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Pharmaceuticals
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Selective Histone Deacetylase Isoforms as Potential Therapeutic Targets
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Selective Histone Deacetylase Isoforms as Potential Therapeutic Targets

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 15 February 2025 | Viewed by 5908

Special Issue Editor

Prof. Dr. Anna Artese

E-Mail Website
Guest Editor
Dipartimento di Scienze della Salute, Università “Magna Graecia” di Catanzaro, Campus “Salvatore Venuta”, Viale Europa, 88100 Catanzaro, Italy
Interests: drug design; molecular modeling; molecular dynamics; virtual screening; pharmacophore modeling; drug repurposing; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Due to the crucial role of histone deacetylases (HDACs) in regulating fundamental cellular processes, this thematic issue aims to highlight important advances in the field of HDACs, including their inhibitors and activators and their pharmacological applications in cancer, neurodegenerative and inflammatory diseases.

The sub-topics to be covered within the issue will be:

  • HDAC inhibitors as anti-inflammatory agents with a novel mechanism of action;
  • HDAC inhibitors targeting the tumor microenvironment: new perspectives;
  • HDAC inhibitor applications in neurodegenerative and psychiatric disorders;
  • HDAC inhibitors as novel antidiabetic agents;
  • HDAC activators and inflammation.

Prof. Dr. Anna Artese
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

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Published Papers (4 papers)

