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Special Issue "HDAC Inhibitors"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 July 2011)

Special Issue Editor

Guest Editor
Prof. Dr. H. Miles Prince

Centre for Blood Cell Therapies, Department of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A\'Beckett St Melbourne 8006, Victoria, Australia
Interests: blood clotting; bleeding disorders; transfusion medics; myeloma therapy (clinical and pre-clinial)and biology; cutaneous T cell lymphoma (clinical); immunotherapy; epigenetics

Special Issue Information

Dear Colleagues,

Histone deacetylase inhibitors are clearly effective therapeutic tools in the treatment of cancers, particularly haematological malignancies. The purpose of this special issue is to provide the reader with a focused review of on the current place of HDACi as a therapy, particularly in blood cancers. We hope to provide a broad overview of the rationale behind their use, with specific papers focusing on diseases where they clearly have biological effects - NHL, Hodgkin disease, myeloid malignancies. Finally we hope to have two seperate papers examining mechanisms of resistance and common toxicities.

I hope you will be able to contribute to what I see will be a valuable compendium of insightful reviews in this very topical subject.

Prof. Dr. H. Miles Prince
Guest Editors

Keywords

  • histone deacetylase
  • epigenetics
  • demethylation
  • novel therapies
  • transcription factors

Published Papers (5 papers)

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Research

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Open AccessArticle Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich’s Ataxia: A New Synthetic Route
Pharmaceuticals 2011, 4(12), 1578-1590; doi:10.3390/ph4121578
Received: 18 October 2011 / Revised: 30 November 2011 / Accepted: 30 November 2011 / Published: 14 December 2011
Cited by 7 | PDF Full-text (368 KB) | HTML Full-text | XML Full-text
Abstract
Friedreich’s ataxia (FRDA) is caused by transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin. Based on the hypothesis that the acetylation state of the histone proteins is responsible for gene silencing in FRDA, previous work in our [...] Read more.
Friedreich’s ataxia (FRDA) is caused by transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin. Based on the hypothesis that the acetylation state of the histone proteins is responsible for gene silencing in FRDA, previous work in our lab identified a first generation of HDAC inhibitors (pimelic o-aminobenzamides), which increase FXN mRNA in lymphocytes from FRDA patients. Importantly, these compounds also function in a FRDA mouse model to increase FXN mRNA levels in the brain and heart. While the first generation of HDAC inhibitors hold promise as potential therapeutics for FRDA, they have two potential problems: less than optimal brain penetration and metabolic instability in acidic conditions. Extensive optimization focusing on modifying the left benzene ring, linker and the right benzene ring lead to a novel class of HDAC inhibitors that have optimized pharmacological properties (increased brain penetration and acid stability) compared to the previous HDAC inhibitors. This article will describe the chemical synthesis and pharmacological properties of these new HDAC inhibitors. Full article
(This article belongs to the Special Issue HDAC Inhibitors)
Open AccessArticle Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration
Pharmaceuticals 2011, 4(8), 1183-1195; doi:10.3390/ph4081183
Received: 25 July 2011 / Revised: 11 August 2011 / Accepted: 15 August 2011 / Published: 22 August 2011
Cited by 7 | PDF Full-text (571 KB) | HTML Full-text | XML Full-text
Abstract
Mithramycin A (MTM) and histone deacetylase inhibitors (HDACi) are effective therapeutic agents for cancer and neurodegenerative diseases. MTM is a FDA approved aureolic acid-type antibiotic that binds to GC-rich DNA sequences and interferes with Sp1 transcription factor binding to its target sites [...] Read more.
Mithramycin A (MTM) and histone deacetylase inhibitors (HDACi) are effective therapeutic agents for cancer and neurodegenerative diseases. MTM is a FDA approved aureolic acid-type antibiotic that binds to GC-rich DNA sequences and interferes with Sp1 transcription factor binding to its target sites (GC box). HDACi, on the other hand, modulate the activity of class I and II histone deacetylases. They mediate their protective function, in part, by regulating the acetylation status of histones or transcription factors, including Sp1, and in turn chromatin accessibility to the transcriptional machinery. Because these two classes of structurally and functionally diverse compounds mediate similar therapeutic functions, we investigated whether they act on redundant or synergistic pathways to protect neurons from oxidative death. Non-protective doses of each of the drugs do not synergize to create resistance to oxidative death suggesting that these distinct agents act via a similar pathway. Accordingly, we found that protection by MTM and HDACi is associated with diminished expression of the oncogene, Myc and enhanced expression of a tumor suppressor, p21waf1/cip1. We also find that neuroprotection by MTM or Myc knockdown is associated with downregulation of class I HDAC levels. Our results support a model in which the established antitumor drug MTM or canonical HDACi act via distinct mechanisms to converge on the downregulation of HDAC levels or activity respectively. These findings support the conclusion that an imbalance in histone acetylase and HDAC activity in favor of HDACs is key not only for oncogenic transformation, but also neurodegeneration. Full article
(This article belongs to the Special Issue HDAC Inhibitors)

