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1.
微管抑制剂一直是抗肿瘤药物研究的热点。微管抑制剂通过促进或抑制微管的聚合来破坏微管的动态平衡,阻碍肿瘤细胞纺锤体形成,阻滞细胞分裂进程从而发挥抗肿瘤作用。有丝分裂灾难是发生在细胞有丝分裂期,由细胞分裂异常和纺锤体结构的损伤而造成的细胞死亡现象。近年来,微管抑制剂能够诱导肿瘤细胞发生有丝分裂灾难已被临床证实,并越来越受到人们关注。现对微管抑制剂的最新研究进展进行综述,并探讨其诱导肿瘤细胞发生有丝分裂灾难死亡的分子机制。  相似文献   

2.
微管蛋白活性抑制剂研究进展   总被引:8,自引:1,他引:7  
由微管蛋白聚集而成的微管是组成纺锤体的主要成分.微管蛋白聚集或微管解聚的抑制将导致细胞有丝分裂中止.很多天然产物通过结合在微管蛋白的CLC部位或VLB部位而抑制其聚集;少数化合物通过抑制微管的解聚而使细胞有丝分裂中止.本文对近年来微管活性抑制剂的研究进展进行了总结,着重讨论了化合物结构和活性的关系以及新的抑制微管活性化合物.大多数微管活性抑制剂都是抗肿瘤活性化合物.以微管蛋白为靶点筛选抗肿瘤药物是有效的途径之一.  相似文献   

3.
目的 通过网络药理学和分子对接方法探讨淫羊藿抗肿瘤的作用机制。方法 利用TCMSP数据库获取淫羊藿的活性成分以及相对应的靶点,利用Genecards、OMIM数据库获取疾病靶点,绘制药物-疾病韦恩图,获得其共同靶点;利用 Cytoscape 3.8.2 软件构建“淫羊藿活性成分-疾病靶点”网络可视化关系图;利用STRING数据库和Cytoscape 3.8.2 软件构建蛋白相互作用网络,并进行网络拓扑分析;利用R x64 4.0.5软件,对相关靶点进行GO和KEGG富集分析,了解淫羊藿抗肿瘤可能的生物过程及其通路;最后利用SYBYL 2.0软件分子对接进行半柔性对接反向验证。结果 筛选出淫羊藿活性成分23个,靶点193个;疾病相关靶点8 169个,活性成分与疾病两者共同靶点173个;蛋白互作网络显示TP53、AKT1、JUN、CASP3等靶点基因在淫羊藿抗肿瘤的生物网络中起重要作用;潜在作用靶点涉及2 592条生物学功能、176条通路。分子对接结果显示淫羊藿活性化合物与多个疾病关键靶点具有较高结合能力,对接评分较高的为淫羊藿苷与CASP3靶点蛋白。结论 淫羊藿抗肿瘤具有多靶点和多通路的潜在作用机制,为其进一步研究提供参考。  相似文献   

4.
目的 总结抗肿瘤药物产生耐药性的相关机制,探讨临床治疗对策。方法 检索PubMed、Medline、Cochrane图书馆、中国期刊全文数据库(清华同方CJFD)、维普中文科技期刊全文数据库(VIP)、万方数据库发表与抗肿瘤药物的耐药性及临床治疗对策相关的文献,并结合当前抗肿瘤药物使用情况对其进行综述。结果 抗肿瘤药耐药性的产生受多种因素的影响,如药物外排增加使肿瘤细胞中的药物浓度降低、解毒作用加强、DNA修复损伤功能增加、肿瘤细胞通道信号异常、靶点改变等。结论 临床可根据产生耐药性的不同机制予以针对性治疗,中药具有多靶点作用,其逆转耐药优势突出。  相似文献   

5.
目的 利用网络药理学分析康莱特注射液3种主要成分的抗肿瘤作用机制。方法 以康莱特注射液中具有抗肿瘤作用的甘油三油酸酯、薏苡仁酯、薏苡素为研究对象,依托中药系统药理学数据库(TCMSP)、反向分子对接服务器(PharmMapper)、人类基因组注释数据库(GeneCards)、药物治疗靶标数据库(TTD)进行靶点预测和筛选,借助Cytoscape 3.5.1软件构建活性成分-靶点-疾病网络,借助STRING平台构建靶蛋白相互作用网络,通过DAVID平台对靶点基因本位生物过程和KEGG信号通路进行富集分析。结果 康莱特注射液活性成分作用于EGFR、PGR、PTGS2、AR、MAPK1等25个潜在抗肿瘤靶点,调控FoxO、前列腺癌、癌症、Rap1、TNF、Ras、MAPK信号通路,参与细胞增殖调控、蛋白激酶B信号调控、环氧合酶途径、细胞迁移调控等生物过程,可用于20多种癌症的治疗。结论 本研究为进一步深入研究康莱特注射液抗肿瘤机制提供了新的线索与思路。  相似文献   

