丙戊酸抗肿瘤作用的研究进展

乙酰化修饰是染色质重塑中最重要的机制之一。组蛋白乙酰化状态主要取决于组蛋白乙酰基转移酶与组蛋白去乙酰化酶之间的活性竞争。越来越多的证据表明在组蛋白乙酰化的失衡与癌症发生之间存在着密切的联系。近年来发现组蛋白去乙酰化酶抑制剂单用／联合其他药物治疗对肿瘤具有诱导分化、促凋亡等作用，并能提高恶性肿瘤细胞对化疗药物的敏感性等。丙戊酸是临床上常用的一种广谱抗癫痫药物。目前研究发现，单用／联合属于组蛋白去乙酰化酶抑制剂之一的丙戊酸也可以诱导肿瘤细胞分化、细胞周期阻滞和细胞凋亡；在动物实验中抑制动物肿瘤生长等等。因此丙戊酸很可能是一类具有广泛应用前景的化疗新药。     

新型抗肿瘤药物组蛋白去乙酰化酶抑制剂

组蛋白去乙酰化酶抑制剂（HDACi）是一类新型的抗肿瘤药物，具有高效、低毒的特点，其作用于肿瘤细胞后能够抑制肿瘤细胞增殖，诱导细胞周期阻滞，促进细胞分化或凋亡。目前该类药物已经在美国进入Ⅱ期临床研究。现综述HDACi的种类、生物学作用、抗肿瘤作用机制等的研究进展。     

以组蛋白去乙酰化酶为靶点的抗肿瘤研究

细胞核内组蛋白乙酰化与去乙酰化失衡可诱发肿瘤.组蛋白去乙酰化酶(HDAC)作用于组蛋白,使其去乙酰化,维系组蛋白乙酰化与去乙酰化的平衡状态,与癌相关基因转录表达、细胞增殖分化及细胞凋亡等过程密切相关.HDAC抑制剂目前是国内外研究的热点,已有十多种HDAC抑制剂用于治疗血液肿瘤和恶性实体瘤,表现出明显的抗肿瘤活性.     

新型抗肿瘤药物组蛋白去乙酰化酶抑制剂

组蛋白去乙酰化酶抑制剂(HDACi)是一类新型的抗肿瘤药物,具有高效、低毒的特点, 其作用于肿瘤细胞后能够抑制肿瘤细胞增殖,诱导细胞周期阻滞,促进细胞分化或凋亡。目前该类药物已经在美国进入Ⅱ期临床研究。现综述HDACi的种类、生物学作用、抗肿瘤作用机制等的研究进展。     

组蛋白去乙酰化酶抑制剂抗肿瘤的研究进展

核心组蛋白的乙酰化和去乙酰化与基因调控密切相关.组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor,HDACI)通过有效上调抑癌基因的表达、阻断肿瘤生长和诱导肿瘤细胞选择性凋亡来治疗肿瘤.近年来,HDACIs成为肿瘤靶向治疗的研究新热点,其对肿瘤细胞迁移、侵袭、转移的抑制作用和抗肿瘤血管生成作用也被证实.     

组蛋白去乙酰化调控与乳腺癌关系的研究进展

正常的细胞增殖周期是按照一定的程序，在机体严格的调控和精密的平衡下进行的。分子生物学技术的发展提示肿瘤的发生发展几乎都涉及细胞增殖的调控异常。染色质空间构象的局部重塑是细胞增殖调控的重要步骤，而组蛋白去乙酰化／乙酰化修饰是染色质重塑中最重要的机制之一。     

组蛋白乙酰化影响肿瘤细胞多药耐药性的研究进展

在临床治疗中,肿瘤细胞的多药耐药性（multi-drug resistance,MDR）已经成为化疗失败的重要原因之一。肿瘤细胞中组蛋白乙酰化异常与MDR的产生有关,组蛋白去乙酰化酶抑制剂（histone deacety-lases inhibitor,HDACi）能够抑制肿瘤生长,避免肿瘤产生耐药性,已经作为一种新型的抗肿瘤药物应用于临床。HDACi可能通过阻滞细胞周期、促进细胞分化、诱导细胞凋亡等多种生物学效应发挥其抗肿瘤的作用,HDACi与其他药物联合应用在抗肿瘤方面也展现了良好的应用前景。     

