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。     

新型组蛋白去乙酰化酶抑制剂致U251细胞周期阻滞、凋亡及其机制的研究

目的探讨新型组蛋白去乙酰化酶抑制剂(HDACi)2,2,3,3-四甲基环丙酰硫脲(TCCT)诱导人脑胶质瘤U251细胞周期阻滞、凋亡及其作用机制。方法以不同药物浓度与U251细胞共同培养48 h后,采用MTT法检测药物作用48 h后肿瘤细胞的增殖。药物作用24 h后,采用RT-PCR检测肿瘤细胞的p21WAF1/CIP1与Cyclin D1 mRNA的表达,Western blot检测HDAC3、HDAC4、Cyclin D1与p21WAF1/CIP1蛋白的表达,PI单染法分析细胞周期,Annexin V-PI双染法检测肿瘤细胞凋亡。结果 TCCT对U251细胞增殖具有明显抑制作用,药物干预48 h时的IC50为(0.461±0.108)mmol·L-1,并呈现剂量依赖性。TCCT药物干预24 h后U251细胞p21WAF1/CIP1mRNA表达上调,Cyclin D1 mRNA下调;组蛋白去乙酰化酶3(HDAC3)和组蛋白去乙酰化酶4(HDAC4)表达下调,Cyc-lin D1蛋白表达弱下调,p21WAF1/CIP1蛋白表达上调;S期细胞比例明显提高(P<0.05);细胞凋亡率明显增高(P<0.01)。结论 TCCT对U251细胞增殖有明显的抑制作用,引起肿瘤细胞S期阻滞和凋亡。其作用机制可能与其下调HDAC3、HDAC4表达,促进组蛋白乙酰化,而影响p21WAF1/CIP1和Cyclin D1的基因、蛋白的表达有关。     

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.     

组蛋白去乙酰化酶抑制剂放射增敏作用与DNA损伤修复机制关系的研究进展

组蛋白去乙酰化酶抑制剂(HDACIs)是抑制HDAC活性并造成组蛋白过度乙酰化作用的一类化合物,根据其化学结构的特点,HDACIs化合物被分成短链脂肪酸、异羟肟酸、环肽和苯甲酰胺四大类。研究表明,HDACIs能抑制多种肿瘤细胞的生长,某些具有抗肿瘤作用的HDACIs已经进入临床试验阶段。近年来还发现,HDACIs能增加肿瘤细胞对电离辐射的敏感性,具有较强的放射增敏作用,但该类化合物的放射增敏机制目前还不十分清楚,可能与其能增强肿瘤细胞的凋亡和自噬作用,以及DNA损伤修复机制破坏等有关,其中HDACIs通过导致DNA双链断裂修复机制障碍发挥放射增敏作用已越来越引起学者们的关注。为此,本文就HDACis的放射增敏作用与DNA损伤修复机制之间关系的研究进行综述。     

组蛋白去乙酰化酶抑制剂抗肿瘤机制研究进展

肿瘤是威胁人类身体健康严重疾病之一,传统抗肿瘤药物因为选择性差而容易引起比较严重的毒副作用。随着近些年来临床医学研究水平的不断提高,有关肿瘤致病与发病机制的相关基本过程也逐渐被阐明,新型的抗肿瘤药物组蛋白去乙酰化酶（HDAC）抑制剂在临床中广泛应用开来。HDAC抑制剂能够作用于患者的肿瘤细胞,使肿瘤细胞的增殖受抑制,诱导肿瘤细胞凋亡,具有非常高的临床应用价值。本文就HDAC抑制剂在抗肿瘤方面所取得的效果以及药用机制等问题做了相关描述,供相关人员做参考。     

大环类HDAC抑制剂研究进展

组蛋白去乙酰化酶（Histone deacetylase,HDAC）是控制表观遗传修饰的重要酶,它的异常表达与癌症等疾病密切相关。通过对大环类HDAC抑制剂的来源和环的大小进行分类,对它们结构和生物活性等方面进行总结。     

FDA批准抗肿瘤药Belinostat上市

美国FDA于2014年7月3日批准Spectrum制药公司的Belinostat（商品名：Beleodaq）粉针剂上市。用于治疗复发性或难治性外周T细胞淋巴瘤（PTCL）。Belinostat为组蛋白去乙酰化酶（HDAC）抑制药。HDAC可促进组蛋白及某些非组蛋白的乙酰基从赖氨酸残基脱离。体外试验中,Belinostat可致乙酰化组蛋白及其他蛋白积聚,诱导细胞周期停滞或某些转化细胞凋亡。Belinostat对肿瘤细胞毒性作用强于正常细胞。Belinostat在纳摩尔浓度（〈250nM）时即可抑制HDAC活性。     

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。     

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。     

Comparative mutagenicity of apicidin and apicidin derivatives (SD-0203 and SD-2007), histone deacetylase inhibitors

The fungal metabolite apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)] is known to inhibit histone deacetylase (HDAC). In this study, the genotoxicity of apicidin and its derivatives were tested using three tests: a bacterial reverse mutation assay (Ames test), an in vitro chromosome aberration (CA) test, and an in vivo micronucleus (MN) test. Apicidin was negative in the Ames test in the presence and absence of the microsomal metabolizing enzyme system. Apicidin induced a significant increase in the total chromosome aberrations in Chinese hamster ovary (CHO) cells. In the MN test, apicidin induced mutagenic activity at the highest dose (1000 microM/kg). The apicidin derivatives SD-0203 and SD-2007 did not induce mutagenic activity in the Ames test and no significant mutagenic potency was observed in the CA test. However, these compounds significantly and dose-dependently increased the number of micronucleated polychromatic erythrocytes (MNPCEs) as well as the PCE/(PCE + NCE) ratio in the MN test. These results suggest that apicidin and its derivatives preferentially induce CA and MN but are not effective in the Ames test.     

