahydroisoquinoline (5a)||ND||36||1250 (HDAC1), >1000 (HDAC2, 4, 5, 7, 10, 11), 1278 (HDAC3), 58 (HDAC8)||0.21 (cervical cancer)||ND|||
|Tubacin||DD2 of an HDAC6 homology model||4||350 (HDAC1)||5 (prostate cancer)SangtingTao2.5 (acute lymphoblastic leukemia)||IC50: 1.2 to 2 µM (acute lymphoblastic leukemia)|||
|Tubastatin A||His610, His611, Phe679, Phe680 and Tyr782 of HDAC6||15||1093 (HDAC1)||2.5 (unspecified)||ND|||
|Tubathian A||ND||1.9||5790 (HDAC1)||0.1 (ovarian cancer)||ND|||
|Other||3-hydroxypyridine-2-thione (3-HPT)||Tyr306 of HDAC8||681||5 (HDAC8)||ND||Inactive against two prostate cancer cell lines and one acute T cell leukemia cell line|||
|1-hydroxypyridine-2-thione (1HPT)-6-carboxylic acid||DD||150||287 (HDAC1), 4733 (HDAC2), 473 (HDAC4), 233 (HDAC5), 1933 (HDAC7), 22 (HDAC8), 313 (HDAC9)||ND||CI50: 18 to 75 µM (leukemia)|||
|Adamantylamino derivative (20a)||ND||82||46 (HDAC1), 51 (HDAC4)||ND||ND|||
|Mercaptoacetamide derivative (2b)||ND||1.3||3615 (HDAC1)||10 (primary rat cortical culture)||ND|||
|Sulfamide derivative (13e)||ND||440||>23 (HDAC1)||1 (bladder cancer)||ND|||
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 , chronic lymphocytic leukemia , acute myeloid leukemia (AML) , acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) [doi: 10.1016/j.phrs.2020.105058].
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 heat shock protein (HSP90)α, which is involved in the stabilization of the oncogenic tyrosine kinase breakpoint cluster region-Abelson (BCR-ABL) protein   protein. In the acetylated form, HSP90α loses its chaperone function, which leads to the degradation of its client proteins by the proteasome (Figure 3A). 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].
HDAC6 is upregulated in CLL patient samples, cell lines, and euTCL1 transgenic mouse models compared to normal controls. Accordingly, this pathology could be an interesting target for selective HDAC6 inhibitors, as genetic silencing of HDAC6 improves the survival of euTCL1 mice. Moreover, the chemical inhibitor ACY738 reduces the proliferation of CLL B cells leading to their apoptosis. Together with ibrutinib, this HDAC6 inhibitor triggers synergistic cell death in vivo [doi:10.3389/fimmu.2020.590072]. Beyond the direct effect on pathological B cells, HDAC6 inhibition improves CLL-induced immunosuppression of CLL T cells. HDAC6 inhibitors enhances immune checkpoint blockade in CLL so that combination treatment with ACY738 potentializes the in vivo antitumor effect of anti-PD-1 and anti-PD-L1 antibody treatments with increased cytotoxic CD8+ T cells [doi:10.3389/fimmu.2020.590072].
Several HDAC6 inhibitors were assessed as single agents in AML. The HDAC6 inhibitor ST80 shows potent antileukemic activity in myeloid cell lines and primary AML blasts at low micromolar concentrations, leading to preferential acetylation of a-tubulin [doi:10.1016/j.leukres.2012.02.026]. HDAC inhibitors with a central naphthoquinone structure selectively inhibit HDAC6 in the AML cell line MV4-11, further decreasing mutant FLT-3 protein and constitutively active signal transducer and activators of transcription (STAT)5 levels and reducing extracellular regulated kinase (ERK) phosphorylation [doi:10.1021/cb200134p]. HDAC inhibitors with the 2-(oxazol-2-yl)phenol moiety as a novel zinc-binding group exhibited selective inhibition against HDAC1 and class IIb HDACs (HDAC6 and HDAC10) in the MV-4-11 AML cells [doi:10.1039/C4MD00401A]. The in vivo potency of the selective and orally-available HDAC6 inhibitor N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide 23bb was better against MV4-11 AML cells compared to SAHA or ACY-1215 [doi:10.1021/acs.jmedchem.5b01342]. The O-aminobenzamide-based HDAC inhibitor compound 13e down-regulates HDAC6 in MV4-11 cells. 13e induces apoptotic cell death and cycle arrest most likely mediated by a p53-dependent pathway [doi:10.1021/acs.jmedchem.8b00136]. The parthenolide-SAHA hybrid compound 26 more potently reduces the viability of the resistant HL-60/ADR AML cell line compared to SAHA, triggering intrinsic apoptosis and reducing the protein expression levels of HDAC1, HDAC6 and the multidrug resistance-associated protein 1 (ABCC1) leading to an intracellular accumulation of drugs [doi:10.1016/j.bioorg.2019.03.056]. The HDAC6-selective inhibitor PTG-0861 induces apoptosis in MV4-11 AML cells with limited cytotoxicity against non-malignant cells [doi:10.1016/j.ejmech.2020.112411].
