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Cancers
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Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents
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Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 30551

Special Issue Editors

Dr. Francesca Bruzzese

E-Mail Website
Guest Editor
Istituto Nazionale Tumori, IRCCS-Fondazione G. Pascale, Napoli, Via Mariano Semmola, 53, 80131 Napoli NA, Italy
Interests: HDAC Inhibitors; In Vitro and In Vivo Experimental Anticancer Strategies; Drug Combination Studies; Prostate Cancer; Repurposing
Dr. Alfredo Budillon

E-Mail Website
Co-Guest Editor
Istituto Nazionale Tumori, IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 53, 80131 Napoli NA, Italy
Interests: pharmacology; cancer; HDAC inhibitors; cell biology; proteomics; metabolomics; in vivo studies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epigenetic aberrations have been recognized as key drivers of solid and hematopoietic cancers. They are often caused by genetic defects, resulting in functional de-regulation of epigenetic regulators, including histone deacetylases (HDAC), implicated in the regulation of acetylation levels of both histones and non-histone proteins. Several small molecule HDAC inhibitors (HDACi) have been synthetized and tested as anticancer agents, both in the preclinical and clinical setting. HDACi are truly pleiotropic agents, acting through a wide variety of disparate and mutually interactive mechanisms we will highlight in this Special Issue. HDAC inhibitors can have both tumor-cell autonomous and tumor-cell non-autonomous effects, and it remains unclear precisely how important this interplay is for the responses to these agents seen in vivo. HDAC inhibitors, by specifically targeting the cancer stem cell subpopulation, have been suggested to overcome drug resistance. Similarly, the interplay between epigenetic alterations and metabolic reprogramming implies novel applications of HDACi. The ability of HDACi to alter the immunogenicity of tumor cells and/or regulate the activity, effector function, and tumor cell localization of host immune cells has invigorated efforts to therapeutically harness this interaction. This Special Issue will focus on solid cancers where multiple factors contributing to the failure of commonly used therapies suggest the potential of combination therapeutic approaches with HDACi.

Dr. Francesca Bruzzese
Dr. Alfredo Budillon
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • histone deacetylases
  • histone deacetylase inhibitors
  • solid cancers
  • combination therapy
  • radiotherapy
  • immunotherapy
  • cancer stem cells
  • clinical trials
  • metabolic reprogramming

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Published Papers (7 papers)

