Cheng Ziqi, Lu Xuan, Feng Baomin
College of Life Science and Technology, Dalian University, Dalian, China.
Transl Cancer Res. 2020 Jun;9(6):4020-4027. doi: 10.21037/tcr-20-682.
Microtubules exist in all eukaryotic cells and are one of the critical components that make up the cytoskeleton. Microtubules play a crucial role in supporting cell morphology, cell division, and material transport. Tubulin modulators can promote microtubule polymerization or cause microtubule depolymerization. The modulators interfere with the mitosis of cells and inhibit cell proliferation. Tubulin mainly has three binding domains, namely, paclitaxel, vinca and colchicine binding domains, which are the best targets for the development of anticancer drugs. Currently, drugs for tumor therapy have been developed for these three domains. However, due to its narrow therapeutic window, poor selectivity, and susceptibility to drug resistance, it has severely limited clinical applications. The method of combined medication, the change of administration method, the modification of compound structure, and the research and development of new targets have all changed the side effects of tubulin drugs to a certain extent. In this review, we briefly introduce a basic overview of tubulin and the main mechanism of anti-tumor. Secondly, we focus on the application of drugs which developed based on the three domains of tubulin to various cancers in various fields. Finally, we further provide the development progress of tubulin inhibitors currently in clinical trials.
微管存在于所有真核细胞中,是构成细胞骨架的关键成分之一。微管在维持细胞形态、细胞分裂和物质运输中发挥着至关重要的作用。微管蛋白调节剂可促进微管聚合或导致微管解聚。这些调节剂干扰细胞的有丝分裂并抑制细胞增殖。微管蛋白主要有三个结合域,即紫杉醇、长春花碱和秋水仙碱结合域,它们是抗癌药物开发的最佳靶点。目前,针对这三个结构域已开发出用于肿瘤治疗的药物。然而,由于其治疗窗口窄、选择性差以及易产生耐药性,严重限制了其临床应用。联合用药方法、给药方式的改变、化合物结构的修饰以及新靶点的研发,都在一定程度上改变了微管蛋白药物的副作用。在本综述中,我们简要介绍微管蛋白的基本概况及其抗肿瘤的主要机制。其次,我们重点介绍基于微管蛋白三个结构域开发的药物在各个领域对各种癌症的应用。最后,我们进一步介绍目前处于临床试验阶段的微管蛋白抑制剂的研发进展。