组蛋白乙酰化影响肿瘤细胞多药耐药性的研究进展

在临床治疗中,肿瘤细胞的多药耐药性(multi-drug resistance,MDR)已经成为化疗失败的重要原因之一。肿瘤细胞中组蛋白乙酰化异常与MDR的产生有关,组蛋白去乙酰化酶抑制剂(histone deacety-lases inhibitor,HDACi)能够抑制肿瘤生长,避免肿瘤产生耐药性,已经作为一种新型的抗肿瘤药物应用于临床。HDACi可能通过阻滞细胞周期、促进细胞分化、诱导细胞凋亡等多种生物学效应发挥其抗肿瘤的作用,HDACi与其他药物联合应用在抗肿瘤方面也展现了良好的应用前景。     

FK228阻断细胞生存信号通路诱导前列腺癌细胞凋亡

目的：研究组蛋白去乙酰化酶（HDAC）抑制剂FK228诱导前列腺癌细胞系DU145凋亡的作用机制。方法：MTT比色法测定FK228抑制DUl45细胞增殖及其对细胞的杀伤效应；瑞氏-姬姆萨染色观察细胞形态的变化；流式细胞术分析细胞周期的改变；蛋白印迹实验检测细胞内蛋白表达水平的变化。结果：FK228明显抑制DU145细胞体外增殖，并介导细胞死亡；12．5ng／ml FK228作用细胞48h后，细胞存活率降至63．7％；伴有细胞形态改变及细胞周期阻滞于G0／G1期；细胞内多种重要的激酶蛋白，包括EGFR、Her2、Raf-1、Src、Cdk4、Akt及凋亡抑制蛋白Survivin均发生了不同程度的降解，细胞内两条重要的生存信号通路Raf-MEK—ERK及P13K／Akt被阻断，细胞发生凋亡。结论：FK228可以通过清除细胞内重要信号蛋白、阻断细胞生存信号通路来诱导DU145细胞发生凋亡。     

表观遗传学如何诠释人肿瘤转移microRNA的新作用

栏目前言肺癌是目前中国,也是世界上死亡率最高的恶性肿瘤之一。随着中国经济的快速发展,中国肺癌临床科研水平也得到大大提高。国际上新的诊疗技术与临床成果不断在中国的医疗机构得以推广应用,先进的科研理念与科研技术被用于肺癌研究并取得重要成果。尽管如此,中国的肺癌临床科研水平与国际先进水平仍然有一定的差距。为更好的服     

Apoptotic Cytotoxic Effects of a Histone Deacetylase Inhibitor, FK228, on Malignant Lymphoid Cells

Histone deacetylases are promising targets for cancer treatment. Here we studied the in vitro effects of a potent histone deacetylase inhibitor, FK228 (formerly FR901228), on human leukemia/lymphoma cells and cell lines compared with normal hematopoietic cells. In a lymphoma cell line, Raji, a nanomolar concentration of FK228 induced G1 arrest and/or apoptotic cell death, depending on the concentration and exposure time. Growth of lymphoid cell lines including Raji ( N =13) was inhibited by 50% (IC₅₀) after 2-day treatment at concentrations of 0.83 to 1.87 ng/ml. Viability of clinical samples from patients with acute lymphoblastic leukemia was decreased by 50% at 0.78±0.46 ng/ml, whereas the IC₅₀ values for normal mononuclear cells from peripheral blood and bone marrow were 2.3±0.96 and 7.8±1.0 ng/ml, respectively. The IC₅₀ values for normal progenitor cells were 3.1, 4.4 and 7.8 ng/ml for BFU-E, CFU-GM and CFU-Mix, respectively. Expression levels of HDAC-1 and HDAC-3 proteins, which varied among cell lines, but were stable during the treatment with FK228, did not correlate with the sensitivity to FK288. This novel agent might be useful in the treatment of lymphoid malignancies, because the above concentrations are clinically achievable in vivo according to a recent clinical study.     

