scholarly journals Overexpression of Adenoviral E1A Sensitizes E1A+Ras-Transformed Cells to the Action of Histone Deacetylase Inhibitors

Acta Naturae ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 70-78 ◽  
Author(s):  
M. V. Igotti ◽  
S. B. Svetlikova ◽  
V. A. Pospelov
Keyword(s):  
Histone Deacetylases ◽  
Cytotoxic Effect ◽  
Histone Deacetylase Inhibitors ◽  
Malignant Tumors ◽  
Hdac Inhibitors ◽  
Tumor Formation ◽  
Cytotoxic Agents ◽  
Combined Use ◽  
Ras Oncogenes ◽  
The One

The adenoviral E1A protein induces cell proliferation, transformation, and tumor formation in rodents, on the one hand. On the other hand, E1A expression increases cell sensitivity to a number of cytotoxic agents. Therefore, E1A is a candidate for use as a component of combination therapy for malignant tumors. The highest augmentation in the cytotoxic effect was achieved by a combined use of E1A expression and histone deacetylases (HDAC) inhibitors. However, HDAC inhibitors do not induce apoptosis in cells transformed with E1A and cHa-ras oncogenes. In this study, it was shown that HDAC inhibitors reduce the expression of adenoviral E1A. However, under unregulated E1A overexpression, these cells undergo apoptosis in the presence of HDAC inhibitors. Treatment with a HDAC inhibitor, sodium butyrate (NaBut), was shown to activate the anti-apoptotic factor NF-kB in control cells. However, NaBut was unable to modulate the NF-kB activity in E1A overexpressed cells. Therefore, it is fair to postulate that cells transformed with E1A and cHa-ras oncogenes avoid the apoptosis induced by HDAC inhibitors thanks to a NaBut-dependent decrease in E1A expression.

Recent Advances in Multi-target Drugs Targeting Protein Kinases and Histone Deacetylases in Cancer Therapy

2020 ◽  
Vol 27 (42) ◽  
pp. 7264-7288 ◽  
Author(s):  
Yong Ling ◽  
Ji Liu ◽  
Jianqiang Qian ◽  
Chi Meng ◽  
Jing Guo ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Kinase Inhibitors ◽  
Malignant Tumors ◽  
Synergistic Effects ◽  
Hdac Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Biological Targets ◽  
Single Target

Protein Kinase Inhibitors (PKIs) and Histone Deacetylase Inhibitors (HDACIs) are two important classes of anticancer agents and have provided a variety of small molecule drugs for the treatment of various types of human cancers. However, malignant tumors are of a multifactorial nature that can hardly be “cured” by targeting a single target, and treatment of cancers hence requires modulation of multiple biological targets to restore the physiological balance and generate sufficient therapeutic efficacy. Multi-target drugs have attracted great interest because of their advantages in the treatment of complex cancers by simultaneously targeting multiple signaling pathways and possibly leading to synergistic effects. Synergistic effects have been observed in the combination of kinase inhibitors, such as imatinib, dasatinib, or sorafenib, with an array of HDACIs including vorinostat, romidepsin, or panobinostat. A considerable number of multi-target agents based on PKIs and HDACIs have been developed. In this review, we summarize the recent literature on the development of multi-target kinase-HDAC inhibitors and provide our view on the challenges and future directions on this topic.

Histone deacetylase inhibitors and their potential role in inflammatory bowel diseases

2011 ◽  
Vol 39 (4) ◽  
pp. 1092-1095 ◽  
Author(s):  
Alexander J.P. Edwards ◽  
Sylvia L.F. Pender
Keyword(s):  
Gene Transcription ◽  
Inflammatory Bowel Diseases ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
T Regulatory Cells ◽  
Hdac Inhibitors ◽  
Novel Treatments ◽  
Bowel Diseases ◽  
Normal Gene ◽  
Inflammatory Bowel

