基于蛋白质组学的组蛋白表观遗传酶抑制剂研究进展

组蛋白作为真核生物体细胞染色质上核小体的重要组成部分,其上发生的如乙酰化和甲基化等能够调控表观遗传的翻译后修饰,在肿瘤疾病发生、发展的过程中发挥了重要的作用。与此同时,靶向干预甲基转移酶和去乙酰化酶的药物开发,为肿瘤疾病提供了新的治疗策略。基于生物质谱技术的蛋白质组学,可解析疾病进展过程中药物作用下组蛋白修饰的全景变化,进而为揭示药物作用及其耐药机制,研究新型药物联用策略提供重要支持。本文重点介绍了包括甲基转移酶抑制剂和去乙酰化酶抑制剂在内的多种组蛋白修饰酶抑制剂的蛋白质组学研究进展和现状,有助于了解蛋白质组学在组蛋白表观遗传酶抑制剂方面的最新研究,为蛋白质组学在更多表观遗传酶及其特异性抑制剂的研究中提供新线索。     

子宫内膜癌治疗药物的研究进展

药物治疗是子宫内膜癌治疗的重要组成部分,常用药物包括激素治疗药物（孕激素、抗雌激素药物、促性腺激素释放激素激动剂）、化疗药物（紫杉醇、铂类、蒽环类）和靶向药物（表皮生长因子受体拮抗剂、哺乳动物雷帕霉素靶蛋白抑制剂等）。随着研究的深入,越来越多的抗子宫内膜癌新靶点被发现,包括血管内皮生长因子（VEGF）、聚腺苷二磷酸核糖聚合酶（PARP）、程序性死亡受体1（PD-1）和PD-1配体（PD-L1）,中药和天然单体化合物也是目前的研究热点。对子宫内膜癌治疗药物的作用机制及研究进展进行综述,以期对该病治疗及新药研发有所裨益。     

抗结核药物性肝损伤分子机制研究进展

结核病是全球公共卫生问题,抗结核药物所伴随的肝损伤严重影响预后,因此阐明抗结核药物性肝损伤的分子机制尤为重要。抗结核药物诱导的肝损伤分子机制纷繁复杂,本文将着重从当前最新研究热点进行综述,研究表明抗结核药物性肝损伤（ATB-DILI）与脂质过氧化、铁死亡、表观遗传修饰、代谢组学、环状RNA密切相关。脂质过氧化和铁死亡介导ATB-DILI发生的信号通路与谷胱甘肽代谢有关;表观遗传修饰通过DNA甲基化（和去甲基化）、组蛋白修饰和非编码RNA参与ATB-DILI的致病机制;靶向与非靶向代谢组学在阐明抗结核药物的毒性机制方面具有重要贡献;环状RNA在转录翻译水平参与调控ATBDILI的发生发展。本文旨在阐明抗结核药物性肝损伤分子机制的最新研究进展,以期为后续研究提供理论参考依据及新的研究方向。     

小细胞肺癌靶向治疗研究进展

小细胞肺癌是一种生长快、易转移的肺神经内分泌肿瘤,约占肺癌发病总数的15%。临床上治疗小细胞肺癌一般采用放化疗结合,在治疗初期通常响应良好,但病人很快产生耐药和复发。早期开发的靶向药物的临床测试均不太理想,迫切需要新的靶向药物和有效的治疗手段。近年来,随着对小细胞肺癌病理机制的深入了解和转化研究,开发了多种针对小细胞肺癌遗传变异的靶向药物,如激酶抑制剂、血管生成抑制剂、凋亡通路抑制剂、蛋白酶体抑制剂、表观遗传抑制剂、免疫检查点抑制剂等。部分靶向治疗正在进行临床试验,同时多种针对小细胞肺癌的新型治疗策略如免疫治疗和联合用药也值得关注。该文总结小细胞肺癌的分子机制和靶向药物的研究进展,以及在此基础上已完成、正在开展的临床研究和临床前研究的现状,同时展望未来可能的小细胞肺癌新型治疗策略。     

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.     

