Antitubulin drugs: Mechanisms of action and resistance

抗微管蛋白药物：作用机制和耐药性

• 批准号: 7027635
• 负责人: PARASKEVI GIANNAKAKOU
• 金额: $ 28.35万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027635
• 关键词: Binding; Binding Sites; Biological; Biological Assay; Biological Factors; Biological Markers; Cancer cell line; Cell Death; Cell Line; Cells; Chemical Structure; Chemotherapy-Oncologic Procedure; Classification; Clinical Trials; Collaborations; Complex; Cytoskeleton; DNA; Data; Depth; Disease; Drug Delivery Systems; Drug resistance; Drug-sensitive; Electrons; Elements; Exhibits; Experimental Designs; Generations; Genes; Goals; Human; In Vitro; Inherited; Investigation; Laboratories; Letters; Malignant Epithelial Cell; Maps; Marines; Mediating; Methods; Microtubules; Mitotic; Modeling; Molecular; Molecular Conformation; Molecular Mechanisms of Action; Mutate; Mutation; Ovarian Carcinoma; P-Glycoprotein; P-Glycoproteins; Paclitaxel; Parents; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Photoaffinity Labels; Point Mutation; Porifera; Principal Investigator; Property; Protein Overexpression; Radiolabeled; Range; Relative (related person); Reporting; Research; Resistance; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Scientist; Side; Site; Structural Models; Structure-Activity Relationship; Taxane Compound; Techniques; Testing; Tubulin; Tubulin Interaction; Vinblastine; Vincristine; Work; analog; antitumor drug; base; beta Tubulin; cancer cell; cell type; chemotherapy; cytotoxicity; density; design; dimer; discodermolide; docetaxel; drug mechanism; electron crystallography; functional group; gene repair; improved; in vitro Assay; insight; interest; molecular modeling; mutant; neoplastic cell; novel; polymerization; programs; prototype; radiotracer; research study; resistance mechanism; response; taxane; tool; tumor; uptake

DESCRIPTION (provided by applicant): Our overall research initiative is focused on understanding the molecular mechanism of action and resistance to antitumor drugs that target the microtubule (MT) cytoskeleton. MT- targeting drugs are among the most effective agents introduced in cancer chemotherapy. Taxol is the prototype of MT-stabilizing drugs, and its activity in a broad range of human tumors has ignited intense interest in tubulin as a chemotherapy target. The emergence of drug resistant tumor cells, however, limits Taxol's ability to cure disease. Resistance to Taxol is primarily mediated through overexpression of P-glycoprotein (Pgp) and the presence of beta-tubulin mutations. Thus, while tubulin appears to be a very important chemotherapy target, there is an increasing need for novel MT-targeting agents with activity in resistant cells. One such agent is discodermolide, a marine-sponge natural product, with a similarity to Taxol's mechanism of action but with several unique features. Discodermolide has a nontaxane chemical structure and is active against Taxol-resistance cell lines, both those that overexpress Pgp or harbor beta-tubulin mutations. In addition, discodermolide is the only MT-stabilizing drug reported to date to be synergistic with Taxol in various human cancer cell lines. The molecular mechanism of this synergistic interaction, however, is currently unknown. In an effort to better understand how discodermolide and Taxol interact with their intracellular target, tubulin, we have established human cancer cell lines resistant to discodermolide and to the synergistic combination of discodermolide and Taxol. The specific aims of our proposal are :(a) Elucidate the molecular mechanism of resistance to discodermolide or to the discodermolide/-taxol combinations in the drug selected clones. (b) Perform structure-activity relationship (SAR) studies on discodermolide analogs to determine the structural requirements for biological activity. We will also perform molecular modeling and structural studies of discodermolide-tubulin binding (c) Introduce specific tubulin mutations into human cancer cells to investigate their effect on drug-binding.

