组蛋白去乙酰酶抑制剂的研究进展

组蛋白乙酰转移酶(histone acetyltransferase,HAT)和组蛋白去乙酰酶(histone deacetylase,HDAC)通过对组蛋白氮端氨基酸残基进行乙酰化或去乙酰化,调节组蛋白的乙酰化水平,调控基因表达,该过程与癌症的发生具有密切的关系.组蛋白去乙酰酶抑制剂通过增加细胞内组蛋白的乙酰化程度,提高p21等基因的表达水平等途径,抑制肿瘤细胞的增殖,诱导细胞分化和(或)凋亡.该文对HDAC抑制剂的研究进展进行系统的综述.     

组蛋白去乙酰化酶3在心血管疾病中的研究进展

组蛋白去乙酰化酶(histone deacetylases,HDACs)是表观遗传的一种修饰酶,其与染色质结构和基因转录调控密切相关。HDAC3属于第Ⅰ类组蛋白去乙酰化酶,研究报道HDAC3在心脏发育过程中起着关键的作用,最新研究发现HDAC3在心血管疾病中发挥着重要的调控作用。本文主要围绕Ⅰ类组蛋白去乙酰化酶家族中的HDAC3,综述其定位和酶活性与先天性心脏病、冠心病、心肌疾病、心力衰竭、心律失常的关系,为心血管疾病临床治疗提供新的药物靶点。     

在治疗肿瘤领域中组蛋白去乙酰化酶抑制剂的研究进展

近年来在治疗肿瘤领域中组蛋白去乙酰化酶（HDAC）抑制剂的研究已成为热点。组蛋白乙酰化转移酶（HAT）与组蛋白去乙酰化酶（HDAC）之间保持的动态平衡调控着有序的基因表达, HDAC表达过度造成乙酰化的失衡会形成肿瘤,而HDAC抑制剂可诱导肿瘤细胞分化、细胞周期停滞和凋亡,抑制肿瘤的生成。HDAC抑制剂是很有前途的新型癌症靶向治疗药物。本文将重点阐述HDAC抑制剂的作用机制以及在肿瘤治疗领域中的研究进展。     

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。     

组蛋白去乙酰化酶抑制剂的研究进展

表观遗传学是目前遗传学研究的热点,而肿瘤的发生与表观遗传学关系密切.表观遗传修饰中组蛋白乙酰化酶(HAT)和组蛋白去乙酰化酶(HDAC)之间的动态平衡控制着染色质结构和基因表达.HDAC抑制剂作为新一代潜在靶向抗肿瘤药物,为国内外药学研究的热点.本文综述HDAC抑制剂的作用机制及临床研究进展.     

组蛋白去乙酰酶抑制剂联合应用治疗肿瘤的研究进展

组蛋白去乙酰酶(histone deacetylase,HDAC)抑制剂可促进组蛋白乙酰化,调节染色质结构和基因转录。临床前研究,Ⅰ和(或)Ⅱ期临床试验都已证实,HDAC的小分子抑制剂能够有效地促进抑癌基因表达,抑制肿瘤生长并诱导细胞凋亡。在多种肿瘤中都已观察到,HDAC抑制剂与其他抗肿瘤药物联合应用,可在较低的剂量下产生更好的疗效,而不良反应减轻。     

锌依赖的组蛋白去乙酰化酶选择性抑制剂研究进展

组蛋白去乙酰化酶(histone deacetylases,HDACs)抑制剂是当前国际抗肿瘤研究的热点。由于HDAC家族存在多个亚型,而HDAC的各个亚型,特别是锌依赖的HDAC各个亚型(HDAC1-11),其生物学功能及在各种肿瘤中的表达各不相同,导致HDAC泛抑制剂的应用会产生较大的毒副作用,临床应用受到限制。因此特异性强、毒副作用低的,具有亚型选择性的HDAC抑制剂成为抗肿瘤药物研发的趋势。目前已有的亚型选择性HDAC抑制剂主要靶向HDAC1、2、6、8。该文将阐述HDAC抑制剂的发展趋势及现有的HDAC选择性抑制剂的研究进展。     

组蛋白去乙酰化酶6的结构、功能及选择性抑制剂的研究进展

组蛋白去乙酰化酶6(HDAC6)是组蛋白去乙酰化酶家族中独具特色的一员。该酶具有两个去乙酰化功能区,可特异性催化非组蛋白底物,参与并调节众多生理或病理进程。目前已报道的选择性HDAC6抑制剂结构种类较多,有的正处于临床试验阶段。本文将对HDAC6的结构、功能及其选择性抑制剂的研究进展进行综述。     

组蛋白去乙酰化酶抑制剂抗肿瘤作用研究进展

组蛋白去乙酰化酶(histone deacetylase, HDAC)在肿瘤发生和发展的多个环节中扮演着非常重要的角色,如肿瘤抑癌基因沉默、细胞分化、血管生成、细胞迁移、细胞周期异常、信号传导及细胞附着等。组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACIs)可以靶向组蛋白去乙酰化酶调控组蛋白的乙酰化,进而调控关键的抑制肿瘤蛋白和原癌基因,是极具潜力的抗肿瘤药物。HDACIs已经在血液/淋巴系统肿瘤治疗方面取得了一定成果,目前已经有2种HDACIs：SAHA(suberoylanilide hydroxamic acid)和FK228被批准用于治疗皮肤T细胞淋巴癌,当前大量的临床试验正在挖掘HDACIs在实体瘤治疗方面的潜力。尽管目前基于细胞的研究发现HDACIs可以诱导肿瘤细胞凋亡,细胞周期抑制,细胞分化,抑制血管生成和自噬等,但HDACIs发挥抗肿瘤活性的分子机制仍未阐明,其对实体瘤的临床治疗效果及相关治疗策略有待进一步确证。     

茶碱类药物的研究进展及其临床应用

近年来的研究表明,低浓度的茶碱具有抗炎和免疫调节作用,这与茶碱可直接激活组蛋白去乙酰化酶(HDAC)有关.HDAC逆转了组蛋白的乙酰化,从而抑制了炎症基因的表达.而茶碱和糖皮质激素(GCS)在抑制炎症基因的表达方面可能起到了协同作用.因而,对于激素抵抗或者激素依赖型哮喘患者,低剂量茶碱的应用可能会改善患者对GCS的反应性,减少GCS的用量.     

