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。     

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.     

组蛋白乙酰化的研究进展

染色质中最基本的重复单位就是核小体核心颗粒,它包含147 bp的DNA包绕在中心组蛋白八聚体周围.     

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.     

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。     

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。     

组蛋白去乙酰化酶及其抑制剂与妇科肿瘤

妇科肿瘤严重威胁着妇女的身心健康，非手术药物治疗亦存在许多问题。近年来，研究表明，组蛋白去乙酰化酶及其抑制剂与妇科肿瘤存在密切的联系，其作用及机制也是目前研究的热点，并是今后有望在妇科肿瘤治疗方面取得重大突破的方向。因此组蛋白去乙酰化酶及其抑制剂与妇科肿瘤的关系将作为本文的重点做一讨论。     

组蛋白去乙酰化酶9在肿瘤中的作用

组蛋白去乙酰化酶9（histone deacetylase 9,HDAC9）属于组蛋白去乙酰化酶（histone deacetylases,HDACs）Ⅱa亚型,在体内通过催化组蛋白3（H3）、组蛋白4（H4）和非组蛋白的去乙酰化,改变染色体的结构,调节基因的转录。研究表明HDAC9表达异常与肿瘤关系密切,但不同肿瘤中HDAC9的表达和功能不同,最终造成促癌或抑癌的相反结果,具体机制尚不明确。当前利用组蛋白去乙酰化酶抑制剂（histone deacetylases inhibitors,HDACIs）的表观遗传治疗已成为热点,研制特异性HDACIs并与化疗、放疗以及免疫治疗相结合已成为未来的方向,但靶向针对HDAC9的治疗研究非常有限。本文就HDAC9在肿瘤中的作用进行综述。      

组蛋白乙酰化与白血病

  核心组蛋白N-末端的乙酰化修饰引起的染色质结构的改变在真核细胞基因表达调控中起重要作用,组蛋白乙酰化酶使染色质处于相对松散的结构可以促进基因的表达,组蛋白去乙酰化酶则使染色质结构致密抑制基因的表达。组蛋白乙酰化酶或去乙酰化酶功能紊乱导致的基因表达异常与白血病发生、发展密切相关。组蛋白去乙酰化酶抑制剂是一种新型的白血病化疗药物,体内和体外试验均显示组蛋白去乙酰化酶抑制剂能抑制白血病细胞增生,阻滞细胞周期,诱导肿瘤细胞分化和凋亡。     

Histone deacetylase inhibitors upregulate plakoglobin expression in bladder carcinoma cells and display antineoplastic activity in vitro and in vivo

Histone deacetylase inhibitors (HDACis) are emerging as a promising new class of anticancer agents displaying growth-inhibitory activity and low toxicity in vivo. In this study, we examined the effect of sodium butyrate (NaB) and trichostatin A (TSA) on the growth of human bladder carcinoma cell lines in culture and TSA on the growth of EJ and UM-UC-3 human bladder xenografts in nude mice. NaB and TSA suppressed the growth of bladder cell lines at millimolar (1.5-4.3 mM) and micromolar (0.03-0.33 microM) concentrations, respectively, inducing concentration-dependent cell death. Bladder carcinoma cells within the experimental panel displayed the phenotype of late-stage bladder lesions expressing N-cadherin in the absence of E-cadherin accompanied by low levels of plakoglobin expression. Exposure of these cells to HDACis resulted in upregulation of plakoglobin with no change in E-cadherin expression. A 2-hr exposure to TSA was the minimal time required to upregulate plakoglobin in cells with downregulation to baseline levels occurring within 24 hr following drug removal. In mice bearing EJ and UM-UC-3 bladder xenografts, TSA (500 microg/kg/day) caused suppression of tumor growth compared with mice receiving vehicle alone. A > 70% reduction in mean final tumor volume was recorded in both bladder xenograft models with no detectable toxicity. The results suggest that TSA inhibits bladder carcinoma cell growth and may be a useful, relatively nontoxic agent for consideration in the treatment of late-stage bladder tumors.     

Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P-glycoprotein-expressing cells

Multidrug resistance (MDR) mediated by the ATP-dependent efflux protein P-glycoprotein (P-gp) is a major obstacle to the successful treatment of many cancers. In addition to effluxing toxins, P-gp has been shown to protect tumor cells against caspase-dependent apoptosis mediated by Fas and tumor necrosis factor receptor (TNFR) ligation, serum starvation and ultraviolet (UV) irradiation. However, P-gp does not protect against caspase-independent cell death mediated by granzyme B or pore-forming proteins (perforin, pneumolysin and activated complement). We examined the effects of the chemotherapeutic hybrid polar compound suberoylanilide hydroxamic acid (SAHA) on P-gp-expressing MDR human tumor cell lines. In the CEM T-cell line, SAHA, a histone deacetylase inhibitor, induced equivalent death in P-gp-positive cells compared with P-gp-negative cells. Cell death was marked by the caspase-independent release of cytochrome c, reactive oxygen species (ROS) production and Bid cleavage that was not affected by P-gp expression. However, consistent with our previous findings, SAHA-induced caspase activation was inhibited in P-gp-expressing cells. These data provide evidence that P-gp inhibits caspase activation after chemotherapeutic drug treatment and demonstrates that SAHA may be of value for the treatment of P-gp-expressing MDR cancers.     

Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells

HDAC inhibitors induce histone hyperacetylation by a relative increase of histone acetyltransferase activity. Histone hyperacetylation may affect chromatin structure and susceptibility to DNA-damaging stress, such as IR. We here investigate whether these inhibitors can radiosensitize human gastric MKN45 and colorectal DLD1 adenocarcinoma cells. In both cells, FK228 pretreatment at minimally toxic concentrations clearly augmented IR-induced cell death, DNA fragmentation and caspase-3/-8 activation. In contrast, 5-FU did not clearly augment IR-induced cell death and caspase-3 activation. FK228 increased expression of proapoptotic BH3-only Bim proteins, and gene transfer-mediated overexpression of Bimalpha radiosensitized DLD1 cells. These data suggest that the FK228-mediated increase of Bim expression may at least partially contribute to its augmentation of radiation-induced apoptosis. However, FK228 did not distinctly affect IR-induced phosphorylation of H2AX, which is an initial event followed by DNA damage. FK228 strongly augmented IR-induced growth suppression of MKN45 tumor xenografts. In addition, other HDAC inhibitors, MS275 and CBHA, similarly augmented IR-induced cell death in both cell types. Our results suggest that these HDAC inhibitors may enhance the efficacy of radiation therapy in gastrointestinal cancer cells.     

Induction of histone acetylation in mouse erythroleukemia cells by some organosulfur compounds including allyl isothiocyanate

In previous studies we observed that some allyl sulfides can cause increased acetylation of histones and differentiation in DS19 mouse erythroleukemia cells. In the present work we observed increased acetylation of histones with allyl isothiocyanate and butanethiol but not with butyl sulfide or butyl disulfide. Increased acetylation of histones was established by change in electrophoretic mobility, incorporation of [3H]acetate or immunoblotting. Histone deacetylase in nuclei of DS19 cells was inhibited 74% by 0.5 mM allyl mercaptan and 43% by 0.5 mM butanethiol but was not significantly affected by 0.5 mM allyl isothiocyanate. There was some degree of reversibility in the effect of allyl isothiocyanate when the cells were incubated for 15 hr in fresh medium. The data suggested that allyl isothiocyanate may stimulate histone acetylation rather than inhibit histone deacetylation. Addition of allyl isothiocyanate, however, had very little or no additional effect on the induction of histone acetylation caused by trichostatin A. Histone acetyltransferase activity determined in cell homogenates was not increased by preincubation of cells with allyl isothiocyanate or inclusion of allyl isothiocyanate in the assay medium. It was concluded that treatment of mouse erythroleukemia cells with allyl isothiocyanate can cause increased acetylation of histones but the mechanism for this effect requires further elucidation.