HDAC Inhibitors as Epigenetic Regulators of the Immune System: Impacts on Cancer Therapy and Inflammatory Diseases

Hull, Elizabeth; Montgomery, McKale R.; Leyva, Kathryn J.

doi:10.1155/2016/8797206

Cited by 240 publications

(230 citation statements)

References 145 publications

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“…On the contrary, histone deacetylases (HDAC) remove acetyl groups from histones, thereby tightening the chromatin structure, which hinders binding of transcription factors and hence suppress gene transcription. Numerous studies demonstrated that HDAC inhibitors have therapeutic potential to treat diseases such as cancer, inflammation, fibrosis and even cognitive disorders (Eckschlager et al, 2017;Fischer et al, 2010;Hull et al, 2016;Liu et al, 2015).…”

Section: Histone Deacetylases (Hdac)mentioning

confidence: 99%

The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

Huwiler

Zangemeister‐Wittke

2018

Pharmacology & Therapeutics

169

134

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The immunomodulatory drug fingolimod (FTY720, Gilenya) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P subtype by induction of receptor downregulation. Since S1P is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression. Numerous preclinical studies have since been performed with the aim to increase the spectrum of potential indications for fingolimod with emphasis on other autoimmune disorders and diseases associated with inflammation and uncontrolled cell proliferation, including cancer. As an alternative to fingolimod, novel S1PR modulators with a more selective receptor activation profile and improved pharmacokinetic performance and tolerability have also been developed. Preclinical and clinical studies are ongoing to investigate their therapeutic potential. This review discusses the most relevant preclinical and clinical findings from S1PR-targeting and from less-well defined off-target effects reported in the literature, and reveals perspectives for using fingolimod and functionally-related derivatives and new formulations in the management of an increasing number of diseases.

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Section: Histone Deacetylases (Hdac)mentioning

confidence: 99%

The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

Huwiler

Zangemeister‐Wittke

2018

Pharmacology & Therapeutics

169

134

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“…This class includes azacitidine (AZA) and decitabine (DEC: 5‐aza‐2'‐deoxycytidine), which are hypomethylating prodrugs whose active triphosphate forms are incorporated into RNA and DNA, respectively, and induce hypomethylation of the DNA (DEC) and ribosomal disassembly and disruption of protein translation (AZA) . Another group of epigenetic modifiers includes inhibitors of histone deacetylase, such as panabinostat, which prevent the deacetylation of histone and nonhistone proteins resulting in alterations of both gene transcription and protein activity …”

Section: Posttransplant Therapymentioning

confidence: 99%

“…Panobinostat is a potent oral nonselective histone deacetylase inhibitor with preclinical activity in myeloid malignancies . The phase I/II PANOBEST trial evaluated maintenance panabinostat for 42 high‐risk MDS and AML patients following RIC allo‐HSCT for up to 1 year.…”

Section: Posttransplant Therapymentioning

confidence: 99%

Prevention of relapse after allogeneic stem cell transplantation in acute myeloid leukemia: Updates and challenges

2019

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Acute myeloid leukemia (AML) is a disease with heterogeneous prognosis based on the clinical, cytogenetic, and molecular profile of the patient. Despite high post-induction remission rates in adult patients up to 40% of patients relapse. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective and potentially curative post-remission treatment for AML. 1 The antileukemic effect of allo-HSCT depends on the cytotoxicity of the pretransplant conditioning therapy and the posttransplant graft versus leukemia (GVL) effect. In a meta-analysis, allo-HSCT significantly improves survival in patients in first complete remission (CR) with poor-risk and intermediate-risk cytogenetic abnormalities (poor-risk: HR -0.73; 95% CI, 0.59-0.90); (intermediate-risk AML: HR, 0.83%-95% CI, 0.74-0.93). 2,3 The introduction of non-myeloablative (NMA) and reduced intensity conditioning (RIC) regimens, advances in HLA-matching, improved supportive care, and tailored graft versus host disease (GVHD) prophylaxis have allowed for a larger application of allo-HSCT to older patients and those with comorbidities. Although Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). Reduced intensity regimens, alternative graft sources, advances in HLA-matching, improved supportive care, and tailored graft versus host disease (GVHD) prophylaxis have led to a wider application of allo-HSCT to eligible patients. Unfortunately, 30-40% of patients with AML will relapse after transplant and this is the major cause of treatment failure. Careful consideration should be paid in choosing the type of graft, graft source, and conditioning regimen to minimize the risk of disease recurrence. In addition, maintenance therapy following allo-HSCT is a potential method to keep the disease in remission, especially in those with high-risk disease characteristics. Pharmacological targeted agents with low side effect profile such as tyrosine kinase inhibitors, hypomethylating agents (HMAs), HDAC inhibitors, antibody drug conjugates (ADCs), isocitrate dehydrogenase inhibitors, and hedgehog inhibitors may prevent relapse in posttransplant setting and are under investigation. Immunological therapies including donor lymphocyte infusions (DLIs), natural killer (NK) cell therapy, peptide vaccine targeting tumor antigens, and adoptive T-cell therapies all hold promises in this area as well. As targeted agents and immunotherapies continue to be developed, patients at high risk of recurrence may benefit from prophylactic maintenance therapy. Here we review the current landscape in this rapidly evolving clinical setting. K E Y W O R D S Acute myeloid leukemia, Allogeneic Transplant, Immunotherapy, Posttransplant relapse, Targeted agents

