Taccalonolides: Mechanisms of Action and Cellular Resistance

他卡酮内酯：作用机制和细胞耐药性

• 批准号: 7474606
• 负责人: Susan L Mooberry
• 金额: $ 5.4万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474606
• 关键词: Antimitotic Agents; Apoptosis; Binding; Binding Sites; Bypass; Cancer cell line; Cell Line; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Class; Clinic; Clinical; Clinical Trials; Data; Defect; Drug resistance; Drug usage; Epothilones; Event; Future; Goals; Human; Investigation; Lead; Malignant Neoplasms; Mediating; Microtubule Stabilization; Microtubule stabilizing agent; Microtubules; Mitosis; Mitotic; Molecular; Mutation; Nature; Neoplasm Metastasis; P-Glycoprotein; P-Glycoproteins; Paclitaxel; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Plants; Protein Overexpression; Range; Research; Resistance; Series; Signal Pathway; Signal Transduction; Structure-Activity Relationship; Taxane Compound; Testing; Today; Toxic effect; Tubulin; base; cancer therapy; cytotoxic; design; discodermolide; docetaxel; human STK6 protein; improved; in vivo; novel; novel therapeutics; pill; pregnane X receptor; protein function; resistance mechanism; taxane; therapeutic target; tumor

DESCRIPTION (provided by applicant): Microtubule stabilizing agents are important drugs used in the treatment of cancer. The focus of this project is a new class of plant-derived microtubule stabilizers, the taccalonolides. The taccalonolides have a unique mechanism of action. They are the first microtubule stabilizers identified that have Taxol-like effects in cells but they do not bind to tubulin. Comprehensive studies are presented to identify the cellular mechanisms of action and resistance of the taccalonolides. These studies are expected to identify new targets for stabilizing microtubules that can lead to antitumor effects. Information gained from these studies will also identify the signaling pathways invoked by chemically and biologically diverse microtubule stabilizers to initiate mitotic arrest and subsequent apoptosis. This is expected to lead to the identification of new therapeutic targets for cancer. These targets could provide the anticancer efficacy of the taxanes and the ability to circumvent taxane drug resistance and tubulin-related toxicity. The first goal of this effort is to identify the cellular binding site of the taccalonolides. We will test the hypothesis that the taccalonolides bind and inhibit an intrinsic cellular microtubule destabilizing factor resulting in microtubule stabilization. A second goal is to elucidate the mechanisms by which the taccalonolides interrupt mitotic signaling leading to mitotic arrest and apoptosis. We will test the hypothesis that the taccalonolides inhibit Aurora A expression and activity. Drug resistance is a serious problem in the treatment of cancer. We will identify the nature of cellular resistance to the taccalonolides and test the hypothesis that these compounds can circumvent resistance mechanisms that contribute to taxane resistance in the clinic. The ability of the taccalonolides to bypass resistance due to P-glycoprotein expression, tubulin alterations and PXR-mediated resistance will be tested. Cell lines generated by taccalonolide exposure will be evaluated to identify the mechanisms of acquired taccalonolide resistance. The final aim will identify the structural basis for the taccalonolides mechanisms of action and resistance. Specific chemical constituents important for optimal cytotoxic efficacy and potency, antimitotic actions and antitumor activities will be determined.

说明(申请人提供)：微管稳定剂是治疗癌症的重要药物。本项目的重点是一种新型的植物来源的微管稳定剂--塔卡洛内酯。塔卡洛内酯有一种独特的作用机制。它们是第一个被证实在细胞中具有紫杉醇样作用但不与微管蛋白结合的微管稳定剂。提出了全面的研究，以确定塔卡洛内酯的作用和耐药性的细胞机制。这些研究有望确定稳定微管的新靶点，从而产生抗肿瘤作用。从这些研究中获得的信息还将确定由化学和生物上不同的微管稳定剂激活的信号通路，以启动有丝分裂停滞和随后的细胞凋亡。预计这将导致确定新的癌症治疗靶点。这些靶点可以提供紫杉烷的抗癌效果，以及规避紫杉烷耐药性和微管蛋白相关毒性的能力。这项工作的第一个目标是确定塔卡洛内酯的细胞结合部位。我们将测试这样一种假设，即塔卡洛内酯结合并抑制一种内在的细胞微管不稳定因子，从而导致微管稳定。第二个目标是阐明塔卡洛内酯中断有丝分裂信号导致有丝分裂停滞和凋亡的机制。我们将检验塔卡洛内酯抑制Aurora A表达和活性的假设。抗药性是癌症治疗中的一个严重问题。我们将确定细胞对塔卡洛内酯的耐药性的性质，并验证这样的假设，即这些化合物可以规避导致临床上紫杉烷耐药性的耐药性机制。将测试塔卡洛内酯绕过由于P-糖蛋白表达、微管蛋白改变和PXR介导的耐药性而产生的耐药性的能力。将对暴露于塔卡洛内酯产生的细胞系进行评估，以确定获得性塔卡洛内酯耐药的机制。最终目的将确定塔卡洛内酯作用和耐药机制的结构基础。将确定对最佳细胞毒效果和效力、抗有丝分裂作用和抗肿瘤活性至关重要的特定化学成分。