IBDs (inflammatory bowel diseases) are lifelong manifestations that significantly impair the quality of life of those who suffer from them. Although many therapies are now available, including immunomodulatory drugs such as Infliximab which have efficacy in IBD, not all patients respond and some patients generate autoantibodies against these drugs. Hence the search for novel treatments is ongoing. HDACs (histone deacetylases) are responsible for condensation of chromatin in the nucleus of cells and inhibition of gene transcription and are often dysregulated during cancer. HDAC inhibitors allow normal gene transcription to be restored and provide attractive therapeutic options, as they have been shown to be anti-inflammatory and anti-proliferative in cancer. Indeed, two HDAC inhibitors have been recently approved for the treatment of cutaneous T-cell lymphoma in the U.S.A. Recent research using animal models has shown that HDAC inhibitors may have a beneficial effect in colitis by boosting levels of Foxp3+ (forkhead box P3+) T-regulatory cells that dampen inflammation. In the present paper, we outline the background to IBD, HDACs and their inhibitors as well as discussing their current use in models of IBD.

scholarly journals Synthesis and Biological Evaluation of Novel Thiazolyl-Coumarin Derivatives as Potent Histone Deacetylase Inhibitors with Antifibrotic Activity

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 739 ◽  
Author(s):  
Viviana Pardo-Jiménez ◽  
Patricio Navarrete-Encina ◽  
Guillermo Díaz-Araya
Keyword(s):  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Neonatal Rat ◽  
Zinc Binding ◽  
Coumarin Derivatives

New histone deacetylases (HDAC) inhibitors with low toxicity to non-cancerous cells, are a prevalent issue at present because these enzymes are actively involved in fibrotic diseases. We designed and synthesized a novel series of thiazolyl-coumarins, substituted at position 6 (R = H, Br, OCH3), linked to classic zinc binding groups, such as hydroxamic and carboxylic acid moieties and alternative zinc binding groups such as disulfide and catechol. Their in vitro inhibitory activities against HDACs were evaluated. Disulfide and hydroxamic acid derivatives were the most potent ones. Assays with neonatal rat cardiac fibroblasts demonstrated low cytotoxic effects for all compounds. Regarding the parameters associated to cardiac fibrosis development, the compounds showed antiproliferative effects, and triggered a strong decrease on the expression levels of both α-SMA and procollagen I. In conclusion, the new thiazolyl-coumarin derivatives inhibit HDAC activity and decrease profibrotic effects on cardiac fibroblasts.

Zinc Dependent Histone Deacetylase Inhibitors in Cancer Therapeutics: Recent Update

2020 ◽  
Vol 26 (40) ◽  
pp. 7212-7280 ◽  
Author(s):  
Faria Sultana ◽  
Kesari Lakshmi Manasa ◽  
Siddiq Pasha Shaik ◽  
Srinivasa Reddy Bonam ◽  
Ahmed Kamal
Keyword(s):  
Gene Expression ◽  
Drug Therapy ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Rational Drug Design ◽  
Combination Drug Therapy ◽  
Combination Drug

Background: Histone deacetylases (HDAC) are an important class of enzymes that play a pivotal role in epigenetic regulation of gene expression that modifies the terminal of core histones leading to remodelling of chromatin topology and thereby controlling gene expression. HDAC inhibitors (HDACi) counter this action and can result in hyperacetylation of histones, thereby inducing an array of cellular consequences such as activation of apoptotic pathways, generation of reactive oxygen species (ROS), cell cycle arrest and autophagy. Hence, there is a growing interest in the potential clinical use of HDAC inhibitors as a new class of targeted cancer therapeutics. Methodology and Result: Several research articles spanning between 2016 and 2017 were reviewed in this article and presently offer critical insights into the important strategies such as structure-based rational drug design, multi-parameter lead optimization methodologies, relevant SAR studies and biology of various class of HDAC inhibitors, such as hydroxamic acids, benzamides, cyclic peptides, aliphatic acids, summarising the clinical trials and results of various combination drug therapy till date. Conclusion: This review will provide a platform to the synthetic chemists and biologists to cater the needs of both molecular targeted therapy and combination drug therapy to design and synthesize safe and selective HDAC inhibitors in cancer therapeutics.

scholarly journals Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells

2006 ◽  
Vol 13 (4) ◽  
pp. 1237-1250 ◽  
Author(s):  
Viola Baradari ◽  
Alexander Huether ◽  
Michael Höpfner ◽  
Detlef Schuppan ◽  
Hans Scherübl
Keyword(s):  
Cell Lines ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Treatment Options ◽  
Combined Treatment ◽  
Hdac Inhibitors ◽  
Cyclin B1 ◽  
Hdac Inhibition ◽  
New Approach