Review

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Open AccessReview Clinical Toxicities of Histone Deacetylase Inhibitors
Pharmaceuticals 2010, 3(9), 2751-2767; doi:10.3390/ph3092751
Received: 23 June 2010 / Revised: 18 August 2010 / Accepted: 19 August 2010 / Published: 26 August 2010
Cited by 38 | PDF Full-text (130 KB) | HTML Full-text | XML Full-text
Abstract
The HDAC inhibitors are a new family of antineoplastic agents. Since the entry of these agents into our therapeutic armamentarium, there has been increasing interest in their use. Although this family comprises chemical compounds from unrelated chemical classes that have different HDAC [...] Read more.
The HDAC inhibitors are a new family of antineoplastic agents. Since the entry of these agents into our therapeutic armamentarium, there has been increasing interest in their use. Although this family comprises chemical compounds from unrelated chemical classes that have different HDAC isoform specificities, they surprisingly have very similar toxicity profiles. In contrast, the observed toxicity profile is somewhat different from that of traditional cytotoxic chemotherapeutic agents and from other epigenetic agents. While some of the side effects may be familiar to the oncologist, others are less commonly seen. As some patients remain on therapy for a prolonged period of time, the long-term sequelae need to be characterized. In addition, since preclinical models suggest promising activity when used in combination with other antineoplastic agents, combination trials are being pursued. It will thus be important to distinguish the relative toxicity attributed to these agents and be alert to the exacerbation of toxicities observed in single agent studies. Notably, few of the agents in this class have completed phase 2 testing. Consequently, more clinical experience is needed to determine the relative frequency of the observed side effects, and to identify and develop approaches to mitigate potential clinical sequelae. Full article
(This article belongs to the Special Issue HDAC Inhibitors)
Open AccessReview Overview of Histone Deacetylase Inhibitors in Haematological Malignancies
Pharmaceuticals 2010, 3(8), 2674-2688; doi:10.3390/ph3082674
Received: 23 July 2010 / Revised: 12 August 2010 / Accepted: 13 August 2010 / Published: 17 August 2010
Cited by 2 | PDF Full-text (163 KB) | HTML Full-text | XML Full-text
Abstract
Histone deacetylase inhibitors (HDACi) can induce hyperacetylation of both histone and non-histone target resulting in epigenetic reprogramming and altered activity, stability and localisation of non-histone proteins to ultimately mediate diverse biological effects on cancer cells and their microenvironment. Clinical trials have demonstrated [...] Read more.
Histone deacetylase inhibitors (HDACi) can induce hyperacetylation of both histone and non-histone target resulting in epigenetic reprogramming and altered activity, stability and localisation of non-histone proteins to ultimately mediate diverse biological effects on cancer cells and their microenvironment. Clinical trials have demonstrated single agent HDACi to have activity in hematological malignancies, in particular T-cell lymphoma and Hodgkin lymphoma. Combination strategies with standard therapies based on pre-clinical data are being employed with significant success due to their excellent side effect profile. Correlative studies will provide valuable information on the sub-groups of patients more likely to respond or be resistant to HDACi therapy, while long-term monitoring for toxicities is also needed. Full article
(This article belongs to the Special Issue HDAC Inhibitors)
Open AccessReview Histone Deacetylase Inhibitors: Advancing Therapeutic Strategies in Hematological and Solid Malignancies
Pharmaceuticals 2010, 3(8), 2441-2469; doi:10.3390/ph3082441
Received: 16 July 2010 / Revised: 30 July 2010 / Accepted: 2 August 2010 / Published: 4 August 2010
Cited by 44 | PDF Full-text (413 KB) | HTML Full-text | XML Full-text
Abstract
Advancement in the understanding of cancer development in recent years has identified epigenetic abnormalities as a common factor in both tumorigenesis and refractory disease. One such event is the dysregulation of histone deacetylases (HDACs) in both hematological and solid tumors, and has [...] Read more.
Advancement in the understanding of cancer development in recent years has identified epigenetic abnormalities as a common factor in both tumorigenesis and refractory disease. One such event is the dysregulation of histone deacetylases (HDACs) in both hematological and solid tumors, and has consequently resulted in the development of HDAC inhibitors (HDACI) to overcome this. HDACI exhibit pleiotropic biological effects including inhibition of angiogenesis and the induction of autophagy and apoptosis. Although HDACI exhibit modest results as single agents in preclinical and clinical data, they often fall short, and therefore HDACI are most promising in combinational strategies with either standard treatments or with other experimental chemotherapies and targeted therapies. This review will discuss the induction of autophagy and apoptosis and the inhibition of angiogenesis by HDACI, and also pre-clinical and clinical combination strategies using these agents. Full article
(This article belongs to the Special Issue HDAC Inhibitors)

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