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Research

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22 pages, 3182 KiB  
Article
Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells
by Ipek Bulut, Adam Lee, Buse Cevatemre, Dusan Ruzic, Roman Belle, Akane Kawamura, Sheraz Gul, Katarina Nikolic, A. Ganesan and Ceyda Acilan
Cancers 2022, 14(23), 6014; https://doi.org/10.3390/cancers14236014 - 6 Dec 2022
Cited by 15 | Viewed by 3000
Abstract
Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, [...] Read more.
Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated. Full article
(This article belongs to the Special Issue Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents)
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19 pages, 3168 KiB  
Article
A Histone Deacetylase Inhibitor Induces Acetyl-CoA Depletion Leading to Lethal Metabolic Stress in RAS-Pathway Activated Cells
by Agnes Basseville, Pierre-Christian Violet, Maryam Safari, Carole Sourbier, W. Marston Linehan, Robert W. Robey, Mark Levine, Dan L. Sackett and Susan E. Bates
Cancers 2022, 14(11), 2643; https://doi.org/10.3390/cancers14112643 - 26 May 2022
Cited by 6 | Viewed by 2833
Abstract
Background: The mechanism of action of romidepsin and other histone deacetylase inhibitors is still not fully explained. Our goal was to gain a mechanistic understanding of the RAS-linked phenotype associated with romidepsin sensitivity. Methods: The NCI60 dataset was screened for molecular clues to [...] Read more.
Background: The mechanism of action of romidepsin and other histone deacetylase inhibitors is still not fully explained. Our goal was to gain a mechanistic understanding of the RAS-linked phenotype associated with romidepsin sensitivity. Methods: The NCI60 dataset was screened for molecular clues to romidepsin sensitivity. Histone acetylation, DNA damage, ROS production, metabolic state (real-time measurement and metabolomics), and gene expression alterations (transcriptomics) were determined in KRAS-WT versus KRAS-mutant cell groups. The search for biomarkers in response to HDACi was implemented by supervised machine learning analysis on a 608-cell transcriptomic dataset and validated in a clinical dataset. Results: Romidepsin treatment induced depletion in acetyl-CoA in all tested cell lines, which led to oxidative stress, metabolic stress, and increased death—particularly in KRAS-mutant cell lines. Romidepsin-induced stresses and death were rescued by acetyl-CoA replenishment. Two acetyl-CoA gene expression signatures associated with HDACi sensitivity were derived from machine learning analysis in the CCLE (Cancer Cell Line Encyclopedia) cell panel. Signatures were then validated in the training cohort for seven HDACi, and in an independent 13-patient cohort treated with belinostat. Conclusions: Our study reveals the importance of acetyl-CoA metabolism in HDAC sensitivity, and it highlights acetyl-CoA generation pathways as potential targets to combine with HDACi. Full article
(This article belongs to the Special Issue Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents)
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22 pages, 2979 KiB  
Article
Correlation Analysis of Protein Expression of 10 HDAC/Sirtuin Isoenzymes with Sensitivities of 23 Anticancer Drugs in 17 Cancer Cell Lines and Potentiation of Drug Activity by Co-Treatment with HDAC Inhibitors
by Steven Behnisch-Cornwell, Christoph W. Grathwol, Lukas Schulig, Anika Voigt, Daniel Baecker, Andreas Link and Patrick J. Bednarski
Cancers 2022, 14(1), 187; https://doi.org/10.3390/cancers14010187 - 31 Dec 2021
Cited by 4 | Viewed by 2741
Abstract
Inhibiting the activity of histone deacetylase (HDAC) is an ongoing strategy in anticancer therapy. However, to our knowledge, the relationships between the expression of HDAC proteins and the antitumor drug sensitivity of cancer cells have not been studied until now. In the current [...] Read more.
Inhibiting the activity of histone deacetylase (HDAC) is an ongoing strategy in anticancer therapy. However, to our knowledge, the relationships between the expression of HDAC proteins and the antitumor drug sensitivity of cancer cells have not been studied until now. In the current work, we investigated the relative expression profiles of 10 HDAC isoenzymes comprising the classes I–III (HDAC1/2/4/6; Sirt1/2/3/5/6/7) in a panel of 17 cancer cell lines, including the breast, cervix, oesophageal, lung, oral squamous, pancreas, as well as urinary bladder carcinoma cells. Correlations between the data of mRNA expression for these enzymes obtained from the National Cancer Institute (NCI) 60 cancer cell line program were also examined. Next, we performed univariate analysis between the expression patterns of HDAC/Sirt isoenzymes with the sensitivity of a 16 cell panel of cancer cell lines towards several antitumor drugs. In a univariate correlation analysis, we found a strong relation between Sirt2 expression and cytotoxicity caused by busulfan, etoposide, and hydroxyurea. Moreover, it was identified that Sirt5 correlates with the effects exerted by oxaliplatin or topotecan, as well as between HDAC4 expression and these two drugs. Correlations between the data of mRNA expression for enzymes with the potencies of the same anticancer agents obtained from the NCI 60 cancer cell line program were also found, but none were the same as those we found with our protein expression data. Additionally, we report here the effects upon combination of the approved HDAC inhibitor vorinostat and one other known inhibitor trichostatin A as well as newer hetero-stilbene and diazeno based sirtuin inhibitors on the potency of cisplatin, lomustine, and topotecan. For these three anticancer drugs, we found a significantly enhanced cytotoxicity when co-incubated with HDAC inhibitors, demonstrating a potentially beneficial influence of HDAC inhibition on anticancer drug treatment. Full article
(This article belongs to the Special Issue Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents)
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Review