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Research

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17 pages, 2566 KiB  
Article
Vorinostat Treatment of Gastric Cancer Cells Leads to ROS-Induced Cell Inhibition and a Complex Pattern of Molecular Alterations in Nrf2-Dependent Genes
by Leoni Lorenz, Tamara Zenz, Denys Oliinyk, Florian Meier-Rosar, Robert Jenke, Achim Aigner and Thomas Büch
Pharmaceuticals 2024, 17(8), 1080; https://doi.org/10.3390/ph17081080 - 16 Aug 2024
Viewed by 583
Abstract
Histone deacetylase inhibitors (HDACi) show high antineoplastic potential in preclinical studies in various solid tumors, including gastric carcinoma; however, their use in clinical studies has not yet yielded convincing efficacies. Thus, further studies on cellular/molecular effects of HDACi are needed, for improving clinical [...] Read more.
Histone deacetylase inhibitors (HDACi) show high antineoplastic potential in preclinical studies in various solid tumors, including gastric carcinoma; however, their use in clinical studies has not yet yielded convincing efficacies. Thus, further studies on cellular/molecular effects of HDACi are needed, for improving clinical efficacy and identifying suitable combination partners. Here, we investigated the role of oxidative stress in gastric cancer cells upon treatment with HDACi. A particular focus was laid on the role of the Nrf2 pathway, which can mediate resistance to cell-inhibitory effects of reactive oxidative species (ROS). Using fluorescence-based ROS sensors, oxidative stress was measured in human gastric cancer cell lines. Activation of the Nrf2 pathway was monitored in luciferase reporter assays as well as by mRNA and proteomic expression analyses of Nrf2 regulators and Nrf2-induced genes. Furthermore, the effects of ROS scavenger N-acetyl-L-cysteine (NAC) and Nrf2-knockdown on HDACi-dependent antiproliferative effects were investigated in colorimetric formazan-based and clonogenic survival assays. HDACi treatment led to increased oxidative stress levels and consequently, treatment with NAC reduced cytotoxicity of HDACi. In addition, vorinostat treatment stimulated expression of a luciferase reporter under the control of an antioxidative response element, indicating activation of the Nrf2 system. This Nrf2 activation was only partially reversible by treatment with NAC, suggesting ROS independent pathways to contribute to HDACi-promoted Nrf2 activation. In line with its cytoprotective role, Nrf2 knockdown led to a sensitization against HDACi. Accordingly, the expression of antioxidant and detoxifying Nrf2 target genes was upregulated upon HDACi treatment. In conclusion, oxidative stress induction upon HDAC inhibition contributes to the antitumor effects of HDAC inhibitors, and activation of Nrf2 represents a potentially important adaptive response of gastric cancer cells in this context. Full article
(This article belongs to the Special Issue Selective Histone Deacetylase Isoforms as Potential Therapeutic Targets)
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16 pages, 1729 KiB  
Article
Searching for Novel HDAC6/Hsp90 Dual Inhibitors with Anti-Prostate Cancer Activity: In Silico Screening and In Vitro Evaluation
by Luca Pinzi, Silvia Belluti, Isabella Piccinini, Carol Imbriano and Giulio Rastelli
Pharmaceuticals 2024, 17(8), 1072; https://doi.org/10.3390/ph17081072 - 15 Aug 2024
Viewed by 638
Abstract
Prostate cancer (PCA) is one of the most prevalent types of male cancers. While current treatments for early-stage PCA are available, their efficacy is limited in advanced PCA, mainly due to drug resistance or low efficacy. In this context, novel valuable therapeutic opportunities [...] Read more.
Prostate cancer (PCA) is one of the most prevalent types of male cancers. While current treatments for early-stage PCA are available, their efficacy is limited in advanced PCA, mainly due to drug resistance or low efficacy. In this context, novel valuable therapeutic opportunities may arise from the combined inhibition of histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90). These targets are mutually involved in the regulation of several processes in cancer cells, and their inhibition is demonstrated to provide synergistic effects against PCA. On these premises, we performed an extensive in silico virtual screening campaign on commercial compounds in search of dual inhibitors of HDAC6 and Hsp90. In vitro tests against recombinant enzymes and PCA cells with different levels of aggressiveness allowed the identification of a subset of compounds with inhibitory activity against HDAC6 and antiproliferative effects towards LNCaP and PC-3 cells. None of the candidates showed appreciable Hsp90 inhibition. However, the discovered compounds have low molecular weight and a chemical structure similar to that of potent Hsp90 blockers. This provides an opportunity for structural and medicinal chemistry optimization in order to obtain HDAC6/Hsp90 dual modulators with antiproliferative effects against prostate cancer. These findings were discussed in detail in the study. Full article
(This article belongs to the Special Issue Selective Histone Deacetylase Isoforms as Potential Therapeutic Targets)
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20 pages, 5231 KiB  
Article
Novel Histone Deacetylase (HDAC) Inhibitor Induces Apoptosis and Suppresses Invasion via E-Cadherin Upregulation in Pancreatic Ductal Adenocarcinoma (PDAC)
by Katja Schiedlauske, Alina Deipenbrock, Marc Pflieger, Alexandra Hamacher, Jan Hänsel, Matthias U. Kassack, Thomas Kurz and Nicole E. Teusch
Pharmaceuticals 2024, 17(6), 752; https://doi.org/10.3390/ph17060752 - 7 Jun 2024
Viewed by 1108
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer characterized by therapy resistance and early metastasis, resulting in a low survival rate. Histone deacetylase (HDAC) inhibitors showed potential for the treatment of hematological malignancies. In PDAC, the overexpression of HDAC [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer characterized by therapy resistance and early metastasis, resulting in a low survival rate. Histone deacetylase (HDAC) inhibitors showed potential for the treatment of hematological malignancies. In PDAC, the overexpression of HDAC 2 is associated with the epithelial–mesenchymal transition (EMT), principally accompanied by the downregulation of the epithelial marker E-cadherin and increased metastatic capacity. The effector cytokine transforming growth factor-β (TGF β) is known to be a major inducer of the EMT in PDAC, leading to high metastatic and invasive potential. In addition, the overexpression of HDAC 6 in PDAC is associated with reduced apoptosis. Here, we have demonstrated that a novel HDAC 2/6 inhibitor not only significantly increased E-cadherin expression in PANC-1 cells (5.5-fold) and in 3D PDAC co-culture spheroids (2.5-fold) but was also able to reverse the TGF-β-induced downregulation of E-cadherin expression. Moreover, our study indicates that the HDAC inhibitor mediated re-differentiation resulting in a significant inhibition of tumor cell invasion by approximately 60% compared to control. In particular, we have shown that the HDAC inhibitor induces both apoptosis (2-fold) and cell cycle arrest. In conclusion, the HDAC 2/6 inhibitor acts by suppressing invasion via upregulating E-cadherin mediated by HDAC 2 blockade and by inducing cell cycle arrest leading to apoptosis via HDAC 6 inhibition. These results suggest that the HDAC 2/6 inhibitor might represent a novel therapeutic strategy for the treatment of PDAC tumorigenesis and metastasis. Full article
(This article belongs to the Special Issue Selective Histone Deacetylase Isoforms as Potential Therapeutic Targets)
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Review

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48 pages, 12475 KiB  
Review
The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods
by Antonio Curcio, Roberta Rocca, Stefano Alcaro and Anna Artese
Pharmaceuticals 2024, 17(5), 620; https://doi.org/10.3390/ph17050620 - 10 May 2024
Viewed by 3006
Abstract
Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory [...] Read more.
Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson–Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors. Full article
(This article belongs to the Special Issue Selective Histone Deacetylase Isoforms as Potential Therapeutic Targets)
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