DNA甲基化与药物效应的表观遗传药理学研究进展

除遗传多态性外,DNA序列的表观遗传修饰,也可造成基因表达水平的改变,从而影响个体对药物的反应,造成药物效应的个体差异。表观遗传药理学研究整个环境因素对药物的影响,为临床药物效应的个体差异提供了新的作用机制学说。DNA甲基化是表观遗传修饰的主要机制之一,本文综述了DNA甲基化对药物效应的影响及环境因素对DNA甲基化的影响。     

基于表观遗传调控的中药防治类风湿关节炎作用机制研究进展

表观遗传修饰(epigenetic modifications)代表了调节基因表达的重要机制,使人体能够适应不断变化的环境。应用表观遗传学修饰研究方法是自身免疫疾病机制研究的前沿领域,类风湿关节炎(rheumatoid arthritis,RA)是自身免疫性疾病研究领域的难点之一,其病因不明,发病机制复杂,至今仍然缺乏理想的治疗药物与方法。中医药治疗RA具有独特优势,新近研究发现中药单体成分和复方通过作用于表观遗传修饰而治疗RA。该文拟对表观遗传学在RA发生、发展中的机制,以及中药通过调控表观遗传防治RA的作用进行综述,以期为中药治疗RA临床疗效及其作用机制研究提供新的思路。     

DNA甲基化和组蛋白乙酰化介导的肿瘤抗凋亡机制与靶向治疗

肿瘤发生发展是复杂且多步骤的过程,是遗传和表观遗传异常共同作用的结果。遗传变异能引起细胞增殖、分化和凋亡通路异常而导致肿瘤发生,越来越多的研究表明,表观遗传改变可引起癌基因的扩增或肿瘤抑制基因的沉默,在癌症的发生发展中同样发挥着重要作用。常见的表观遗传修饰包括基因启动子区域CpG岛甲基化、组蛋白修饰（包括组蛋白乙酰化和甲基化）、非编码RNA调控以及RNA的修饰。这些表观遗传变化不仅影响基因功能,还通过影响肿瘤微环境促使癌症特征的形成（包括持续增殖、抵抗治疗、血管生成、局部侵袭和远处转移）。本综述将重点阐述DNA甲基化和组蛋白乙酰化在介导肿瘤抗凋亡机制中的作用,并将讨论靶向表观遗传因子的抗肿瘤药物的发展现状及前景。     

肾癌靶向治疗药物的研究进展

肾细胞癌的发病率占恶性肿瘤的2%,传统的治疗方法是使用细胞因子(干扰素或者白介素-2),但这些免疫治疗生存优势小,疗效有限,需要开发更有效的药物。肾癌分子生物学的研究,揭示血管内皮生长因子和相关受体以及RAS/RAF/MEK/ERK和PI3K/Akt/mTOR信号传导通路与肾癌的发病密切相关,这些受体和通路促进了肿瘤细胞的生长和增殖。最近开发的药物,包括酪氨酸激酶抑制剂、单克隆抗体和mTOR抑制剂,能靶向作用于肾癌的酪氨酸激酶和细胞内通路,产生抗肿瘤作用。文中总结了肾癌发病的分子生物学机制,靶向治疗药物的作用机制以及临床评价的研究进展。     

代谢综合征参与子宫内膜癌发病机制研究进展

子宫内膜癌是女性生殖系统最常见的癌症之一,其疾病的发生发展与代谢综合征具有明确相关性。近年来,以胰岛素抵抗和脂质代谢紊乱为代表的代谢综合征促进子宫内膜癌发生发展关键分子机制的研究取得了很大进展。该研究综述了代谢综合征中关键分子调控通路在内膜癌发生发展机制的研究进展,有利于进一步深入了解子宫内膜癌相关代谢综合征的分子机制,为子宫内膜癌防控及治疗提供新的靶点。     

Insulin-like growth factor-1 receptor (IGF-1R) kinase inhibitors in cancer therapy: advances and perspectives

The insulin-like growth factors (IGF) and their receptors play pivotal roles in cellular signaling transduction and thus regulate cell growth, differentiation, apoptosis, transformation and other important physiological progresses. The insulin-like growth factor 1 receptor (IGF-1R) mainly engages in the Ras/mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, and also forms cross-talk with the epidermal growth factor receptor (EGFR) pathway. Currently, it draws more attention since its overexpression has been demonstrated in various human cancers, such as colorectal cancer, breast cancer, prostate cancer and lung tumors, thus the strategy targeting the IGF-1R would be promising in treatment of these cancers. There are already dozens of agents developed for the inhibition of IGF-1R, which are categorized into monoclonal antibodies, small molecule inhibitors and so on. While in this review, small molecule inhibitors would be the focus for detailed discussion. Herein, we updated previously reported research papers and reviews in this field and summarized developments of small molecule inhibitors up to 2011. Finally, we proposed the application of network pharmacology methods to reconsider the clinical use of inhibitors with concomitant IR inhibition or other kinases inhibition, hoping that more optimal combinations would be obtained for cancer therapy.     

