scholarly journals Regulation of Immune Responses by Histone Deacetylase Inhibitors

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Paul V. Licciardi ◽  
Tom C. Karagiannis
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Adaptive Immune Response ◽  
Immune Gene ◽  
Epigenetic Factors ◽  
New Class ◽  
Adaptive Immune ◽  
Immune Gene Expression

Both genetic and epigenetic factors are important regulators of the immune system. There is an increasing body of evidence attesting to epigenetic modifications that influence the development of distinct innate and adaptive immune response cells. Chromatin remodelling via acetylation, methylation, phosphorylation, and ubiquitination of histone proteins as well as DNA, methylation is epigenetic mechanisms by which immune gene expression can be controlled. In this paper, we will discuss the role of epigenetics in the regulation of host immunity, with particular emphasis on histone deacetylase inhibitors. In particular, the role of HDAC inhibitors as a new class of immunomodulatory therapeutics will also be reviewed.

scholarly journals Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group

MedChemComm ◽  
2015 ◽  
Vol 6 (4) ◽  
pp. 613-618 ◽  
Author(s):  
Youxuan Li ◽  
Patrick M. Woster
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Zinc Binding ◽  
New Class

Substituted 2-(oxazole-2-yl)phenols: a new class of HDAC inhibitors with a novel zinc binding group.

scholarly journals The role of epigenetic modifications for the pathogenesis of Crohn's disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
M. Hornschuh ◽  
E. Wirthgen ◽  
M. Wolfien ◽  
K. P. Singh ◽  
O. Wolkenhauer ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
New Biomarkers ◽  
Insight Into ◽  
Specific Evaluation

AbstractEpigenetics has become a promising field for finding new biomarkers and improving diagnosis, prognosis, and drug response in inflammatory bowel disease. The number of people suffering from inflammatory bowel diseases, especially Crohn's disease, has increased remarkably. Crohn's disease is assumed to be the result of a complex interplay between genetic susceptibility, environmental factors, and altered intestinal microbiota, leading to dysregulation of the innate and adaptive immune response. While many genetic variants have been identified to be associated with Crohn's disease, less is known about the influence of epigenetics in the pathogenesis of this disease. In this review, we provide an overview of current epigenetic studies in Crohn's disease. In particular, we enable a deeper insight into applied bioanalytical and computational tools, as well as a comprehensive update toward the cell-specific evaluation of DNA methylation and histone modifications.

scholarly journals The Effect of Vicinal Difluorination on the Conformation and Potency of Histone Deacetylase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3974
Author(s):  
A. Daryl Ariawan ◽  
Flora Mansour ◽  
Nicole Richardson ◽  
Mohan Bhadbhade ◽  
Junming Ho ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Molecular Conformations ◽  
Fluorinated Analogs ◽  
Selective Agents ◽  
Isoform Selectivity

Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.

scholarly journals Synergism of Heat Shock Protein 90 and Histone Deacetylase Inhibitors in Synovial Sarcoma

Sarcoma ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Anne Nguyen ◽  
Le Su ◽  
Belinda Campbell ◽  
Neal M. Poulin ◽  
Torsten O. Nielsen
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Synovial Sarcoma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Therapeutic Benefit ◽  
Multiple Time

Current systemic therapies have little curative benefit for synovial sarcoma. Histone deacetylase (HDAC) inhibitors and the heat shock protein 90 (Hsp90) inhibitor 17-AAG have recently been shown to inhibit synovial sarcoma in preclinical models. We tested combinations of 17-AAG with the HDAC inhibitor MS-275 for synergism by proliferation and apoptosis assays. The combination was found to be synergistic at multiple time points in two synovial sarcoma cell lines. Previous studies have shown that HDAC inhibitors not only induce cell death but also activate the survival pathway NF-κB, potentially limiting therapeutic benefit. As 17-AAG inhibits activators of NF-κB, we tested if 17-AAG synergizes with MS-275 through abrogating NF-κB activation. In our assays, adding 17-AAG blocks NF-κB activation by MS-275 and siRNA directed against histone deacetylase 3 (HDAC3) recapitulates the effects of MS-275. Additionally, we find that the NF-κB inhibitor BAY 11-7085 synergizes with MS-275. We conclude that agents inhibiting NF-κB synergize with HDAC inhibitors against synovial sarcoma.

