The important role of histone deacetylase enzymes in regulating gene expression, cellular proliferation, and survival has made them attractive targets for the development of histone deacetylase inhibitors as anticancer drugs. Suberoylanilide hydroxamic acid (Vorinostat, Zolinza), a structural analogue of the prototypical Trichostatin A, was approved by the US Food and Drug Administration for the treatment of advanced cutaneous T-cell lymphoma in 2006. This was followed by approval of the cyclic peptide, depsipeptide (Romidepsin, Istodax) for the same disease in 2009. Currently numerous histone deacetylase inhibitors are undergoing preclinical and clinical trials for the treatment of hematological and solid malignancies. Most of these studies are focused on combinations of histone deacetylase inhibitors with other therapeutic modalities, particularly conventional chemotherapeutics and radiotherapy. The aim of this paper is to provide an overview of the classical histone deacetylase enzymes and histone deacetylase inhibitors with an emphasis on potential combination therapies. 1. Introduction Chromatin is a dynamic structure that, via numerous mechanisms including DNA methylation and posttranslational histone modifications, undergoes remodeling to facilitate metabolic processes including transcription, replication, and repair [1]. One of the well-investigated posttranslational histone modifications is acetylation which was first defined in the 1960s [2, 3]. Histone acetylation is controlled by the opposing actions of two groups of enzymes, namely, histone acetyltransferases (HATs) and histone deacetylases (HDACs) [4–6]. HATs catalyze the transfer of the acetyl moiety of the substrate acetyl-coA to the ε-amino group of lysine residues on histones. This neutralizes the positive charge of histones, weakening their interaction with the negatively charged DNA. This results in a more relaxed, transcriptionally permissive chromatin conformation [7, 8]. HDAC enzymes remove acetyl groups from histones resulting in a more condensed, transcriptionally repressive chromatin state [4, 5]. The 18 mammalian HDAC enzymes identified to date are categorized into two distinct groups. The class III HDAC enzymes which include the sirtuins 1–7 require nicotinamide adenine dinucleotide (NAD+) to deacetylate lysine residues [12, 13]. These have been implicated with numerous diseases and in the process of aging [14]. The remaining 11 enzymes are typically known as the classical HDAC enzymes and will be the focus of the remaining of this paper [9]. An intense interest in function
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