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27 pages, 2277 KiB  
Review
Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors
by Laura Grumetti, Rita Lombardi, Federica Iannelli, Biagio Pucci, Antonio Avallone, Elena Di Gennaro and Alfredo Budillon
Cancers 2022, 14(3), 695; https://doi.org/10.3390/cancers14030695 - 29 Jan 2022
Cited by 6 | Viewed by 3882
Abstract
Although fluoropyrimidines were introduced as anticancer agents over 60 years ago, they are still the backbone of many combination chemotherapy regimens for the treatment of solid cancers. Like other chemotherapeutic agents, the therapeutic efficacy of fluoropyrimidines can be affected by drug resistance and [...] Read more.
Although fluoropyrimidines were introduced as anticancer agents over 60 years ago, they are still the backbone of many combination chemotherapy regimens for the treatment of solid cancers. Like other chemotherapeutic agents, the therapeutic efficacy of fluoropyrimidines can be affected by drug resistance and severe toxicities; thus, novel therapeutic approaches are required to potentiate their efficacy and overcome drug resistance. In the last 20 years, the deregulation of epigenetic mechanisms has been shown to contribute to cancer hallmarks. Histone modifications play an important role in directing the transcriptional machinery and therefore represent interesting druggable targets. In this review, we focused on histone deacetylase inhibitors (HDACis) that can increase antitumor efficacy and overcome resistance to fluoropyrimidines by targeting specific genes or proteins. Our preclinical data showed a strong synergistic interaction between HDACi and fluoropyrimidines in different cancer models, but the clinical studies did not seem to confirm these observations. Most likely, the introduction of increasingly complex preclinical models, both in vitro and in vivo, cannot recapitulate human complexity; however, our analysis of clinical studies revealed that most of them were designed without a mechanistic approach and, importantly, without careful patient selection. Full article
(This article belongs to the Special Issue Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents)
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13 pages, 589 KiB  
Review
HDAC Inhibition to Prime Immune Checkpoint Inhibitors
by Edith Borcoman, Maud Kamal, Grégoire Marret, Celia Dupain, Zahra Castel-Ajgal and Christophe Le Tourneau
Cancers 2022, 14(1), 66; https://doi.org/10.3390/cancers14010066 - 23 Dec 2021
Cited by 41 | Viewed by 4625
Abstract
Immunotherapy has made a breakthrough in medical oncology with the approval of several immune checkpoint inhibitors in clinical routine, improving overall survival of advanced cancer patients with refractory disease. However only a minority of patients experience a durable response with these agents, which [...] Read more.
Immunotherapy has made a breakthrough in medical oncology with the approval of several immune checkpoint inhibitors in clinical routine, improving overall survival of advanced cancer patients with refractory disease. However only a minority of patients experience a durable response with these agents, which has led to the development of combination strategies and novel immunotherapy drugs to further counteract tumor immune escape. Epigenetic regulations can be altered in oncogenesis, favoring tumor progression. The development of epidrugs has allowed targeting successfully these altered epigenetic patterns in lymphoma and leukemia patients. It has been recently shown that epigenetic alterations can also play a key role in tumor immune escape. Epidrugs, like HDAC inhibitors, can prime the anti-tumor immune response, therefore constituting interesting partners to develop combination strategies with immunotherapy agents. In this review, we will discuss epigenetic regulations involved in oncogenesis and immune escape and describe the clinical development of combining HDAC inhibitors with immunotherapies. Full article
(This article belongs to the Special Issue Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents)
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16 pages, 1839 KiB  
Review
HDAC6 Inhibition Extinguishes Autophagy in Cancer: Recent Insights
by Eugenia Passaro, Chiara Papulino, Ugo Chianese, Antonella Toraldo, Raffaella Congi, Nunzio Del Gaudio, Maria Maddalena Nicoletti, Rosaria Benedetti and Lucia Altucci
Cancers 2021, 13(24), 6280; https://doi.org/10.3390/cancers13246280 - 14 Dec 2021
Cited by 12 | Viewed by 5062
Abstract
Autophagy is an essential intracellular catabolic mechanism involved in the degradation and recycling of damaged organelles regulating cellular homeostasis and energy metabolism. Its activation enhances cellular tolerance to various stresses and is known to be involved in drug resistance. In cancer, autophagy has [...] Read more.
Autophagy is an essential intracellular catabolic mechanism involved in the degradation and recycling of damaged organelles regulating cellular homeostasis and energy metabolism. Its activation enhances cellular tolerance to various stresses and is known to be involved in drug resistance. In cancer, autophagy has a dual role in either promoting or blocking tumorigenesis, and recent studies indicate that epigenetic regulation is involved in its mechanism of action in this context. Specifically, the ubiquitin-binding histone deacetylase (HDAC) enzyme HDAC6 is known to be an important player in modulating autophagy. Epigenetic modulators, such as HDAC inhibitors, mediate this process in different ways and are already undergoing clinical trials. In this review, we describe current knowledge on the role of epigenetic modifications, particularly HDAC-mediated modifications, in controlling autophagy in cancer. We focus on the controversy surrounding their ability to promote or block tumor progression and explore the impact of HDAC6 inhibitors on autophagy modulation in cancer. In light of the fact that targeted drug therapy for cancer patients is attracting ever increasing interest within the research community and in society at large, we discuss the possibility of using HDAC6 inhibitors as adjuvants and/or in combination with conventional treatments to overcome autophagy-related mechanisms of resistance. Full article
(This article belongs to the Special Issue Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents)
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29 pages, 1298 KiB  
Review
Vorinostat (SAHA) and Breast Cancer: An Overview
by Anna Wawruszak, Lidia Borkiewicz, Estera Okon, Wirginia Kukula-Koch, Syeda Afshan and Marta Halasa
Cancers 2021, 13(18), 4700; https://doi.org/10.3390/cancers13184700 - 19 Sep 2021
Cited by 51 | Viewed by 6983
Abstract
Vorinostat (SAHA), an inhibitor of class I and II of histone deacetylases, is the first histone deacetylase inhibitor (HDI) approved for the treatment of cutaneous T-cell lymphoma in 2006. HDIs are promising anticancer agents that inhibit the proliferation of many types of cancer [...] Read more.
Vorinostat (SAHA), an inhibitor of class I and II of histone deacetylases, is the first histone deacetylase inhibitor (HDI) approved for the treatment of cutaneous T-cell lymphoma in 2006. HDIs are promising anticancer agents that inhibit the proliferation of many types of cancer cells including breast carcinoma (BC). BC is a heterogeneous disease with variable biological behavior, morphological features, and response to therapy. Although significant progress in the treatment of BC has been made, high toxicity to normal cells, serious side effects, and the occurrence of multi-drug resistance limit the effective therapy of BC patients. Therefore, new active agents which improve the effectiveness of currently used regimens are highly needed. This manuscript analyzes preclinical and clinical trials data of SAHA, applied individually or in combination with other anticancer agents, considering different histological subtypes of BC. Full article
(This article belongs to the Special Issue Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents)
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