6.
《中国海洋药物》2010,29(4):59-65
海洋生物是抗肿瘤活性物质的重要来源,不同的活性物质因其结构不同而具备不同的生物活性。大环内酯是其中的重要部分,其作用机制主要与结构中的内酯环相关。大多数海洋大环内酯类化合物通过作用于细胞骨架发挥其抗肿瘤活性。细胞骨架包括微丝、微管和中间纤维,微丝和微管分别由肌动蛋白和微管蛋白聚合而成,药物正是通过改变它们的解聚、聚合作用而发挥其抗肿瘤作用。细胞骨架在功能上与细胞结构、胞内运输和细胞分裂密切相关,已成为肿瘤化疗中的新靶点。现综述以细胞骨架为靶点的具有抗肿瘤活性的海洋大环内酯类化合物,以及其作用机制、生物活性的研究进展。  相似文献   

7.
目的 了解某院抗肿瘤药物应用情况,探讨其临床用药特点及发展趋势。 方法 采用药物经济学方法对该院2012-2013年间抗肿瘤药物应用情况进行回顾性分析。 结果 居主导地位的是抗肿瘤植物药,用药金额最大的是康艾注射液,用药频度最大的是乌苯美司胶囊,日均用药金额最小的是乌苯美司胶囊,抗肿瘤药物中大多数药物利用指数接近1。 结论 该院抗肿瘤药物临床应用基本合理。该院应用的抗肿瘤药物主要以植物药为主,植物药在肿瘤治疗方面起到了很大的作用。  相似文献   

8.
目的 基于网络药理学筛选治疗化疗所致恶心呕吐(CINV)的潜在靶点、化合物及中药,并分析中药的性味归经以及中药治疗CINV的作用机制。方法 利用PubChem、Swiss Target Prediction平台获得具有致吐风险的化疗药物靶点;基于Gene Cards、Drugbank及OMIM数据库收集CINV疾病靶点,取“疾病-药物”交集靶点,并通过临床指南获得CINV治疗药物靶点,将交集靶点及治疗药物靶点视为治疗CINV的潜在靶点。通过TCMSP平台筛选化合物和中药。利用Cytoscape 3.7.2建立“靶点-化合物-中药”网络图,使用网络分析功能获得重要靶点、化合物及中药,并对中药性味归经进行频率分析。结果 获得35个潜在靶点、799种候选化合物和395味中药。395味中药以苦味、辛味及温性为主,主要分布在肝经和肺经中,其次是脾经及胃经。结论 运用中药治疗CINV具有广阔的发展空间,该研究为CINV的中药治疗及新药的开发提供了思路及理论依据。  相似文献   

9.
Stathmin蛋白不同的研究组给予其不同的命名,主要有P17、P18、P19、P19K、metablastin、癌蛋白18(Op18)、LAP18等。研究发现,由于其特有的微管解聚活性,在细胞周期纺锤体的形成过程中发挥十分重要的作用。多种恶性肿瘤中Stathmin都有高水平表达,通过抑制其表达可以干扰恶性细胞的分裂,从而使细胞生长停滞于G2/M期。Stathmin的过表达会影响作用于微管化疗药物的疗效。Stathmin基因反义核酸对多种恶性肿瘤有抗细胞增殖和抗肿瘤效应,为肿瘤生物治疗提供了一个分子新靶点。  相似文献   

10.
作用于微管的抗肿瘤药物研究进展   总被引:6,自引:0,他引:6  
以微管为作用靶点的药物是一类重要的抗肿瘤药物。独特的作用机制和良好的治疗效果使其一直成为研究的热点。近年来,有关它们的作用机制、结合构象、结合位点及构效关系得到了更加深入细致的研究。本文从以上几个方面综述了这类药物的研究进展。  相似文献   