Macrocyclic Peptoid–Peptide Hybrids as Inhibitors of Class I Histone Deacetylases

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Possible mechanism of action of the histone deacetylase inhibitors for the induction of differentiation of HL-60 clone 15 cells into eosinophils

1 We have examined the effect of the histone deacetylase inhibitors apicidin, trichostatin A (TSA) and n-butyrate on the histone acetylation and the differentiation of human eosinophilic leukemia HL-60 clone 15 cells into eosinophils. 2 Viability of the cells incubated with apicidin (100 nm), TSA (30 nm) or n-butyrate (500 microm) did not change significantly, but higher concentrations of apicidin (> or =300 nm) or TSA (> or =100 nm) decreased the viability when examined at day 1. 3 Apicidin (100 nm) as well as n-butyrate (500 microm) induced continuous acetylations of histone H4 and lysine14 residue on histone H3, while TSA (30 nm) induced transient acetylations. 4 After 6 days incubation, eosinophilic cells stained by Luxol-fast-blue were generated by apicidin (100 nm) and n-butyrate (500 microm) but not by TSA (30 nm). Other markers for differentiation into eosinophils such as changes in intracellular structure, and expressions of integrin beta7 and major basic protein, and the inhibition of cell proliferation were also induced by apicidin and n-butyrate but not by TSA. 5 Continuous acetylation of histone H4 achieved by repeated treatment with TSA (30 nm) at an interval of 12 h for more than three times induced such changes when examined on day 6. In addition, the induction was impaired by shortening the period of incubation with apicidin (100 nm) or n-butyrate (500 microm). 6 CCAAT/enhancer binding protein was continuously activated by apicidin (100 nm) and n-butyrate (500 microm), but was transiently activated by TSA (30 nm). 7 These findings suggest that the continuous acetylation of histones H3 and H4 is necessary for the differentiation of HL-60 clone 15 cells into eosinophils.     

Regulation of adipocyte differentiation by histone deacetylase inhibitors

In this study, we investigated the effects of various histone deacetylase (HDAC) inhibitors on adipocyte differentiation. Treatment of 3T3-L1 cells with HDAC inhibitors such as apicidin, trichostatin A, or suberoylanilide hydroxamic acid, under conditions that normally promote differentiation led to a dramatic attenuation of adipocyte differentiation. In contrast, sodium butyrate (NaB) treatment increased adipocyte differentiation. Accordingly, the expression of adipogenic marker genes such as FAS, aP2, PPARγ, resistin, C/EBPα, ADD1/SREBP1c, and adiponectin were inhibited by apicidin treatment but not NaB, indicating that the adipocyte differentiation process could be differentially regulated depending on the type of HDAC inhibitor utilized. In addition, this differential effect seemed not to be due to disruption of the insulin- signaling pathway. Interestingly, our data showed that apicidin treatment could induce dedifferentiation of fully differentiated adipocytes, as evident by the fact that apicidin treatment led to a decrease of Oil Red O-stained adipocytes with a concomitant reduction in the expression levels of adipogenic marker genes. Collectively, our results suggest that adipocyte differentiation and dedifferentiation may be regulated by HDAC inhibitors.     

A novel series of potent and selective ketone histone deacetylase inhibitors with antitumor activity in vivo

Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy, and the first generation HDAC inhibitors are currently in the clinic. Entirely novel ketone HDAC inhibitors have been developed from the cyclic tetrapeptide apicidin. These compounds show class I subtype selectivity and levels of cellular activity comparable to clinical candidates. A representative example has demonstrated tumor growth inhibition in a human colon HCT-116 carcinoma xenograft model comparable to known inhibitors.     

Development of tetrahydroisoquinoline-based hydroxamic acid derivatives: potent histone deacetylase inhibitors with marked in vitro and in vivo antitumor activities

Inhibition of histone deacetylase (HDAC) results in growth arrest, differentiation, and apoptosis in nearly all tumor cell lines, promoting HDACs as promising targets for antitumor therapy. In our previous study we developed a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDAC inhibitors (HDACi), among which compound 7d exhibited promising HDAC8 inhibitory and antiproliferative activities. Herein, we report the design and development of a new class of tetrahydroisoquinoline-bearing hydroxamic acid analogues as potential HDACi and anticancer agents. In vitro biological evaluation of these compounds showed improved HDAC8 inhibition (compounds 31a and 31b exhibited mid-nM IC(50) values against HDAC8) and potent growth inhibition in multiple tumor cell lines. Most importantly, compounds 25e, 34a, and 34b exhibited excellent in vivo anticancer activities in a human breast carcinoma (MDA-MB-231) xenograft model compared with suberoylanilide hydroxamic acid (SAHA), an approved HDACi. Collectively, our results indicate that tetrahydroisoquinoline bearing a hydroxamic acid is an excellent template to develop novel HDACi as potential anticancer agents.     

Novel histone deacetylase inhibitors bearing a 4-piperidin-4-yl-triazole scaffold as antitumor agents

Histone deacetylases have proven to be promising targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of 20 novel hydroxamic acid-based histone deacetylase inhibitors with 4-piperidin-4-yl-triazole as the core structure. Five newly obtained compounds displayed excellent HDAC6 inhibitory activities. Among them, compounds WY-12 and WY-15 also exhibited excellent antiproliferative activities against six human tumor cell lines. WY-15 could increase the level of acetylated histone H3 in a dose-dependent manner. Furthermore, WY-15 remarkably induced cell cycle arrest of Sy5y cancer cells in G₀/G₁ phase. Finally, the high potency of compound WY-15 toward HDAC6 was rationalized by molecular docking study.