Targeting histone deacetylases for heart failure

Background: Stresses such as chronic hypertension and myocardial infarction can trigger the heart to undergo a remodeling process characterized by myocyte hypertrophy, myocyte death and fibrosis, often resulting in impaired cardiac function and heart failure. Recent studies suggest key roles for histone deacetylases (HDACs) in the control of pathological cardiac remodeling. Objective/methods: Here, we review these target validation experiments and highlight non-cardiac functions of HDACs that will need to be addressed during development of HDAC-directed therapies for heart failure. Results/conclusions: HDACs are unique and attractive therapeutic targets for heart failure because of their positions far downstream in pathological signaling cascades. Confirmation of the validity and viability of approaches aimed at HDACs awaits in vivo proof-of-concept testing with novel small molecule regulators of these enzymes.     

Targeting histone deacetylases for cancer therapy: Trends and challenges

Dysregulation of histone deacetylases(HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors(HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. Thi...     

Sensitization of tumor cells by targeting histone deacetylases

Epigenetic mechanisms may contribute to drug resistance by interfering with tumor growth regulatory pathways and pro-apoptotic programs. Since gene expression is regulated by acetylation status of histones, a large variety of histone deacetylase (HDAC) inhibitors have been studied as antitumor agents. On the basis of their pro-apoptotic activity, HDAC inhibitors have been combined with conventional antitumor agents or novel target-specific agents to increase susceptibility to apoptosis and drug sensitivity of cancer cells. Several combination strategies including HDAC inhibitors have been explored in preclinical studies. Promising therapeutic effects have been reported in combination with DNA damaging agents, taxanes, targeted agents, death receptor agonists and hormonal therapies. Some histone deacetylases, such as HDAC6, can also modulate the function of non-histone proteins involved in critical regulatory processes which may be relevant as therapeutic targets. Given the pleiotropic effects of most of the available inhibitors, the mechanisms of the sensitization are not completely elucidated. A better understanding of the involved mechanisms will provide a rational basis to improve the therapeutic outcome of the available antitumor agents.     

Synthesis and activity of some new histone deacetylases inhibitors

To explore novel histone deacetylase (HDAC) inhibitors with anti-tumor activity, twelve target compounds were synthesized, and their structures were confirmed by 1H NMR, MS and elemental analyses. Evaluation results in vitro showed that compound Ia exhibited potent inhibition against HDAC and is worth for further investigation. And compounds IIa, IIb, IIIa-IIIi possessed moderate HDAC inhibitory activity.     

Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment

Mycophenolic acid (MPA), an inhibitor of IMP-dehydrogenase (IMPDH), is used worldwide in transplantation. Recently, numerous studies showed its importance in cancer treatment. Consequently, MPA entered clinical trials in advanced multiple myeloma patients. Suberoylanilide hydroxamic acid (SAHA), a potent differentiation agent acting through inhibition of histone deacetylases (HDACs), was recently approved for treatment of cutaneous T cell lymphoma. We report herein the synthesis of dual inhibitors of IMPDH and HDACs. We found that mycophenolic hydroxamic acid (9, MAHA) inhibits both IMPDH (Ki=30 nM) and HDAC (IC50=5.0 microM). A modification of SAHA with groups known to interact with IMPDH afforded a SAHA analogue 14, which inhibits IMPDH (Ki=1.7 microM) and HDAC (IC50=0.06 microM). Both MAHA (IC50=4.8 microM) and SAHA analogue 14 (IC50=7.7 microM) were more potent than parent compounds as antiproliferation agents. They were also significantly more potent as differentiation inducers.     