In AML, inhibition of HDAC6 was essentially investigated in combination with other pharmacologically active compounds at a pre-clinical level. For instance, a combination of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a synthetic derivative of the ansamycin benzoquinone antibiotic geldanamycin, with the HDAC6 inhibitor tubacin reduces the viability of primary AML samples, validating HDAC6 as a HSP90 client protein also in AML and that its hyperacetylation facilitates the anticancer potential of 17-AAG [doi:10.1182/blood-2008-03-143644]. LBH-589 and PXD101 inhibit HDAC1 and HDAC6 and synergize with cytarabine to induce cell death in pediatric AML, accompanied by DNA damage induction and increased Bim expression levels [doi:10.1371/journal.pone.0017138]. Similarly, Bim protein induction and inhibition of nuclear factor-kappa B (NF-kB) pathway were identified as a mechanistic basis for the synergistic anti-cancer effects of belinostat in combination with the proteasome inhibitor bortezomib in AML and ALL cells [doi:10.1111/j.1365-2141.2011.08591.x]. The selective JAK2/HDAC6 dual inhibitor 20a shows excellent in vivo antitumor efficacy in HEL AML mouse xenograft assays and synergizes with the antifungal drug fluconazole [doi:10.1021/acs.jmedchem.8b00393]. The selective HDAC6 inhibitor MPT0G211 combined with doxorubicin displays anti-cancer effect by inducing a DNA damage response associated with increased Ku70 acetylation and BAX activation in HL-60 and MOLT-4 AML cell lines. Accordingly, ectopic expression of HDAC6 successively reverses the apoptosis triggered by the combined treatment [doi:10.1186/s13148-018-0595-8].
The HDAC6 inhibitor tubacin enhances the anti-cancer effects of the Na+/K+-ATPase inhibitor ouabain or the proteasome inhibitor MG-13 against pre-B and T ALL cells in vitro and in vivo. These results suggest that selectively targeting HDAC6 alone or in combination with conventional chemotherapeutic drugs could provide a novel approach for ALL therapy [doi:10.3109/10428194.2011.570821]. Similarly, belinostat synergizes with the proteasome inhibitor bortezomib to kill ALL cells through Bim up-regulation and NF-kB inhibition. Altogether the perturbation of intracellular microtubular transport network, combined with the interference with protein homeostasis via proteasomal inhibition, could be a general and efficient mechanism explaining the synergistic effect observed [doi:10.1111/j.1365-2141.2011.08591.x]. MPT0G211 combined with vincristine interrupts ALL mitosis via interference with microtubular dynamics leading to apoptosis. In vivo, MPT0G211 plus doxorubicin or vincristine reduces tumor growth xenograft models [doi:10.1186/s13148-018-0595-8].
Remarkably, it has been shown that the inhibition of HDAC6 using either the pan-HDAC inhibitor trichostatin, the selective HDAC6 inhibitor tubacin, or a genetic knock-down efficiently reduces Notch3 signaling through a post-translational-mediated protein down-regulation, leading to enhanced apoptosis in T-ALL cells and impairing leukemia growth in mice xenografted with T-ALL cell lines and primary human T-ALL cells. These results highlights the therapeutic potential of HDAC6 targeting in Notch3-addicted tumors [doi:10.1038/s41388-018-0234-z].
Inhibition of HDAC6 activity increases CD20 levels in B-cell tumor cell lines and malignant patient cells, potentializing the in vivo effect of anti-CD20 monoclonal antibodies like rituximab. Translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition as CD20 mRNA was abundant within the polysomal fraction, indicating a post-transcriptional function of HDAC6. Collectively, these findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors [doi:10.1002/mc.22983].
The HDAC6 inhibitor A452 combined with the Bruton's tyrosine kinase inhibitor ibrutinib efficiently kills non-Hodgkin lymphoma cells, including follicular lymphoma [doi:10.1002/mc.22983].
The HDAC6 inhibitor KT-531 displays the highest anti-cancer potency against T-cell prolymphocytic leukemia (T-PLL) cells compared to other hematological neoplasms, together with safe differential toxicity compared to non-transformed cell lines. Accordingly, HDAC6 is overexpressed in primary T-PLL patient samples in which KT-531 exerts a potent anti-cancer activity. Moreover, a combination of KT-531 with various approved drugs including bendamustine, idasanutlin, and venetoclax shows promising synergistic effects against T-PLL patient cells [doi:10.1021/acs.jmedchem.1c00420].