11.
Microtubules, major structural components in cells, are the target of a large and diverse group of natural product anticancer drugs. Given the success of this class of drugs in cancer treatment, it can be argued that microtubules represent the single best cancer target identified to date. Microtubules are highly dynamic assemblies of the protein tubulin. They readily polymerize and depolymerize in cells, and they undergo two interesting kinds of dynamics called dynamic instability and treadmilling. These dynamic behaviors are crucial to mitosis, the process of chromosomal division to form new cells. Microtubule dynamics are highly regulated during the cell cycle by endogenous cellular regulators. In addition, many antitumor drugs and natural compounds alter the polymerization dynamics of microtubules, blocking mitosis, and consequently, inducing cell death by apoptosis. These drugs include several that inhibit microtubule polymerization at high drug concentrations, namely, the Vinca alkaloids, cryptophycins, halichondrins, estramustine, and colchicine. Another group of these compounds stimulates microtubule polymerization and stabilizes microtubules at high concentrations. These include Taxol, Taxotere, eleutherobins, epothilones, laulimalide, sarcodictyins, and discodermolide. Importantly, considerable evidence indicates that, at lower concentrations, these drugs have a common mechanism of action; they suppress the dynamics of microtubules without appreciably changing the mass of microtubules in the cell. The drugs bind to diverse sites on tubulin and at different positions within the microtubule, and they have diverse effects on microtubule dynamics. However, by their common mechanism of suppression microtubule dynamics, they all block mitosis at the metaphase/anaphase transition, and induce cell death.  相似文献   

12.
Microtubules are highly dynamic cellular polymers made of alphabeta-tubulin and associated proteins. They play a key role during mitosis, participating in the exact organization and function of the spindle, and are critical for assuring the integrity of the segregated DNA. Therefore, they represent one of the more effective targets in current cancer therapy. Paclitaxel (Taxol) is the prototype of the taxane family of antitumor drugs, and it was the first natural product shown to stabilize microtubules. This unique mechanism of action is in contrast to other microtubule poisons, such as Vinca alkaloids, colchicine, and cryptophycines, which inhibit tubulin polymerization. Taxanes block cell cycle progression through centrosomal impairment, induction of abnormal spindles and suppression of spindle microtubule dynamics. Triggering of apoptosis by aberrant mitosis or by subsequent multinucleated G1-like state related to mitotic slippage, depends on cell type and drug schedule. The development of fluorescent derivatives of paclitaxel led us to locate spindle pole microtubules and centrosomes as main sub-cellular targets of cytotoxic taxoids in living cells. In this review we discuss these findings in the context of a cell cycle-dependent response to taxanes, based on the cellular targets, and the status of the implicated cell cycle checkpoints. We also review those events that can influence this response, like the different signal transduction pathways activated/inactivated in relation to Bcl-2 phosphorylation and induction of apoptosis, and the controversial role of the p53 status on cell sensitivity to paclitaxel. Finally, cell cycle-dependent resistance, an emerging concept in combination sequential chemotherapy, is discussed on the basis of the cell cycle-dependent mechanisms of action of taxanes.  相似文献   

13.
Introduction: About 20 patents have been published from 2013 to 2018 for developing advanced cancer therapeutics by targeting tubulin polymerization. Currently, there are several tubulin inhibitors that are in the drug development pipeline for various cancers alone or in combination including antibody-conjugated drugs (ACDs).

Areas covered: Important patents focusing on the development of tubulin inhibitors published from 2013 to 2018 are covered. This review mainly focuses on the tubulin inhibitors that are being synthesized and studied in cancer research along with their structures and their phases of development in preclinical and clinical research.

Expert opinion: Regulation of microtubules is important for cell division, cell motility, intracellular transport, and cell shape maintenance. Modulating its activity proved to be very effective in various diseases including different types of cancers. Microtubules are composed of two units, namely, alpha and beta-tubulin, and modifications at these ends affect both its functions and dynamics. A number of compounds that have been designed and synthesized bearing various heterocyclic scaffolds have been proven to modulate its activity and have emerged as potent tubulin inhibitors. This encourages more to study microtubules in order to find a variety of novel, potent compounds as anticancer drugs.  相似文献   

14.
Noscapine, an antitussive drug, has been previously shown to inhibit the growth of cultured tumor cells and tumors implanted in nude mice. Like some other antitumor agents, noscapine targets a cellular protein, tubulin, that is responsible for the assembly of important scaffolding polymers, microtubules. As a result, noscapine causes the aberrant assembly of the cellular machinery necessary for cell division, the mitotic spindle. This is followed by apoptotic cell death. Current evidence suggests that the antitumor activity of noscapine might lie in its initiation of apoptotic pathways. Compared with other microtubule drugs, noscapine has low toxicity and wide efficacy in animal models. For clinical use, noscapine affords simple means of administration including oral, rectal, parenteral or by simple inhalation of suitable aerosols. Thus, noscapine and its analogues are potential cost-effective chemotherapeutic agents for the treatment of human cancers.  相似文献   

