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.

Research Advances in the Use of Histone Deacetylase Inhibitors for Epigenetic Targeting of Cancer

2019 ◽  
Vol 19 (12) ◽  
pp. 995-1004 ◽  
Author(s):  
Yu Bai ◽  
Daid Ahmad ◽  
Ting Wang ◽  
Guihua Cui ◽  
Wenliang Li
Keyword(s):  
Signaling Pathways ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Epigenetic Therapy ◽  
Therapeutic Effects ◽  
Oncogenic Signaling ◽  
Anticancer Treatment ◽  
Oncogenic Signaling Pathways ◽  
Interesting Area

The causes and progression of cancer are controlled by epigenetic processes. The mechanisms involved in epigenetic regulation of cancer development, gene expression, and signaling pathways have been studied. Histone deacetylases (HDACs) have a major impact on chromatin remodeling and epigenetics, making their inhibitors a very interesting area of cancer research. This review comprehensively summarizes the literature regarding HDAC inhibitors (HDACis) as an anticancer treatment published in the past few years. In addition, we explain the mechanisms of their therapeutic effects on cancer. An analysis of the beneficial characteristics and drawbacks of HDACis also is presented, which will assist preclinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy. Future therapeutic strategies may include a combination of HDACis and chemotherapy or other inhibitors to target multiple oncogenic signaling pathways.

scholarly journals The ETO Protein Disrupted in t(8;21)-Associated Acute Myeloid Leukemia Is a Corepressor for the Promyelocytic Leukemia Zinc Finger Protein

2000 ◽  
Vol 20 (6) ◽  
pp. 2075-2086 ◽  
Author(s):  
Ari M. Melnick ◽  
Jennifer J. Westendorf ◽  
Adam Polinger ◽  
Graeme W. Carlile ◽  
Sally Arai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Acute Myeloid

ABSTRACT The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1–ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor α in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.

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.

Chemoprevention and epigenetic multitargeted approach.

2016 ◽  
Vol 34 (3_suppl) ◽  
pp. e297-e297
Author(s):  
M. A. Nezami
Keyword(s):  
Solid Tumors ◽  
Advanced Cancer ◽  
Histone Deacetylases ◽  
Epigenetic Therapy ◽  
Significant Shift ◽  
Breast Cancers ◽  
Suppressor Genes ◽  
Preliminary Results ◽  
Epigenetic Modifiers

e297 Background: In 2012 there were 11,957,599 advanced cancer cases in the US reported by CDC and the incidence has been almost unchanged over the previous 8 years (482,000 cases in 2000 versus 456,000 cases in 2008). There has been an annual percentage change of only (-0.6) between years 1999 to 2008 in cancer incidence. It is described in recent literature that epigenetic alterations are at least if not more important than genetic defects for the development and progression of malignant diseases. Transcriptional therapy is a very promising form of cancer treatment that is being extensively evaluated. It is speculated that inhibitors of DNA methylation and histone deacetylases can reactivate expression of tumor suppressor genes. Hypermethylation and transcription silencing of suppressor genes has been shown in 33% of breast cancers, 60% of prostate CA and 92% of colon CA. The value of combination therapy both in chemoprevention, as well as treatment in patients with cancer is extremely important and can cause a significant shift in the current practice of oncology and cancer prevention, the results in clinical studies have been poor as the target histone hyperacetylation does not correlate with survival (possibly due to P 16/21 resistance and unselectiveness of the conventional therapies/targets). Methods: In vitro application of epigenetic modifiers, consisting of nontoxic natural substances tested in cell cultures showed preliminary results confirming apoptosis. Application of the relevant scientific merits described above, using combination of epigenetic modifiers, and natural compounds in a protocol called Multi targeted epigenetic therapy (MTET) in a set of advanced patients showed synergistic effect which was clinically relevant. Results: Clinical application of this method of treating cancer has caused promising preliminary results. We present the summary of outcomes in one hundred cases of advanced cancer (refractory solid tumors) with thirteen cases, described in detail. Conclusions: Our preliminary findings were encouraging and supports further research in a large randomized trial to evaluate the efficacy of such method, in refractory and advanced solid tumors.

scholarly journals Effect of Trichostatin A on Histone Deacetylases 1, 2 and 3, p21Cip1/Waf1/Sdi1, p27Kip1, and p57Kip2 Gene Expression in Breast Cancer SK-BR-3 Cell Line

2020 ◽  
Vol 5 (2) ◽  
pp. 57-62
Author(s):  
Masumeh Sanaei ◽  
Fraidoon Kavoosi
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Line ◽  
Cell Apoptosis ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Histone Deacetylation ◽  
Relative Expression Level ◽  
Hematological Cancers

Objective: DNA methylation, the covalent addition of a methyl group to cytosine, and histone modification play an important role in the establishment and maintenance of the program of gene expression. The balance of histone acetylation is determined by the activities of two groups of enzymes including histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histone deacetylation is generally associated with silencing gene expression resulting in several solid tumors. HDAC inhibitors (HDACIs) are the new class of potential anticancer compounds for the treatment of the solid and hematological cancers. The current study was designed to evaluate the effect of trichostatin A (TSA) on histone deacetylases 1, 2 and 3, p21Cip1/Waf1/Sdi1 (p21), p27Kip1 (p27), and p57Kip2 (p57) gene expression in breast cancer SK-BR-3 cell line. Materials and Methods: The breast cancer SK-BR-3 line was treated with TSA. To determine cell viability, cell apoptosis, and the relative expression level of the genes, MTT assay, cell apoptosis assay, and qRT-PCR were done respectively. Results: TSA significantly inhibited cell growth, and induced apoptosis. Furthermore, this compound increased p21, p27, and p57 and decreased histone deacetylases 1, 2 and 3 gene expression significantly. Conclusion: The TSA can reactivate the p21, p27, and p57 through down-regulation of histone deacetylases 1, 2 and 3 gene expression.

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.

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 Histone Deacetylase Inhibitors in the Treatment of Hematological Malignancies and Solid Tumors

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Mario Federico ◽  
Luigi Bagella
Keyword(s):  
Solid Tumors ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Hematological Malignancies ◽  
Histone Proteins ◽  
Histone Deacetylases Inhibitors ◽  
Recent Developments ◽  
Nucleosomal Structure

The human genome is epigenetically organized through a series of modifications to the histone proteins that interact with the DNA. In cancer, many of the proteins that regulate these modifications can be altered in both function and expression. One example of this is the family of histone deacetylases (HDACs), which as their name implies remove acetyl groups from the histone proteins, allowing for more condensed nucleosomal structure. HDACs have increased expression in cancer and are also believed to promote carcinogenesis through the acetylation and interaction with key transcriptional regulators. Given this, small molecule histone deacetylases inhibitors have been identified and developed, which not only inhibit HDACs, but can also lead to growth arrest, differentiation, and/or apoptosis in tumors bothin vitroandin vivo. Here, we will discuss some of the recent developments in clinical trials utilizing HDACs inhibitors for the treatment of both hematological malignancies as well as solid tumors.

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