IMMU-22. THE IMPACT OF MICROGLIA MODULATION ON GBM PROGRESSION IN SYNGENEIC MOUSE MODELS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi96-vi96
Author(s):  
Marie-Françoise Ritz ◽  
Tala Shekarian ◽  
Tomás A Martins ◽  
Philip Schmassmann ◽  
Gregor Hutter
Keyword(s):  
Mouse Models ◽  
Tumor Development ◽  
Adaptive Immune Response ◽  
Tamoxifen Treatment ◽  
Mouse Strains ◽  
Intracerebral Injection ◽  
Adaptive Immune ◽  
Tumor Immune Microenvironment ◽  
The Impact

Abstract BACKGROUND The tumor immune microenvironment (TME) of Glioblastoma consists of almost myeloid-derived macrophages and microglia called TAMs. We have shown that the disruption of CD47-Sirpα-axis induces an antitumor activity of TAMs against GBM in immune-deficient mice, through increases of phagocytosis of tumor cells by TAMs. We have aimed to study the role of microglia and its activation/depletion on GBM progression, in the syngeneic GBM model in immune-competent mice. We have studied the interplay of innate and adaptive immune response after activation and depletion of microglia and the effect on tumor progression and outcome of the mice. MATERIAL AND METHODS We used different colonies of genetically modified immunocompetent mouse strains to genetically activate/deplete microglia in the tumor context. We generated Sall1 CreERT2/fl mice and Cre-negative littermates. The application of Tamoxifen in this constellation leads to the excision of the transcription factor Sall1 and subsequent enhanced microglia activity. Conversely, we generated Sall1 CreERT2 x Csf1r fl/fl animals and the respective heterozygous and Cre-negative littermates in which Tamoxifen treatment leads to inactivation of microglia through the deletion of Csf1r. Glioblastoma tumors were induced by intracerebral injection of GL261, CT2A, or retrovirus-induced PDGF-Akt in pups and Tamoxifen treatment was started once the tumors were detected. RESULTS We observed a survival advantage in tumor-bearing mice after activation of microglia in Sall1 CreERT/fl animals compared to Cre-negative littermates. Genetic depletion of microglia in this model resulted in a shorter lifespan in microglia-depleted animals compared to Cre-negative littermates. Furthermore, the iTME in these tumors is subjected to scRNAseq analysis to identify mechanistic insights. CONCLUSION Microglia are important players in tumor development and progression of glioblastoma in mouse models. These cells may be targeted in future immunotherapeutic approaches for patients.

scholarly journals Epigenetic Targeting of Autophagy via HDAC Inhibition in Tumor Cells: Role of p53

2018 ◽  
Vol 19 (12) ◽  
pp. 3952 ◽  
Author(s):  
Maria Mrakovcic ◽  
Lauren Bohner ◽  
Marcel Hanisch ◽  
Leopold F. Fröhlich
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Histone Deacetylase ◽  
Stress Responses ◽  
Histone Deacetylase Inhibitors ◽  
Tumor Therapy ◽  
Regulatory System ◽  
Anticancer Activities ◽  
Mutational Status

Tumor development and progression is the consequence of genetic as well as epigenetic alterations of the cell. As part of the epigenetic regulatory system, histone acetyltransferases (HATs) and deacetylases (HDACs) drive the modification of histone as well as non-histone proteins. Derailed acetylation-mediated gene expression in cancer due to a delicate imbalance in HDAC expression can be reversed by histone deacetylase inhibitors (HDACi). Histone deacetylase inhibitors have far-reaching anticancer activities that include the induction of cell cycle arrest, the inhibition of angiogenesis, immunomodulatory responses, the inhibition of stress responses, increased generation of oxidative stress, activation of apoptosis, autophagy eliciting cell death, and even the regulation of non-coding RNA expression in malignant tumor cells. However, it remains an ongoing issue how tumor cells determine to respond to HDACi treatment by preferentially undergoing apoptosis or autophagy. In this review, we summarize HDACi-mediated mechanisms of action, particularly with respect to the induction of cell death. There is a keen interest in assessing suitable molecular factors allowing a prognosis of HDACi-mediated treatment. Addressing the results of our recent study, we highlight the role of p53 as a molecular switch driving HDACi-mediated cellular responses towards one of both types of cell death. These findings underline the importance to determine the mutational status of p53 for an effective outcome in HDACi-mediated tumor therapy.

scholarly journals Role of Histone Deacetylase Inhibitors in Relapsed Refractory Multiple Myeloma: A Focus on Vorinostat and Panobinostat

2015 ◽  
Vol 35 (12) ◽  
pp. 1173-1188 ◽  
Author(s):  
Salma Afifi ◽  
Angela Michael ◽  
Mahshid Azimi ◽  
Mabel Rodriguez ◽  
Nikoletta Lendvai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Refractory Multiple Myeloma
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