天然来源的赖氨酸乙酰基转移酶小分子调节剂在治疗学中的意义（英文）

The altered function of any epigenetic modification also causally affects the physiological homeostasis in different pathophysiological conditions such as cancer,neurodegenerative disorders,diabetes,asthma,COPD etc.Among the different epigenetic enzymes we focus on three important classes:lysine acetyltransferases,arginine methyltransferases and aurora kinases in the context of cancer and neurodegenerative diseases.Our laboratory has discovered several small molecule modulators of these enzymes,which may serve as lead scaffolds to design new generation therapeutics.We have shown that specific as well as broad spectrum inhibitors of lysine acetyltransferases repress the oral,liver as well as prostate cancer progression in the xenografted animal model system.Furthermore,we have shown that one of the p300 specific inhibitors discovered in our laboratory potently inhibit the multiplication of HIV in a cellular system.By using a novel histone acetyltransferase activator molecule,we find that p300/CBP mediated acetylation of histones is an important inducing factor for robust neurogenesis;which presumably contributes to long-term spatial memory.Remarkably,the p300/CBP activator treatment efficiently enhances the memory of Tau mice almost to the normal level.The molecular basis of this phenomenon is being understood.     

Inhibition of PI3K/Akt signaling: an emerging paradigm for targeted cancer therapy

The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB) signaling pathway plays a critical role in cell growth and survival. Dysregulation of this pathway has been found in a variety of cancer cells. Recently, constitutively active PI3K/Akt signaling has been firmly established as a major determinant for cell growth and survival in an array of cancers. Blocking the constitutively active PI3K/AKT signaling pathway provides a new strategy for targeted cancer therapy. Thus, inhibitors of this signaling pathway would be potential anticancer agents, particularly for cancer cells whose survival and growth are dominated by constitutively active PI3K/Akt signaling. This review describes the current understanding of small molecule drugs targeting this pathway both in vitro and in vivo. Inhibitors and functions of the upstream and downstream molecular targets of the PI3K/Akt pathway are discussed in the context of using the inhibitors to block this pathway for targeted cancer therapy. Special emphasis is placed on the following targets: receptor tyrosine kinases, PI3K, Akt, and the mammalian target of rapamycin. While the molecular therapeutic strategy holds great promise for the treatment of a variety of cancers, few small molecule inhibitors with potential high therapeutic indexes are available. Thus, new inhibitors with high selectivity, bioavailability, and potency are greatly needed. Novel approaches toward the development of PI3K/Akt pathway inhibitors as anticancer therapeutics are discussed in detail, with emphasis on chemical genetics-based and structure-based drug design.     

Exploiting the therapeutic potential of the PI3K-AKT-mTOR pathway in enriched populations of gynecologic malignancies

Given the prevalence of phosphatase & tensin homolog mutations in histologic specimens harvested from patients with endometrial cancer, significant interest in systemic treatment with PI3K/Akt/mTOR inhibitors has emerged. Several Phase II trials have been completed studying mTOR inhibitors in advanced/recurrent endometrial cancer. The mTOR pathway also appears to be important in some cervical cancers. Finally, because clear cell carcinoma of the ovary and renal cell carcinoma have a shared histology, the potential for activity of mTOR inhibitors in clear cell cancer of the ovary is implicit. This article reviews the results of Phase II clinical trials of PI3K/Akt/mTOR pathway inhibitors in patients with endometrial cancer, and discusses the potential therapeutic landscape of mTOR inhibition in enriched populations in gynecologic cancers.     

ZD1839: targeting the epidermal growth factor receptor in cancer therapy

The erbB family of receptors, which includes the epidermal growth factor receptor, has been widely implicated in promoting proliferation of malignant cells. The critical role played by epidermal growth factor receptor in cancer has resulted in extensive research for selective inhibitors of the epidermal growth factor receptor signalling pathway. Selective small molecule epidermal growth factor receptor-tyrosine kinase inhibitors, such as ZD1839 (Iressa^?), block signal transduction pathways implicated in proliferation and survival of cancer cells and other host-dependent processes promoting cancer cell growth. In preclinical studies, ZD1839, alone and in combination with other agents, has demonstrated antitumour activity in a range of tumour types. Results from Phase I trials, in healthy volunteers and in patients with advanced disease, have shown that ZD1839 has excellent bioavailability and an acceptable tolerability profile. In these studies, ZD1839 has also shown promising clinical activity in patients with a variety of tumour types. Furthermore, Phase II studies confirmed clinically meaningful antitumour activity and have demonstrated symptom relief in the second- and third-line treatment of non-small cell lung cancer. Phase III trials are currently evaluating ZD1839 in combination with gemcitabine/cisplatin or paclitaxel/carboplatin as first-line treatment of non-small cell lung cancer and an ongoing clinical trial programme is investigating other tumours (i.e., head and neck, prostate, colon and breast) and other combinations. This article provides an overview of the current profile of ZD1839.     