辛二酰苯胺异羟肟酸（SAHA）对乳腺癌细胞增殖影响的动物实验研究

目的探讨组蛋白去乙酰化酶抑制剂SAHA对乳腺癌细胞株增殖周期的影响。方法饲养Balb/c-nu/nu雌性裸鼠,细胞悬液皮下注射法构建人乳腺癌细胞株MCF-7裸鼠移植瘤模型,随机分为6组,经尾静脉注射不同剂量的SAHA,获取血细胞分析、血脂、肝功能、肾功能、裸鼠体重、瘤重等数据,计算肿瘤生长抑制率、移植瘤的体积,进行统计分析。结果不同剂量的SAHA作用于乳腺癌荷瘤裸鼠后,通过比较肿瘤体积及抑瘤率均显示出疗效,在0.10~0.42 mg/kg剂量范围内,SAHA的治疗效应呈现剂量依赖关系;其作用后导致血清胆红素和谷丙转氨酶水平升高,对红细胞、白细胞及血小板计数、尿素氮、肌酐水平影响不明显。结论 SAHA是乳腺癌细胞增殖抑制剂,其抑制效应有一定的量效关系;其对机体副作用较小。     

组蛋白乙酰化/去乙酰化与白血病的研究进展

组蛋白乙酰化/去乙酰化与基因调控密切相关.组蛋白乙酰化水平的异常在白血病的发展、增殖和分化中起着很重要的作用.随着对组蛋白乙酰化的深入研究,组蛋白去乙酰化酶抑制剂在白血病中的作用机制越来越受到人们的关注.     

组蛋白去乙酰化酶抑制剂FK228通过阻断Hsp90功能杀伤乳腺癌MCF-7细胞

背景与目的：雌激素受体α（estrogen receptor α,ERα）与乳腺癌发生,发展及耐药密切相关,促进ERα降解可能成为解决乳腺癌耐药的一种新策略.本研究旨在观察组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor,HDACi）FK228对乳腺癌MCF-7细胞系ERα的清除作用,并对其抗肿瘤作用机制进行深入研究.方法：MTF比色法测定FK228对MCF-7细胞杀伤的剂量-时间-效应关系;流式细胞仪分析细胞周期的改变;蛋白印迹及免疫共沉淀实验检测细胞内蛋白表达水平及翻译后修饰的变化.结果：FK228呈时间依赖性杀伤MCF-7细胞,阻断细胞周期于G2/M期,增强Hsp90乙酰化修饰,清除ERα及其他Hsp90底物蛋白,阻断Ras/Raf/MEK/ERK及PI3K/Akt信号通路,诱导细胞凋亡.结论：FK228通过乙酰化修饰影响Hsp90分子伴侣功能,介导ERα及其他Hsp90底物蛋白降解是其有效杀伤乳腺癌细胞的分子机制.FK228有可能成为乳腺癌治疗的新型药物.     

FK228 (depsipeptide): a HDAC inhibitor with pleiotropic antitumor activities

Purpose: The fundamental role of epigenetic events in carcinogenesis has resulted in the evolution of epigenetic targeting as a new paradigm in anticancer therapeutics. Aberrant histone deacetylase (HDAC) activity has been documented in many human malignancies resulting in the repression of tumor suppressor genes and promotion of tumorigenesis. FK228, also known as depsipeptide, is a novel, natural, bicyclic tetrapeptide with significant antitumor properties which are mostly mediated by inhibition of HDACs. Results: FK228 induces the expression of genes linked to the inhibition of cell growth, induction of cell differentiation, promotion of apoptotic cell death and inhibition of angiogenesis. Conclusion: Its multitargeting properties, its ability to act on non-histone targets, its clinical activity and its acceptable side-effect profile render FK228 a very promising novel anticancer agent.     

Selective Inhibition of Bicyclic Tetrapeptide Histone Deacetylase Inhibitor on HDAC4 and K562 Leukemia Cell