The structure and function of histone deacetylases: the target for anti-cancer therapy

Histone deacetylases (HDACs) and Histone acetyltransferases (HATs) are two kinds of enzymes, which can, by reversible deacetylation and acetylation, modify the structure and function of chromatin histones that are involved in the regulation of gene expression, as well as many non-histone proteins that regulate cell function in eukaryotes. Compared with HATs, HDACs have attracted more and more attentions for two main reasons over the past few years. First, the relationship of HDACs and cancer, as well as several other diseases has been confirmed. Second, many HDAC inhibitors (HDACi) have entered pre-clinical or clinical research as anti-cancer agents and shown satisfying effects. HDACs, including 18 members at least, are subdivided into 4 classes that generally have high structure similarity and related substrate specificity within classes, but have divergent sequence and different functions even between within classes. This review will introduce the relationship between HDACs and cancer along with the enzymes' structure and main function.     

Inhibitors of NAD+ dependent histone deacetylases (sirtuins)

Histone deacetylases (HDACs) are enzymes that deacetylate acetyl lysines in histones and various non-histone proteins. Three classes of histone deacetylases have been described in humans: class I, II and IV were shown to be zinc dependent amidohydrolases and eleven subtypes are known today (HDAC1-11). Class III enzymes depend in their catalysis on NAD+ with the subsequent formation of nicotinamide and O acetyl-ADP ribose. Based on the homology to the yeast histone deacetylase Sir2p the NAD+-dependent deacetylases have been termed sirtuins and seven members (SIRT1-7) have been described in humans. Whereas class I and II HDACs have been identified as valid anticancer targets and clinical studies of their inhibitors as new anticancer agents are under way much less is known about the consequences of class III histone deacetylase inhibition. Sirtuins have been linked to ageing and overexpression of sirtuins leads to a prolonged lifespan in yeast. Lately, sirtuin activity has been tied to the pathogenesis of HIV, cancer and neurodegenerative disease. In the last two years several reports of new sirtuin inhibitors have emerged. Additionally, sirtuin activators have been identified and have been implicated as potential drugs for the amelioration of metabolic diseases. Thus, the field of sirtuin biology can be investigated with these new tools which will allow in turn to assess the therapeutic potential of those compounds. We will present an overview over sirtuins and their available inhibitors and activators.     

组蛋白去乙酰化酶抑制剂抗肿瘤临床研究进展

综述了近年来组蛋白去乙酰化酶(HDAC)抑制剂作为抗肿瘤药的临床研究进展。组蛋白去乙酰化酶抑制剂可以引导肿瘤细胞生长停滞、分化和凋亡,是很有前途的癌症治疗药物。目前,超过十多种组蛋白去乙酰化酶抑制剂作为治疗血液肿瘤和恶性实体瘤药物,有上百个临床试验正在进行中。     

1,3,5-Triazine inhibitors of histone deacetylases: synthesis and biological activity

A series of 1,3,5-triazine-based hydroximic acids 6a–6i were designed and synthesized, and they were found to be potent inhibitors of human histone deacetylases. These compounds were evaluated for their antiproliferative activity by MTT assay, and most of them exhibited significant antiproliferative effect on HCT-116, MCF-7, and HeLa cancer cell lines. DNA flow cytometric analysis revealed that compound 6i induced apoptosis and cell cycle arrest at G2/M phase in HCT-116 cells.     

Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats

Background and purpose:

Histone deacetylases (HDACs) silence genes by deacetylating lysine residues in histones and other proteins. HDAC inhibitors represent a new class of compounds with anti-inflammatory activity. This study investigated whether treatment with a broad spectrum HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), would prevent cardiac fibrosis, part of the cardiovascular remodelling in deoxycorticosterone acetate (DOCA)-salt rats.

Experimental approach:

Control and DOCA-salt rats were treated with SAHA (25 mg·kg⁻¹·day⁻¹ s.c.) for 32 days. Changes in cardiovascular structure and function were assessed by blood pressure in vivo and in Langendorff perfused hearts, ventricular papillary muscle and in aortic rings in vitro. Left ventricular collagen deposition was assessed by histology.

Key results:

Administration of SAHA to DOCA-salt rats attenuated the following parameters: the increased concentration of over 20 pro-inflammatory cytokines in plasma, increased inflammatory cell infiltration and interstitial collagen deposition, increased passive diastolic stiffness in perfused hearts, prolongation of action potential duration at 20% and 90% of repolarization in papillary muscle, development of left ventricular hypertrophy, systolic hypertension and changes in vascular dysfunction.