Treatment options of advanced neuroendocrine tumors (NETs) are unsatisfactory. Hence, innovative therapeutic approaches are urgently needed. Inhibition of histone deacetylases (HDACs) is a promising new approach in cancer therapy. While several HDAC inhibitors have already entered clinical trials, the effect of HDAC inhibition on NET has not been investigated. Therefore, we evaluated the antineoplastic effects of three different HDAC inhibitors, trichostatin A (TSA), sodium butyrate (NaB), and MS-275, on growth and apoptosis of the gastrointestinal NET cell lines CM and BON. We could demonstrate that HDAC inhibition dose-dependently inhibited proliferation of both cell lines with IC50 values varying from the millimolar (NaB) to the micromolar (MS-275) and the nanomolar range (TSA). Moreover, HDAC inhibition potently induced apoptosis, which was accompanied by DNA-fragmentation, an up to 12-fold caspase-3 activation and downregulated Bcl-2 expression. Furthermore, HDAC inhibition resulted in cell cycle arrest at the G1–S-transition, which was associated with the suppression of cyclin D1 expression and induction of p21 and p27 expression. For BON cells, we observed an additional block in the G2/M phase, which was aligned with a downregulation of cyclin B1. In addition, combined treatment with MS-275 and somatostatin or the synthetic somatostatin analog octreotide was evaluated. Neither somatostatin nor its stable analog octreotide augmented the antiproliferative effect of MS-275 in NET cells. To conclude, our data show that HDAC inhibition is a promising new approach in the treatment of NET disease, which should be evaluated in clinical studies.

scholarly journals Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus

2021 ◽  
Vol 8 ◽  
Author(s):  
Natália Lourenço de Freitas ◽  
Maria Gabriela Deberaldini ◽  
Diana Gomes ◽  
Aline Renata Pavan ◽  
Ângela Sousa ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Human Papillomaviruses ◽  
Therapeutic Interventions ◽  
Cellular Targets

The role of epigenetic modifications on the carcinogenesis process has received a lot of attention in the last years. Among those, histone acetylation is a process regulated by histone deacetylases (HDAC) and histone acetyltransferases (HAT), and it plays an important role in epigenetic regulation, allowing the control of the gene expression. HDAC inhibitors (HDACi) induce cancer cell cycle arrest, differentiation, and cell death and reduce angiogenesis and other cellular events. Human papillomaviruses (HPVs) are small, non-enveloped double-stranded DNA viruses. They are major human carcinogens, being intricately linked to the development of cancer in 4.5% of the patients diagnosed with cancer worldwide. Long-term infection of high-risk (HR) HPV types, mainly HPV16 and HPV18, is one of the major risk factors responsible for promoting cervical cancer development. In vitro and in vivo assays have demonstrated that HDACi could be a promising therapy to HPV-related cervical cancer. Regardless of some controversial studies, the therapy with HDACi could target several cellular targets which HR-HPV oncoproteins could be able to deregulate. This review article describes the role of HDACi as a possible intervention in cervical cancer treatment induced by HPV, highlighting the main advances reached in the last years and providing insights for further investigations regarding those agents against cervical cancer.

scholarly journals Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 634
Author(s):  
Robert Jenke ◽  
Nina Reßing ◽  
Finn K. Hansen ◽  
Achim Aigner ◽  
Thomas Büch
Keyword(s):  
Solid Tumors ◽  
Cancer Progression ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Epigenetic Therapy ◽  
Cancer Therapies ◽  
Comprehensive Overview ◽  
Hematological Cancers

The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

scholarly journals Factors governing the affinity and selectivity of histone deacetylase inhibitors for the HDAC8 enzyme active site: Implications for anticancer therapy

2020 ◽  
Author(s):  
Nikolay Toshev ◽  
Diana Cheshmedzhieva ◽  
Todor Dudev
Keyword(s):  
Cancer Progression ◽  
Histone Deacetylases ◽  
Density Functional ◽  
Rational Design ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Density Functional Theory Calculations ◽  
Post Translational Modifications ◽  
Enzyme Active Site ◽  
Anticancer Properties

Disruptions in post-translational modifications of chromatin structure promote uncontrollable cell growth branded as a hallmark of tumor lesions. The overexpression/hyperactivity of histone deacetylases (HDACs) is a common feature for the tumorogenesis and cancer progression. Several inhibitors of histone deacetylases (mainly hydroxamic acid derivatives) have been successfully used as drugs in fighting tumor formations. However, there is no systematic study on the factors controling the affinity and selectivity of this type of inhibitors to the host enzyme thus hampering successful rational design of more potent and selective anticancer drugs. Herein, in an attempt to illuminate the mechanism of the host – guest interactions in these systems at atomic level we systematically study the effect of various factors in the process and unravel its key determinants.  Density functional theory calculations have been employed. Our findings have the potential to be employed as guidelines in designing new HDAC inhibitors with improved anticancer properties.