ZD1839: targeting the epidermal growth factor receptor in cancer therapy

The erbB family of receptors, which includes the epidermal growth factor receptor, has been widely implicated in promoting proliferation of malignant cells. The critical role played by epidermal growth factor receptor in cancer has resulted in extensive research for selective inhibitors of the epidermal growth factor receptor signalling pathway. Selective small molecule epidermal growth factor receptor-tyrosine kinase inhibitors, such as ZD1839 (Iressa), block signal transduction pathways implicated in proliferation and survival of cancer cells and other host-dependent processes promoting cancer cell growth. In preclinical studies, ZD1839, alone and in combination with other agents, has demonstrated antitumour activity in a range of tumour types. Results from Phase I trials, in healthy volunteers and in patients with advanced disease, have shown that ZD1839 has excellent bioavailability and an acceptable tolerability profile. In these studies, ZD1839 has also shown promising clinical activity in patients with a variety of tumour types. Furthermore, Phase II studies confirmed clinically meaningful antitumour activity and have demonstrated symptom relief in the second- and third-line treatment of non-small cell lung cancer. Phase III trials are currently evaluating ZD1839 in combination with gemcitabine/cisplatin or paclitaxel/carboplatin as first-line treatment of non-small cell lung cancer and an ongoing clinical trial programme is investigating other tumours (i.e., head and neck, prostate, colon and breast) and other combinations. This article provides an overview of the current profile of ZD1839.     

Human endometrial and ovarian cancer cells: histone deacetylase inhibitors exhibit antiproliferative activity, potently induce cell cycle arrest, and stimulate apoptosis

Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in endometrial cancers and ovarian cancers, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. Clonogenic assay in soft agar and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed that many endometrial and ovarian cancer cell lines were sensitive to the growth inhibitory effect of HDAC inhibitors (HDACIs), although normal endometrial epithelial cells were viable after the treatment with the same doses of HDACIs that induced growth inhibition of endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to HDACIs decreased the proportion of cells in the S-phase and increased the proportion in the G0/G1 phases and/or G2/M phases of the cell cycle. Induction of apoptosis was confirmed by TUNEL assay, annexin V staining of externalized phosphatidylserine, and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis. In nude mice experiments, valproic acid significantly inhibited human endometrial and ovarian tumor growth without toxic side-effects. Although there are few clinical trials on these cancers, some clinical trials showed that HDACIs in well tolerated doses have significant antitumoral activities in another cancers. These results raise the possibility that HDACIs may prove particularly effective in the treatment of endometrial cancers and ovarian cancers.     

Novel strategies in cancer therapeutics: targeting enzymes involved in cell cycle regulation and cellular proliferation

Tumor development, growth, and progression depend on some combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. Understanding the complex molecular mechanisms that underlie these processes should therefore lead to the identification of potential targets for therapeutic intervention. The estrogen receptor and HER-2/neu were among the earliest targets investigated, ultimately leading to the widespread use of tamoxifen and trastuzumab, respectively, in the treatment of breast cancer. Major research advances have since led to other classes of targeted therapies, including cyclin-dependent kinase inhibitors, histone deactylase inhibitors, and receptor tyrosine kinase inhibitors. The following review provides a discussion of the molecular biology associated with each of these types of therapies as well as a detailed summary of the preclinical and clinical data published on selected compounds from each of these subgroups.     

Targeting angiogenesis in endometrial cancer - new agents for tailored treatments

Introduction: Endometrial carcinoma represents the most frequent gynecologic tumor in developed countries. The majority of women presents with low-grade tumors but a significant subset of women experience recurrence and do not survive their disease. Patients with stage III/ IV or recurrent endometrial cancer have a poor prognosis. Identification of active and tolerable new targeted agents versus specific molecular targets is a priority objective. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer and in particular endometrial cancer.

Areas covered: In this review, the authors highlight the main angiogenetic molecular pathways and the anti-angiogenic agents in Phase II clinical trials for endometrial cancer treatment. The authors focus on reports from recent years on angiogenesis inhibitors used in endometrial cancer, including anti- vascular endothelial growth factor (VEGF) monoclonal antibodies (bevacizumab and aflibercept), mammalian target of rapamycin inhibitors (mTORi) (everolimus, temsirolimus and ridaforolimus), PI3 K inhibitors (BKM120), tyrosine kinase inhibitors (brivanib, sunitinib, dovitinib and nintedanib) and thalidomide.

Expert opinion: These anti-angiogenic drugs, while used either alone or in combination with chemotherapy, have presented mixed results in treating endometrial cancer patients. Challenges for the future include the identification of new pathways, early identification and overcoming resistance and the use of these molecules in combination with old and new chemotherapeutic and targeted agents.