Romidepsin for the treatment of non-Hodgkin’s lymphoma

Introduction: Patients with relapsed or refractory lymphoma remain a population with unmet medical needs. Histone deacetylase inhibitors (HDACIs) represent a novel class of anticancer drugs currently in development in several malignancies. Inhibition of HDACs leads to acetylation of histone and non-histone proteins, which in turn results in epigenetic modification of gene expression that leads to a plethora of effects, such as cell cycle arrest, apoptosis and inhibition of angiogenesis. Romidepsin is a novel HDACI that has demonstrated preclinical and clinical activity.

Areas covered: This review discusses the different HDACs and epigenetic regulation with a particular focus on the preclinical and clinical development of romidepsin in lymphoma. The review of romidepsin includes: the mechanism of action, its synergistic interaction with novel agents, pivotal clinical trials that lead to its US FDA approval in cutaneous T-cell lymphoma and peripheral T-cell lymphoma as well as active combinations currently in clinical trials.

Expert opinion: Romidepsin is a potent HDACI with clinical activity in T-cell lymphoma where novel agents and combinations are desperately needed. A deeper understanding of the molecular characteristics of this class of agents will allow the design of more potent drugs with improved toxicity profiles and future rational combinations that will expand the indication and benefit from these novel agents.     

表观遗传学药物的研究进展

随着表观遗传学研究的不断深入,表观遗传学药物的研究取得了巨大进展。目前已有研究并批准上市的表观遗传学药物主要针对DNA异常甲基化和组蛋白的异常修饰。潜在的药物有DNA甲基转移酶抑制剂、赖氨酸去甲基化酶抑制剂、蛋白质甲基转移酶抑制剂、组蛋白去乙酰化酶抑制剂、组蛋白乙酰基转移酶抑制剂、含溴结构域蛋白抑制剂及甲基化组蛋白结合蛋白的抑制剂等。该文综述了近年来表观遗传学治疗在药理学上的进展,以期为疾病防治和基础研究提供一些新的思路。     

Pharmacology of epigenetics in brain disorders

Epigenetics is a rapidly growing field and holds great promise for a range of human diseases, including brain disorders such as Rett syndrome, anxiety and depressive disorders, schizophrenia, Alzheimer disease and Huntington disease. This review is concerned with the pharmacology of epigenetics to treat disorders of the epigenome whether induced developmentally or manifested/acquired later in life. In particular, we will focus on brain disorders and their treatment by drugs that modify the epigenome. While the use of DNA methyl transferase inhibitors and histone deacetylase inhibitors in in vitro and in vivo models have demonstrated improvements in disease-related deficits, clinical trials in humans have been less promising. We will address recent advances in our understanding of the complexity of the epigenome with its many molecular players, and discuss evidence for a compromised epigenome in the context of an ageing or diseased brain. We will also draw on examples of species differences that may exist between humans and model systems, emphasizing the need for more robust pre-clinical testing. Finally, we will discuss fundamental issues to be considered in study design when targeting the epigenome.     

Histone deacetylase inhibitors in cancer therapy

Histones are a family of nuclear proteins that interact with DNA, resulting in DNA being wrapped around a core of histone octamer within the nucleosome. Acetylation/deacetylation of histones is an important mechanism that regulates gene expression and chromatin remodeling. Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic drugs that regulate gene expression by enhancing the acetylation of histones, and thus inducing chromatin relaxation and altering gene expression. HDAC inhibitors have been shown in preclinical studies to have potent anticancer activities. A range of structurally diverse HDAC inhibitors have been purified as natural products or synthetically produced. Due to the promising preclinical activity of these agents, numerous clinical trials have been initiated. In this review, the results of published data of single agent and combination trials of these drugs are reviewed, with a focus on dosing, scheduling and toxicity. Although still early in drug development, there is a picture that is starting to develop as to the common toxicities and which tumors seem to be the most susceptible to this class of drugs.     

Histone deacetylase inhibitors: from target to clinical trials

Transformed cells, characterised by inappropriate cell proliferation, do not necessarily lose the capacity to undergo growth arrest under certain stimuli. DNA, genetic information, is packaged in chromatin proteins, for example, histones. The structure of chromatin may be altered by post-translational modifications (e.g., acetylation, phosphorylation, methylation and ubiquitylation) which play a role in regulating gene expression. Two groups of enzymes, histone deacetylases (HDACs) and acetyl transferases, determine the acetylation status of histones. This review focuses on compounds that inhibit HDAC activity. These agents have been shown to be active in vitro and in vivo in causing cancer cell growth arrest, differentiation and/or apoptosis. Several HDAC inhibitors are currently in clinical trials as anticancer agents and, in particular, hydroxamic acid-based HDAC inhibitors have shown activity against cancers at well-tolerated doses.