描述(由申请人提供)：我们的整体研究计划集中在了解针对微管(MT)细胞骨架的抗肿瘤药物的作用和耐药性的分子机制。MT靶向药物是癌症化疗中引入的最有效的药物之一。紫杉醇是MT稳定药物的原型，它在广泛的人类肿瘤中的活性已经点燃了人们对微管蛋白作为化疗靶点的浓厚兴趣。然而，耐药肿瘤细胞的出现限制了紫杉醇治疗疾病的能力。紫杉醇的耐药性主要是通过P-糖蛋白(Pgp)的过度表达和β-微管蛋白突变的存在而介导的。因此，尽管微管蛋白似乎是一个非常重要的化疗靶点，但对具有耐药细胞活性的新型MT靶向药物的需求越来越大。其中一种药物是盘状海绵，一种海洋海绵天然产品，与紫杉醇的作用机制相似，但有几个独特的特点。Discodermolide具有非紫杉烷的化学结构，对紫杉醇耐药细胞株具有活性，这两种细胞株都过度表达Pgp或含有β-微管蛋白突变。此外，Discodermolide是迄今为止报道的唯一一种与紫杉醇在各种人类癌细胞系中具有协同作用的MT稳定药物。然而，这种协同作用的分子机制目前尚不清楚。为了更好地了解discodermolide和紫杉醇如何与它们的细胞内靶点微管蛋白相互作用，我们建立了对discodermolide以及discodermolide和紫杉醇协同作用的人类癌细胞株。我们建议的具体目的是：(A)阐明在所选药物克隆中对盘状病毒或对盘状病毒/紫杉醇组合的耐药性的分子机制。(B)对盘状除草剂类似物进行构效关系研究，以确定生物活性的结构要求。我们还将进行盘状物-微管蛋白结合的分子建模和结构研究(C)将特定的微管蛋白突变引入人类癌细胞，以研究它们对药物结合的影响。

项目成果

Microtubule disruption targets HIF-1alpha mRNA to cytoplasmic P-bodies for translational repression.

• DOI: 10.1083/jcb.201004145
• 发表时间: 2011-01-10
• 期刊: The Journal of cell biology
• 作者: Carbonaro M;O'Brate A;Giannakakou P
• 通讯作者: Giannakakou P

Integrating image analysis algorithms in a web interface for the quantification of microtubule dynamics.

将图像分析算法集成到网络界面中以量化微管动力学。

• DOI: 10.1504/ijcbdd.2012.049211
• 发表时间: 2012
• 期刊: International journal of computational biology and drug design
• 作者: Kong,KoonYin;Marcus,AdamI;Giannakakou,Paraskevi;Wang,MayDongmei
• 通讯作者: Wang,MayDongmei

A Web Interface for the Quantification of Microtubule Dynamics.

用于量化微管动力学的 Web 界面。

• DOI: 10.1109/bibmw.2011.6112376
• 发表时间: 2011
• 期刊: IEEE International Conference on Bioinformatics and Biomedicine workshops. IEEE International Conference on Bioinformatics and Biomedicine
• 作者: Kong,KoonYin;Marcus,AdamI;Giaanakakou,Paraskevi;Wang,MayD
• 通讯作者: Wang,MayD

Automatic microtubule tracking for QD-based in vivo cell imaging and drug efficacy study.

用于基于 QD 的体内细胞成像和药效研究的自动微管跟踪。

• DOI: 10.1109/iembs.2006.259750
• 发表时间: 2006
• 期刊: Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference
• 作者: Kong,KoonYin;Marcus,AdamI;Hong,JinYoung;Giannakakou,Paraskevi;Wang,MayD
• 通讯作者: Wang,MayD

Peloruside- and laulimalide-resistant human ovarian carcinoma cells have βI-tubulin mutations and altered expression of βII- and βIII-tubulin isotypes.

• DOI: 10.1158/1535-7163.mct-10-1057
• 发表时间: 2011-08
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Kanakkanthara A;Wilmes A;O'Brate A;Escuin D;Chan A;Gjyrezi A;Crawford J;Rawson P;Kivell B;Northcote PT;Hamel E;Giannakakou P;Miller JH
• 通讯作者: Miller JH