文章：

微管与对微管蛋白结合剂的耐药性

Microtubules and resistance to tubulin-binding agents

原文发布日期：2010-02-11

DOI: 10.1038/nrc2803

类型: Review Article

开放获取: 否

要点：

1. Microtubules are required for many aspects of cellular function, including mitosis. This has made them an attractive target for the development of cancer drugs.
2. Although drugs that target tubulin and microtubules are widely used in the clinic, resistance — both inherent and acquired — is common.
3. Understanding the function of tubulin in cancer development and resistance to tubulin-binding agents (TBAs) might aid the development of more effective drugs.
4. The expression of different β-tubulin isotypes is disrupted in cancer cells, and understanding how this contributes to disease progression and drug resistance is essential. Overexpression or aberrant expression of βIII-tubulin can affect the response of tumour cells to TBAs. The mechanisms that underlie this are currently unclear. Understanding the role of the other β-tubulin isotypes in cancer development is also at an early stage.
5. Proteins that regulate microtubules, such as microtubule-associated proteins and stathmin, are also implicated in drug resistance. How, mechanistically, these proteins influence resistance to TBAs is under investigation.
6. Changes to the actin cytoskeleton also contribute to drug resistance but how such changes relate to the microtubule system needs further clarification.

要点翻译：

1. 微管是细胞多种功能所必需的结构，包括有丝分裂。这使其成为癌症药物开发的一个有吸引力的靶点。
2. 尽管靶向微管蛋白和微管的药物在临床上广泛应用，但耐药性——无论是固有性还是获得性——均十分常见。
3. 理解微管蛋白在癌症发展及微管蛋白结合剂耐药性中的作用，或有助于开发更有效的药物。
4. 癌细胞中不同β-微管蛋白同种型的表达存在紊乱，理解这种紊乱如何促进疾病进展和耐药性至关重要。βIII-微管蛋白的过度表达或异常表达会影响肿瘤细胞对微管蛋白结合剂的反应，其作用机制目前尚不明确。其他β-微管蛋白同种型在癌症发展中的作用也处于研究初期。
5. 调控微管的蛋白质，如微管相关蛋白和斯塔斯明，也与耐药性相关。这些蛋白质如何通过分子机制影响微管蛋白结合剂的耐药性正在研究中。
6. 肌动蛋白细胞骨架的变化同样会导致耐药性，但这些变化与微管系统的关联尚需进一步阐明。

英文摘要：

Microtubules are dynamic structures composed of α–β-tubulin heterodimers that are essential in cell division and are important targets for cancer drugs. Mutations in β-tubulin that affect microtubule polymer mass and/or drug binding are associated with resistance to tubulin-binding agents such as paclitaxel. The aberrant expression of specific β-tubulin isotypes, in particular βIII-tubulin, or of microtubule-regulating proteins is important clinically in tumour aggressiveness and resistance to chemotherapy. In addition, changes in actin regulation can also mediate resistance to tubulin-binding agents. Understanding the molecular mechanisms that mediate resistance to tubulin-binding agents will be vital to improve the efficacy of these agents.

摘要翻译： 

微管是由α-β-微管蛋白异二聚体组成的动态结构，在细胞分裂中不可或缺，也是抗癌药物的重要靶点。β-微管蛋白突变可通过影响微管聚合量和/或药物结合，导致对紫杉醇等微管结合剂的耐药。特定β-微管蛋白亚型（尤其是βIII-微管蛋白）或微管调节蛋白的异常表达，在临床上与肿瘤侵袭性及化疗耐药密切相关。此外，肌动蛋白调控的改变也可介导对微管结合剂的耐药。阐明介导微管结合剂耐药的分子机制，对于提高这些药物的疗效至关重要。

原文链接：

Microtubules and resistance to tubulin-binding agents