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“…Epigenetic modification in gene expression and cellular responses by histone deacetylase (HDAC) has gained much attention in recent years and HDAC inhibitors have been tested to treat various diseases [7,8]. Currently, 18 mammalian HDACs have been identified and grouped into 4 classes (Class I: HDAC1, HDAC2, HDAC3, and HDAC8; Class IIa: HDAC4, HDAC5, HDAC7, and HDAC9; Class IIb: HDAC6 and HDAC10; Class III: sirtuins 1-7; Class IV: HDAC11) [9].…”

Section: Introductionmentioning

confidence: 99%

Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury

Lin

Hsu

HuangFu

et al. 2020

BMC Pharmacol Toxicol

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Background: Despite the fact that histone deacetylase (HDAC) inhibitors have been tested to treat various cardiovascular diseases, the effects of selective HDAC6 inhibitor ACY1215 on infarct size during cardiac ischemiareperfusion (IR) injury still remain unknown. In the present study we aimed to investigate the effects of ACY1215 on infarct size in rats with cardiac IR injury, as well as to examine the association between HDAC6 inhibitors and the gene expression of hypoxia inducible factor-1α (HIF-1α), a key regulator of cellular responses to hypoxia. Methods: By using computational analysis of high-throughput expression profiling dataset, the association between HDAC inhibitors (pan-HDAC inhibitors panobinostat and vorinostat, and HDAC6 inhibitor ISOX) and their effects on HIF-1α geneexpression were evaluated. The male Wistar rats treated with ligation of left coronary artery followed by reperfusion were used as a cardiac IR model. ACY1215 (50 mg/kg), pan-HDAC inhibitor MPT0E028 (25 mg/kg), and vehicle were intraperitoneally injected within 5 min before reperfusion. The infarct size in rat myocardium was determined by 2,3,5-triphenyltetrazolium chloride staining. The serum levels of transforming growth factor-β (TGF-β) and C-reactive protein (CRP) were also determined. Results: The high-throughput gene expression assay showed that treatment of ISOX was associated with a more decreased gene expression of HIF-1α than that of panobinostat and vorinostat. Compared to control rats, ACY1215treated rats had a smaller infarct size (49.75 ± 9.36% vs. 19.22 ± 1.70%, p < 0.05), while MPT0E028-treated rats had a similar infarct size to control rats. ACY-1215-and MPT0E028-treated rats had a trend in decreased serum TGF-β levels, but not statistically significant. ACY1215-treated rats also had higher serum CRP levels compared to control rats (641.6 μg/mL vs. 961.37 ± 64.94 μg/mL, p < 0.05). Conclusions: Our research indicated that HDAC6 inhibition by ACY1215 might reduce infarct size in rats with cardiac IR injury possibly through modulating HIF-1α expression. TGF-β and CRP should be useful biomarkers to monitor the use of ACY1215 in cardiac IR injury.

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HDAC Inhibitors as Epigenetic Regulators of the Immune System: Impacts on Cancer Therapy and Inflammatory Diseases

Cited by 240 publications

References 145 publications

The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

Prevention of relapse after allogeneic stem cell transplantation in acute myeloid leukemia: Updates and challenges

Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury

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