Histone deacetylase (HDAC) inhibitors of cyclic peptide have been proved to be the most complex but themost stable and relative efficient inhibitors because of their large cap region. In this paper, a series of studieswere carried out to evaluate the efficacy of synthetic bicyclic tetrapeptide inhibitors 1-5 containing hydroxamicacid referring molecular docking, anti-proliferation, morphology and apoptosis. Docking analysis, togetherwith enzyme inhibitory results, verified the selective capability of inhibitor 4 to HDAC4, which might closelyrelated to haematological tumorigenesis, with Phe227, Asp115, Pro32, His198 and Ser114 participating intohydrophobic interactions and Van der Waals force which was familiar with former study. Moreover, inhibitor4 inhibited K562 cell line at the IC50 value of 1.22 μM which was 51-67 times more efficient than that for U937and HL60 cell lines. Inhibitor 4 exhibited the cell cycle-arrested capability to leukemia at S phase or G2/Mphase as well as apoptosis-induced ability in different degrees. Finally, we considered that bicyclic tetrapeptideinhibitors were promising inhibitors used in cancer treatment and inhibitor 4 could prevent K562 cell line wellfrom proliferation, arrest cell cycle and induce K562 towards apoptosis to achieve the goals of reversing cancercells which could become a potential leukemia therapeutic agent in the future.     

Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation

Malignant rhabdoid tumors (MRT) exhibit a very poor prognosis because of their resistance to chemotherapeutic agents and new therapies are needed for the treatment of this cancer. Here, we show that the histone deacetylase (HDAC) inhibitor FK228 (depsipeptide) has an antitumor effect on MRT cells both in vitro and in vivo. FK228 is a unique cyclic peptide and is among the most potent inhibitors of both Class I and Class II HDACs. FK228 inhibited proliferation and induced apoptosis in all MRT cell lines tested. Preincubation with the pancaspase inhibitor zVAD-fmk did not completely rescue FK228-induced cell death, although it did inhibit apoptosis. Transmission electron microscopy (TEM) showed that FK228 could stimulate MRT cells to undergo apoptosis, necrosis or autophagy. FK228 converted unconjugated microtubule-associated protein light chain 3 (LC3-I) to conjugated light chain 3 (LC3-II) and induced localization of LC3 to autophagosomes. Apoptosis inducing factor (AIF), which plays a role in caspase-independent cell death, translocated to the nucleus in response to FK228 treatment. Moreover, small interfering RNA (siRNA) targeting of AIF prevented the morphological changes associated with autophagy and redistribution of LC3 to autophagosomes. Disrupting autophagy with chloroquine treatment enhanced FK228-induced cell death. In vivo, FK228 caused a reduction in tumor size and induced autophagy in tumor tissues. Using immunoelectron microscopy, we confirmed AIF translocation into the nucleus of FK228-induced autophagic cells in vivo. Thus, FK228 is a novel candidate for an antitumor agent for MRT cells.     

A Novel Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitor Derivative,N25, Exhibiting Improved Antitumor Activity in both Human U251 and H460 Cells

N1- (2, 5-dimethoxyphenyl)-N8-hydroxyoctanediamide (N25) is a novel SAHA cap derivative of HDACi,with a patent (No. CN 103159646). This invention is a hydroxamic acid compound with a structural formulaof RNHCO(CH2)6CONHOH (wherein R=2, 5dimethoxyaniline), a pharmaceutically acceptable salt which issoluble. In the present study, we investigated the effects of N25 with regard to drug distribution and moleculardocking, and anti-proliferation, apoptosis, cell cycling, and LD50. First, we designed a molecular approach formodeling selected SAHA derivatives based on available structural information regarding human HDAC8 incomplex with SAHA (PDB code 1T69). N25 was found to be stabilized by direct interaction with the HDAC8.Anti-proliferative activity was observed in human glioma U251, U87, T98G cells and human lung cancer H460,A549, H1299 cells at moderate concentrations (0.5-30μM). Compared with SAHA, N25 displayed an increasedantitumor activity in U251 and H460 cells. We further analyzed cell death mechanisms activated by N25 in U251and H460 cells. N25 significantly increased acetylation of Histone 3 and inhibited HDAC4. On RT-PCR analysis,N25 increased the mRNA levels of p21, however, decreased the levels of p53. These resulted in promotion ofapoptosis, inducing G0/G1 arrest in U251 cells and G2/M arrest in H460 cells in a time-dependent and dosedependentmanner. In addition, N25 was able to distribute to brain tissue through the blood-brain barrier ofmice (LD50: 240.840mg/kg). In conclusion, our findings demonstrate that N25 will provide an invaluable tool toinvestigate the molecular mechanism with potential chemotherapeutic value in several malignancies, especiallyhuman glioma.