Depsipeptide-resistant KU812 cells show reversible P-glycoprotein expression, hyper-acetylated histones, and modulated gene expression profile
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Depsipeptide
Histone deacetylase inhibitor
Depsipeptide (FK228), a new histone deacetylase inhibitor, has been recently introduced into clinical trials. This agent shows interesting metabolic properties, novel mechanism of action, and is undergoing phase I-II clinical studies in hematopoietic malignancies and solid tumors. Mechanism of action, pharmacokinetics and anticancer activity of depsipeptide is the subject of this review. Keywords: Epigenetic therapy, histone deacetylase inhibitors, depsipeptide (FK228), cutaneous T-cell lymphoma, solid tumors
Depsipeptide
Histone deacetylase inhibitor
Romidepsin
Mechanism of Action
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Abstract Spiruchostatins C (Ia) and D (Ib) possess extremely potent inhibitory activities against cyclic depsipeptide histone deacetylase 1, better than previously known spiruchostatins A and B and the clinically approved depsipeptide FK228.
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Histone deacetylase inhibitor
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Lysine acetylation is a posttranslational modification that occurs on thousands of human proteins, most of which are cytoplasmic. Acetylated proteins are involved in numerous cellular processes and human diseases. Therefore, how the acetylation/deacetylation cycle is regulated is an important question. Eleven metal-dependent lysine deacetylases (KDACs) have been identified in human cells. These enzymes, along with the sirtuins, are collectively responsible for reversing lysine acetylation. Despite several large-scale studies which have characterized the acetylome, relatively few of the specific acetylated residues have been matched to a proposed KDAC for deacetylation. To understand the function of lysine acetylation, and its association with diseases, specific KDAC-substrate pairs must be identified. Identifying specific substrates of a KDAC is complicated both by the complexity of assaying relevant activity and by the non-catalytic interactions of KDACs with cellular proteins. Here, we discuss in vitro and cell-based experimental strategies used to identify KDAC-substrate pairs and evaluate each for the purpose of directly identifying non-histone substrates of metal-dependent KDACs. We propose criteria for a combination of reproducible experimental approaches that are necessary to establish a direct enzymatic relationship. This critical analysis of the literature identifies 108 proposed non-histone substrate-KDAC pairs for which direct experimental evidence has been reported. Of these, five pairs can be considered well-established, while another thirteen pairs have both cell-based and in vitro evidence but lack independent replication and/or sufficient cell-based evidence. We present a path forward for evaluating the remaining substrate leads and reliably identifying novel KDAC substrates.
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The histone deacetylase inhibitors (HDIs) are a new class of antineoplastic agents currently being evaluated in clinical trials. While these agents have been studied extensively in the laboratory, only recently has their mechanism of action begun to be elucidated. Several structural classes of compounds have been shown to exert histone deacetylase inhibition, including sodium n-butyrate, suberoylanilide hydroxamic acid, LAQ824, CI-994, MS-275, and depsipeptide. The HDIs have been shown to induce differentiation, to decrease cell proliferation, and to induce cell death. HDIs are thought to exert their anti-neoplastic effects by altering the expression of genes that play a role in the control of cell growth, and transformation. The HDIs have specific and well-defined effects on cancer cells. Preliminary results from clinical trials suggest that these agents are very promising. While there were sporadic case reports of activity using the early generation HDIs, dramatic responses have recently been observed in patients with T-cell lymphomas treated with depsipeptide, one of the newer agents. With the well-defined molecular effects on cancer cells, surrogate markers can be analyzed for evidence of activity and efficacy using either tumor samples or normal tissue. Presented in this review are details from clinical trials with both earlier and newer generations of HDIs. Toxicities specific to this class of agents are outlined and possibilities for rational combination therapies are discussed.
Depsipeptide
Sodium butyrate
Histone deacetylase inhibitor
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The cyclic depsipeptide FK228 is the only natural product histone deacetylase (HDAC) inhibitor that has advanced to clinical trials as an anticancer agent. While currently obtained by fermentation, total synthesis is an attractive alternative that will facilitate the preparation of unnatural analogues. The previous total syntheses of FK228 featured macrocylization by ester bond formation from a seco-hydroxy acid. Such routes are operationally jeopardized by the steric hindrance of the carboxylic acid and the sensitivity of the allylic alcohol toward elimination. We report a strategically different approach whereby the ester bond is formed intermolecularly at an early stage and macrocyclization is efficiently achieved by amide bond formation.
Depsipeptide
Histone deacetylase inhibitor
Peptide bond
Amide
Natural product
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Depsipeptide
Histone deacetylase inhibitor
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The possibility that chromatin domains containing acetylated histones are proximal to domains containing chromosomal high mobility group protein 17 (HMG-17) has been investigated. Oligonucleosomes containing [3H]acetate-labeled histones have been immunofractionated on anti-HMG-17 IgG-Sepharose columns. Ninety-one per cent of the 3H counts present in the oligonucleosomes specifically bound to the anti-HMG-17 column. Extraction of HMG-17 from chromatin by treatment with 0.4 M NaCl abolished the specific binding of acetylated chromatin to the Sepharose columns. Autoradiographic analysis of polyacrylamide gels of the bound fraction revealed that it contained all the major acetylated histone species. We conclude that acetylated histones are present on or near nucleosomes containing protein HMG-17.
High-mobility group
Sepharose
Polyacrylamide
Non-histone protein
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Determining how histone acetylation is regulated is vital for treating the many diseases associated with its misregulation, including heart disease, neurological disorders, and cancer. We have previously reported that acetyl-CoA levels alter p300 histone acetylation in a site-specific manner in vitro. Here, we further investigate how changing acetyl-CoA concentrations alter the histone acetylation pattern by altering p300 specificity. Interestingly, these changes are not a simple global change in acetylation, but rather site specific changes, whereby acetylation at some sites increase while others decrease. We also demonstrate how the p300 inhibitor C646 can pharmacologically alter p300 histone acetylation patterns in vitro and in cells. This study provides insight into the mechanisms regulating p300 residue specificity, a potential means for altering p300 dependent histone acetylation, and an investigation into altering histone acetylation patterns in cells.
SAP30
P300-CBP Transcription Factors
HDAC4
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Abstract Decreased extracellular pH induces sustained global histone deacetylation.
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Histone deacetylase (HDAC) inhibitors are currently used in the study of epigenetics and have potential in clinical cancer therapy. A novel and potent HDAC inhibitor, depsipeptide, also known as FK228 or FR901228, is highly efficient in inhibiting the activity of HDACs even at nanomolar concentrations. Depsipeptide has a unique structure that is distinct from most of the other HDACs, and it thus exhibits diverse pharmacologic functions. In addition, depsipeptide has a metabolic activation pathway, which affects many intracellular processes. However, the specific features of this pathway are as yet not completely worked out. In this article, we will focus on the uniqueness of this molecule's specific structure, the relationship of this structure to its putative metabolic activation pathway, and specifically review its newly discovered biological functions and clinical applications.
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Histone deacetylase inhibitor
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