Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Can Mediate Neuroprotection Independent of HDAC Inhibition

Histone deacetylase (HDAC) is a clinically validated target for anti-tumor therapy. In order to increase HDAC inhibition and efficiency, we developed a series of novel substituted purine hydroxamic acids as potent HDAC inhibitors.

Download Full-text

Histone Deacetylase Inhibitors: Synthesis of Tetrapeptide Analogue SAHA/TPX

E-Journal of Chemistry ◽

10.1155/2011/572546 ◽

2011 ◽

Vol 8 (s1) ◽

pp. S79-S84

Author(s):

Lynda Ekou ◽

Tchirioua Ekou ◽

Isabelle Opalinski ◽

Jean Pierre Gesson

Keyword(s):

Clinical Trial ◽

Cancer Therapy ◽

Phase I ◽

Histone Deacetylase ◽

Hydroxamic Acid ◽

Histone Deacetylase Inhibitors ◽

Hdac Inhibitors ◽

Growth Arrest ◽

Suberoylanilide Hydroxamic Acid ◽

Specific Inhibitors

The inhibition of HDAC (histone deacetylase) activity by specific inhibitors induces growth arrest, differentiation and apoptosis of transformed or several cancer cells. Some of these inhibitors are in clinical trial at phase I or phase II. The discovery and development of specific HDAC inhibitors are helpful for cancer therapy. In this paper we describe the synthesis of simple inhibitorBhybrid analogue suberoylanilide hydroxamic acid (SAHA), trapoxinB(TPX B) in as little as five steps. This compound is interesting lead for the design of potent inhibitors of histone deacetylase.

Download Full-text

Discovery, Synthesis, and Pharmacological Evaluation of Spiropiperidine Hydroxamic Acid Based Derivatives as Structurally Novel Histone Deacetylase (HDAC) Inhibitors

Journal of Medicinal Chemistry ◽

10.1021/jm200146u ◽

2011 ◽

Vol 54 (8) ◽

pp. 3051-3064 ◽

Cited By ~ 38

Author(s):

Mario Varasi ◽

Florian Thaler ◽

Agnese Abate ◽

Chiara Bigogno ◽

Roberto Boggio ◽

...

Keyword(s):

Histone Deacetylase ◽

Hydroxamic Acid ◽

Hdac Inhibitors ◽

Pharmacological Evaluation

Download Full-text

ITF2357, a Novel Histone Deacetylase Inhibitor, Demonstrates Significant Apoptotic Activity Against Human Multiple Myeloma Cells.

Blood ◽

10.1182/blood.v110.11.4791.4791 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4791-4791

Author(s):

Michael Kline ◽

Kathleen A. Donovan ◽

John A. Lust

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Histone Deacetylase ◽

Cell Lines ◽

Hydroxamic Acid ◽

Stromal Cell ◽

Hdac Inhibitors ◽

Annexin V ◽

Myeloma Cells

Abstract We have evaluated the efficacy of a novel hydroxamic acid-derived histone deacetylase (HDAC) inhibitor, ITF2357, to promote cell death in multiple myeloma (MM) cells. HDAC inhibitors, which promote histone hyperacetylation and increase gene expression, have been evaluated as candidate agents for combating malignancies because they impact the expression of genes related to proliferation, differentiation, and survival. Exposure of MM cell lines to 1 micromolar ITF2357 led to dramatically increased levels of histone acetylation at 4 hours and 8 hours by Western analysis. Sub-micromolar concentrations of ITF2357 promoted time- and concentration-dependent cell death in MM cell lines. Using 500 nM ITF2357, a concentration potentially achievable in vivo, viability of KAS-6/1 IL-6 dependent myeloma cells was reduced to 28% of control at 24 hrs and 2% of control at 48 hours (Figure 1). In contrast, viability of normal PBMCs was 100% at 24 hours and 80% at 48 hours (Figure 2). U266 and 8226 myeloma cells were found to be sensitive to ITF-2357 in a similar fashion with U266 being least sensitive. Cell death proceeded via apoptosis as measured using Annexin V/propidium iodide staining. ITF 2357 was superior to suberoylanilide hydroxamic acid (SAHA) at inhibition of stromal cell IL-6 production. IL-1beta (10 pg/ml) was used to stimulate bone marrow stromal cell IL-6 production (105 ng/ml) after 48 hours. Concentration of ITF2357:Stromal Cell IL-6 production after 48 hours were as follows - 10 nM: 78 ng/ml; 100 nM: 79 ng/ml; 1000 nM; 32 ng/ml. SAHA at similar concentrations showed no significant decrease in stromal cell IL-6 production compared with the no drug control. In summary, ITF2357 induces significant myeloma cell apoptosis and can inhibit stromal cell IL-6 production. It represents an attractive therapeutic candidate for MM clinical trials. Figure Figure Figure Figure

Download Full-text

Changes in cardiac Nav1.5 expression, function, and acetylation by pan-histone deacetylase inhibitors

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00156.2016 ◽

2016 ◽

Vol 311 (5) ◽

pp. H1139-H1149 ◽

Cited By ~ 7

Author(s):

Qin Xu ◽

Dakshesh Patel ◽

Xian Zhang ◽

Richard D. Veenstra

Keyword(s):