15.
Microtubules are a proven target for anticancer drug development because they are critical for mitotic spindle formation and the separation of chromosomes at mitosis. We here report a novel synthetic microtubule inhibitor 7-diethylamino-3(2′-benzoxazolyl)-coumarin (DBC). DBC causes destabilization of microtubules, leading to a cell cycle arrest at G2/M stage. In addition, human cancer cells are more sensitive to DBC (IC50 44.8-475.2 nM) than human normal fibroblast (IC50 7.9 μM), and DBC induces apoptotic cell death of cancer cells. Furthermore, our data show that DBC is a poor substrate of drug efflux pumps and effective against multidrug resistant (MDR) cancer cells. Taken together, these results describe a novel pharmacological property of DBC as a microtubule inhibitor, which may make it an attractive new agent for treatment of MDR cancer.  相似文献   

16.
Targeting microtubules for cancer chemotherapy   总被引:3,自引:0,他引:3  
Chemical compounds that interfere with microtubules such as the vinca alkaloids and taxanes are important chemotherapeutic agents for the treatment of cancer. As our knowledge of microtubule-targeting drugs increases, we realize that the mechanism underlying the anti-cancer activity of these agents may mainly lie in their inhibitory effects on spindle microtubule dynamics, rather than in their effects on microtubule polymer mass. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell cycle progression at mitosis and eventually leading to apoptotic cell death. The effectiveness of microtubule-targeting drugs for cancer therapy has been impaired by various side effects, notably neurological and hematological toxicities. Drug resistance is another notorious factor that thwarts the effectiveness of these agents, as with many other cancer chemotherapeutics. Several new microtubule-targeting agents have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to the existing microtubule-targeting drugs. Continued investigation of the mechanisms of action of microtubule-targeting drugs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance may provide more effective therapeutic options for cancer patients.  相似文献   

17.
埃坡霉素类化合物是一种新型的抗肿瘤药物,通过与肿瘤细胞中的微管蛋白结合,促进微管蛋白聚合并抑制微管的解聚,使细胞周期停止,最终诱导细胞凋亡。动物实验显示其具有广泛的抗肿瘤活性,并可作用于已经产生多药耐药性的肿瘤患者。目前有多个此类化合物正处于临床试验阶段,是一类非常有前景的抗肿瘤药物。本文对具有代表性的几个埃坡霉素类化合物的临床药代动力学及其毒性反应研究进行综述。  相似文献   

18.
The effect of phenylazoxycyanide and calvatic acid, its reference antibiotic, on some functions of tubulin obtained from different sources has been studied. Our purpose was to establish a possible correlation between the antitumour activity of these drugs and their antimicrotubular action. Microtubules are subcellular structures involved in proliferation and maintenance of the cell shape and probably in malignant transformation; indeed most antimitotic drugs influence the stability of microtubules through the interaction with tubulin, their main protein. In this work we found phenylazoxycyanide impairs, more than calvatic acid, polymerization of purified tubulin from calf brain. It also damages, in a dose-dependent manner, colchicine-binding ability of tubulin derived from rat liver and AH-130 Yoshida ascite hepatoma cells. Compounds displaying an azoxycyano group may represent new antimicrotubular agents and their effect could be modulated by the different polarity and structural characteristic of the molecule.  相似文献   

19.
摘要:微管是细胞骨架重要组成成分,是筛选抗肿瘤药物的重要靶标。海洋生态系统的极端环境使海洋生物具备产生独特 化学结构和生理活性天然产物的能力,为新药发现提供了物质基础。本文主要综述了1972-2021年从海洋生物中分离鉴定的成 药性较好的微管去稳定剂抗肿瘤药物的研究进展,总结了活性化合物来源、构效关系,临床研究进展,化学全合成及衍生物的 研究情况等,以期为医药工作者提供新的研究思路,推进靶向微管海洋抗肿瘤药物的发展。  相似文献   

20.
Microtubules (MTs) play important and diverse roles in eukaryotic cells. Their function and biophysical properties have made alpha-and beta-tubulin, the main components of MTs, the subject of intense study. Interfering with normal MT dynamics, for example, by the addition of tubulin ligands, can cause the cell great distress and affect MT stability and functions, including mitosis, cell motion and intracellular organelle transport. It has been shown in the literature that tubulin is an important target molecule for developing anticancer drugs. Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. This mode of action is also shared with other natural agents eg colchicine and podophyllotoxin. However various tubulin isotypes have shown resistance to taxanes and other MT agents. Therefore, there is a strong need to design and develop new natural analogs as antimitotic agents to interact with tubulin at sites different from those of vinca alkaloids and taxanes. This minireview provides SAR on several classes of antimitotic agents reported in the literature. The structures and data given are essential to the scientists who are involved in drug design and development in the field of anticancer drugs.  相似文献   

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