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: 6919883
• 负责人: PARASKEVI GIANNAKAKOU
• 金额: $ 27.06万
• 依托单位: EMORY UNIVERSITY
• 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 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919883
• 关键词: P glycoprotein; antineoplastics; binding sites; cell line; chemical binding; chemical models; computer simulation; cytotoxicity; drug interactions; drug metabolism; drug resistance; human tissue; microtubules; molecular dynamics; neoplastic cell; paclitaxel; pharmacokinetics; physical model; point mutation; polymerase chain reaction; polymerization; tubulin

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）：我们的总体研究计划侧重于了解针对微管（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最有效的药物之一。紫杉醇是 MT 稳定药物的原型，其在多种人类肿瘤中的活性引起了人们对微管蛋白作为化疗靶点的强烈兴趣。然而，耐药肿瘤细胞的出现限制了紫杉醇治疗疾病的能力。对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介导的。因此，虽然微管蛋白似乎是一个非常重要的化疗靶点，但对在耐药细胞中具有活性的新型 MT 靶向药物的需求不断增加。其中一种药物是discodermolide，一种海洋海绵天然产物，与紫杉醇的作用机制相似，但具有一些独特的功能。 Discodermolide 具有非紫杉烷化学结构，对紫杉醇抗性细胞系（包括过度表达 Pgp 或含有 β-微管蛋白突变的细胞系）具有活性。此外，discodermolide 是迄今为止唯一报道在多种人类癌细胞系中与紫杉醇具有协同作用的 MT 稳定药物。然而，这种协同相互作用的分子机制目前尚不清楚。为了更好地了解 discodermolide 和紫杉醇如何与其细胞内靶标微管蛋白相互作用，我们建立了对 discodermolide 以及 discodermolide 和紫杉醇协同组合具有抗性的人类癌细胞系。我们建议的具体目标是：(a) 阐明药物选择克隆中对 discodermolide 或 discodermolide/-紫杉醇组合耐药的分子机制。 (b) 对 discodermolide 类似物进行结构-活性关系 (SAR) 研究，以确定生物活性的结构要求。我们还将进行 discodermolide-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中，以研究它们对药物结合的影响。