scholarly journals Synergistic Anticancer Effect of Glycolysis and Histone Deacetylases Inhibitors in a Glioblastoma Model

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1749
Author(s):  
Beata Pająk ◽  
Ewelina Siwiak-Niedbalska ◽  
Anna Jaśkiewicz ◽  
Maja Sołtyka ◽  
Rafał Zieliński ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Therapeutic Strategy ◽  
Aerobic Glycolysis ◽  
Combined Treatment ◽  
Hdac Inhibitors ◽  
Cytotoxic Agents ◽  
Cytotoxic Effects ◽  
Histone Deacetylases Inhibitors ◽  
Tremendous Progress

Over the last decade, we have seen tremendous progress in research on 2-deoxy-D-glucose (2-DG) and its analogs. Clinical trials of 2-DG have demonstrated the challenges of using 2-DG as a monotherapy, due to its poor drug-like characteristics, leading researchers to focus on improving its bioavailability to tissue and organs. Novel 2-DG analogs such as WP1122 and others have revived the old concept of glycolysis inhibition as an effective anticancer strategy. Combined with other potent cytotoxic agents, inhibitors of glycolysis could synergistically eliminate cancer cells. We focused our efforts on the development of new combinations of anticancer agents coupled with 2-DG and its derivatives, targeting glioblastoma, which is in desperate need of novel approaches and therapeutic options and is particularly suited to glycolysis inhibition, due to its reliance on aerobic glycolysis. Herein, we present evidence that a combined treatment of 2-DG analogs and modulation of histone deacetylases (HDAC) activity via HDAC inhibitors (sodium butyrate and sodium valproate) exerts synergistic cytotoxic effects in glioblastoma U-87 and U-251 cells and represents a promising therapeutic strategy.

scholarly journals CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma

2016 ◽  
Vol 113 (52) ◽  
pp. 15090-15095 ◽  
Author(s):  
Michael P. Phelps ◽  
Jenna N. Bailey ◽  
Terra Vleeshouwer-Neumann ◽  
Eleanor Y. Chen
Keyword(s):  
Solid Tumors ◽  
Histone Deacetylases ◽  
High Efficiency ◽  
Malignant Tumors ◽  
Myogenic Differentiation ◽  
Hdac Inhibitors ◽  
Specific Response ◽  
Cancer Genes

Dysregulated gene expression resulting from abnormal epigenetic alterations including histone acetylation and deacetylation has been demonstrated to play an important role in driving tumor growth and progression. However, the mechanisms by which specific histone deacetylases (HDACs) regulate differentiation in solid tumors remains unclear. Using pediatric rhabdomyosarcoma (RMS) as a paradigm to elucidate the mechanism blocking differentiation in solid tumors, we identified HDAC3 as a major suppressor of myogenic differentiation from a high-efficiency Clustered regularly interspaced short palindromic repeats (CRISPR)-based phenotypic screen of class I and II HDAC genes. Detailed characterization of the HDAC3-knockout phenotype in vitro and in vivo using a tamoxifen-inducible CRISPR targeting strategy demonstrated that HDAC3 deacetylase activity and the formation of a functional complex with nuclear receptor corepressors (NCORs) were critical in restricting differentiation in RMS. The NCOR/HDAC3 complex specifically functions by blocking myoblast determination protein 1 (MYOD1)-mediated activation of myogenic differentiation. Interestingly, there was also a transient up-regulation of growth-promoting genes upon initial HDAC3 targeting, revealing a unique cancer-specific response to the forced transition from a neoplastic state to terminal differentiation. Our study applied modifications of CRISPR/CRISPR-associated endonuclease 9 (Cas9) technology to interrogate the function of essential cancer genes and pathways and has provided insights into cancer cell adaptation in response to altered differentiation status. Because current pan-HDAC inhibitors have shown disappointing results in clinical trials of solid tumors, therapeutic targets specific to HDAC3 function represent a promising option for differentiation therapy in malignant tumors with dysregulated HDAC3 activity.

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