Conclusions and implications:

The HDAC inhibitor, SAHA, attenuated the cardiovascular remodelling associated with DOCA-salt hypertensive rats and improved cardiovascular structure and function, especially fibrosis, in the heart and blood vessels, possibly by suppressing inflammation. Control of cardiac histone or non-histone protein acetylation is a potential therapeutic approach to preventing cardiac remodelling, especially cardiac fibrosis.     

基于组蛋白去乙酰化酶设计的多靶点抗肿瘤药物研究进展

肿瘤的发生是一个多因子、多步骤的复杂过程.多靶点抗肿瘤药物能同时作用于肿瘤发生的多个疾病通路,比单靶点抗肿瘤药物有更好的治疗效果.研究显示,组蛋白去乙酰化酶(histone deacetylase,HDACs)在多种肿瘤细胞中过度表达,是肿瘤发生的关键靶点,因此以抑制HDACs为基础设计兼顾作用于其他靶点的多靶点抗肿瘤...     

组蛋白去乙酰化酶抑制剂的合成及其体外抗肿瘤研究

目的设计并合成组蛋白去乙酰化酶抑制剂(HDACi),并对其组蛋白去乙酰化酶(HDACs)抑制活性和体外抗肿瘤活性进行研究。方法以N-Boc-对苯二胺和辛二酸酐为起始原料,反应制得7-(N-Boc-氨基)苯胺甲酰基庚酸,再通过胺醛缩合反应合成HDACi;并采用HDACs试剂盒和CCK-8试剂盒测试所合成目标化合物抑制HDACs的活性和抗肿瘤活性。结果合成了26个新化合物,其结构均经过核磁共振氢谱和质谱进行了确证。初步的生物活性测试结果表明,所合成的目标化合物对HDACs的抑制活性均强于阳性药物伏立诺他,并对MCF-7、PC-3、HepG2、MGC-803和KB 5种肿瘤细胞有不同程度的抑制活性,其中希夫碱含有吸电子基的化合物对HDACs的抑制活性以及抗肿瘤活性强于其他衍生物。尤其是4-氰基化合物11c对HDACs展现出了最强的抑制活性,是阳性药伏立诺他的58倍;同时,化合物11c对肿瘤细胞MCF-7、PC3、MGC-803和HepG2展现出了最强的抗肿瘤活性,其抗胃癌MGC-803甚至是阳性药物伏立诺他的7.2倍。结论希夫碱是一类重要的抗肿瘤药效团,能够提高HDACi的抗肿瘤活性,为今后发展新型、高效的HDACi提供了新的思路。     

The role of NAD+ dependent histone deacetylases (sirtuins) in ageing

Histone deacetylases (HDACs) are enzymes that are able to deacetylate lysine side chains in histones and certain non-histone proteins which leads to altered states of conformation and activity for the proteins in question. Three classes of histone deacetylases have been recognized in humans. Class I and II are zinc-dependent amidohydrolases and eleven subtypes have been discovered (HDAC1-11). Class III enzymes depend in their catalysis on NAD(+) and subsequently, O-acetyl ADP ribose and nicotinamide are formed as a consequence of the acetyl transfer. Due to the homology to the yeast histone deacetylase Sir2p the NAD(+)-dependent deacetylases are also termed sirtuins and seven members (Sirt1-7) are known in humans. Sirtuins are found from bacteria to eukaryotes and altogether about 60 isoforms have been characterized in different organisms. Sirtuins have been implicated in the regulation of molecular mechanisms of aging. The overexpression of sirtuin enzymatic activity leads to an increase of lifespan in Saccharomyces cerevisiae and Caenorhabditis elegans that can also be reached by calorie restriction. Sirtuins have been proposed to act as sensors for glucose uptake that respond to the levels of NAD(+) but more complex ways of action have been suggested as well. This article will present the members of the human sirtuin family with their respective functions and review the existing druglike inhibitors and activators of sirtuin activity.