Histone Deacetylase ◽

Hdac Inhibitor ◽

Qt Interval ◽

Trichostatin A ◽

Hdac Inhibitors ◽

Mrna Levels ◽

Hdac Inhibition ◽

Interval Prolongation ◽

Protein Levels ◽

Qt Interval Prolongation

Histone deacetylase (HDAC) inhibitors are small molecule anticancer therapeutics that exhibit limiting cardiotoxicities including QT interval prolongation and life-threatening cardiac arrhythmias. Because the molecular mechanisms for HDAC inhibitor-induced cardiotoxicity are poorly understood, we performed whole cell patch voltage-clamp experiments to measure cardiac sodium currents ( INa) from wild-type neonatal mouse ventricular or human-induced pluripotent stem cell-derived cardiomyocytes treated with trichostatin A (TSA), vorinostat (VOR), or romidepsin (FK228). All three pan-HDAC inhibitors dose dependently decreased peak INa density and shifted the voltage activation curve 3- to 8-mV positive. Increases in late INa were not observed despite a moderate slowing of the inactivation rate at low activating potentials (<−40 mV). Scn5a mRNA levels were not significantly altered but NaV1.5 protein levels were significantly reduced. Immunoprecipitation with anti-NaV1.5 and Western blotting with anti-acetyl-lysine antibodies indicated that NaV1.5 acetylation is increased in vivo after HDAC inhibition. FK228 inhibited total cardiac HDAC activity with two apparent IC50s of 5 nM and 1.75 μM, consistent with previous findings with TSA and VOR. FK228 also decreased ventricular gap junction conductance ( gj), again consistent with previous findings. We conclude that pan-HDAC inhibition reduces cardiac INa density and NaV1.5 protein levels without affecting late INa amplitude and, thus, probably does not contribute to the reported QT interval prolongation and arrhythmias associated with pan-HDAC inhibitor therapies. Conversely, reductions in gj may enhance the occurrence of triggered activity by limiting electrotonic inhibition and, combined with reduced INa, slow myocardial conduction and increase vulnerability to reentrant arrhythmias.

Download Full-text

Releasing the brakes on BTK-targeting miRNA

Blood ◽

10.1182/blood-2016-11-748145 ◽

2016 ◽

Vol 128 (26) ◽

pp. 3023-3024

Author(s):

Matthew D. Blunt ◽

Andrew J. Steele

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tyrosine Kinase ◽

Histone Deacetylase ◽

Hdac Inhibitors ◽

Lymphocytic Leukemia ◽

Hdac Inhibition ◽

Bruton Tyrosine Kinase

In this issue of Blood, Bottoni et al demonstrate that histone deacetylase (HDAC) inhibition promotes the upregulation of microRNAs (miRNAs or miRs) which target Bruton tyrosine kinase (BTK), subsequently suppressing prosurvival signaling in chronic lymphocytic leukemia (CLL) samples, and highlight a rationale for HDAC inhibitors in combination with ibrutinib to treat patients.1

Download Full-text

Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

Cell Stress and Chaperones ◽

10.1007/s12192-019-01064-1 ◽

2020 ◽

Vol 25 (1) ◽

pp. 173-191 ◽

Cited By ~ 7

Author(s):

Rachel Kuta ◽

Nancy Larochelle ◽

Mario Fernandez ◽

Arun Pal ◽

Sandra Minotti ◽

...

Keyword(s):

Heat Shock ◽

Histone Deacetylase ◽

Motor Neurons ◽

Heat Shock Response ◽

Hdac Inhibitors ◽

Dependent Manner ◽

Hdac Inhibition ◽

Proteotoxic Stress ◽

Shock Response ◽

Stress Dependent

AbstractUpregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSP525Lmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.

Download Full-text

Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents

Blood ◽

10.1182/blood-2011-06-362434 ◽

2012 ◽

Vol 119 (4) ◽

pp. 1008-1017 ◽

Cited By ~ 80

Author(s):

Sajal K. Ghosh ◽

Susan P. Perrine ◽

Robert M. Williams ◽

Douglas V. Faller

Keyword(s):

Gene Expression ◽

Fatty Acids ◽

Histone Deacetylase ◽

Hdac Inhibitor ◽

Hydroxamic Acid ◽

Antiviral Agents ◽

Hdac Inhibitors ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Lymphoma Cells

AbstractInduction of EBV lytic-phase gene expression, combined with exposure to an antiherpes viral drug, represents a promising targeted therapeutic approach to EBV-associated lymphomas. Short-chain fatty acids or certain chemotherapeutics have been used to induce EBV lytic-phase gene expression in cultured cells and mouse models, but these studies generally have not translated into clinical application. The recent success of a clinical trial with the pan-histone deacetylase (pan-HDAC) inhibitor arginine butyrate and the antiherpes viral drug ganciclovir in the treatment of EBV lymphomas prompted us to investigate the potential of several HDAC inhibitors, including some new, highly potent compounds, to sensitize EBV+ human lymphoma cells to antiviral agents in vitro. Our study included short-chain fatty acids (sodium butyrate and valproic acid); hydroxamic acids (oxamflatin, Scriptaid, suberoyl anilide hydroxamic acid, panobinostat [LBH589], and belinostat [PXD101]); the benzamide MS275; the cyclic tetrapeptide apicidin; and the recently discovered HDAC inhibitor largazole. With the exception of suberoyl anilide hydroxamic acid and PXD101, all of the other HDAC inhibitors effectively sensitized EBV+ lymphoma cells to ganciclovir. LBH589, MS275, and largazole were effective at nanomolar concentrations and were 104 to 105 times more potent than butyrate. The effectiveness and potency of these HDAC inhibitors make them potentially applicable as sensitizers to antivirals for the treatment of EBV-associated lymphomas.

Download Full-text