http://www.mdpi.com/journal/pharmaceuticals/special_issues/HDAC-inhibitors/ 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 {snippet name="submission_info"} http://www.mdpi.com/1424-8247/4/12/1578/ 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. http://www.mdpi.com/1424-8247/4/12/1578/ Wed, 14 Dec 2011 00:00:00 CET Pharmaceuticals 2011-12-14 4 12 Article 1578 1590 1424-8247 Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich’s Ataxia: A New Synthetic Route 2011-12-14 doi: 10.3390/ph4121578 Chunping Xu Elisabetta Soragni Vincent Jacques James R. Rusche Joel M. Gottesfeld http://www.mdpi.com/1424-8247/4/8/1183/ 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. http://www.mdpi.com/1424-8247/4/8/1183/ Mon, 22 Aug 2011 00:00:00 CEST Pharmaceuticals 2011-08-22 4 8 Article 1183 1195 1424-8247 Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration 2011-08-22 doi: 10.3390/ph4081183 Sama F. Sleiman Jill Berlin Manuela Basso Saravanan S.Karuppagounder Jürgen Rohr Rajiv R. Ratan http://www.mdpi.com/1424-8247/3/9/2751/ 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. http://www.mdpi.com/1424-8247/3/9/2751/ Thu, 26 Aug 2010 00:00:00 CEST Pharmaceuticals 2010-08-26 3 9 Review 2751 2767 1424-8247 Clinical Toxicities of Histone Deacetylase Inhibitors 2010-08-26 doi: 10.3390/ph3092751 Srividya Subramanian Susan E. Bates John J. Wright Igor Espinoza-Delgado Richard L. Piekarz http://www.mdpi.com/1424-8247/3/8/2674/ 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. http://www.mdpi.com/1424-8247/3/8/2674/ Tue, 17 Aug 2010 00:00:00 CEST Pharmaceuticals 2010-08-17 3 8 Review 2674 2688 1424-8247 Overview of Histone Deacetylase Inhibitors in Haematological Malignancies 2010-08-17 doi: 10.3390/ph3082674 Mark J. Bishton Ricky W. Johnstone Michael Dickinson Simon Harrison H. Miles Prince http://www.mdpi.com/1424-8247/3/8/2441/ 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. http://www.mdpi.com/1424-8247/3/8/2441/ Wed, 04 Aug 2010 00:00:00 CEST Pharmaceuticals 2010-08-04 3 8 Review 2441 2469 1424-8247 Histone Deacetylase Inhibitors: Advancing Therapeutic Strategies in Hematological and Solid Malignancies 2010-08-04 doi: 10.3390/ph3082441 Leigh Ellis Roberto Pili