Resistance to anti-tubulin agents: From vinca alkaloids to epothilones.
Resistance to anti-tubulin agents: From vinca alkaloids to epothilones.
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DOI：
10.20517/cdr.2019.06
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Krause, Werner
中科院分区：
文献类型：
--
作者：
Krause, Werner
关键词：
本文综述了微管抑制的作用机制，以及长春花碱、紫杉烷类和环磷酰胺类药物最重要的耐药机制。耐药性是长春花碱和紫杉烷化疗中的一个主要问题，在大多数情况下，耐药性是由于将药物输送出癌细胞的外排泵的过度表达，以及靶点微管的修饰，通过微管蛋白同型的过度表达或通过将蛋白质附着到微管的末端，从而使靶点不再被药物识别。然而，在某些情况下，这一过程可能会产生相反的效果，导致增敏，例如，在紫杉烷无效或不再有效的情况下，对长春花碱起敏化作用。外排泵引起的耐药性与药物的药代动力学和新陈代谢之间的联系也包括在内。解决的其他类型的耐药性包括癌细胞内药物的解毒和阻止细胞凋亡、微管和其他蛋白质途径的翻译后修饰、微RNA、癌基因的诱导和癌症干细胞，这些加在一起，为预防药物活性提供了特别多的可能性。生物标记物用于临床结果的预测和未来治疗的方向也被提及。
This review describes the mechanism of action - inhibition of microtubules - and the most important mechanisms of resistance for vinca alkaloids, taxanes and epothilones. Resistance is a major problem in vinca and taxane chemotherapy and arises in most cases from overexpression of efflux pumps that transport the drugs out of the cancer cells and from modifications of the target, the microtubules, by overexpression of tubulin isotypes or by attachment of proteins to the ends of the microtubules so that the target is no longer recognized by the drugs. In some cases, however, this process can have the opposite effect, leading to sensitization, e.g., for vinca alkaloids in cases where taxanes are not or no longer effective. The link between resistance due to efflux pumps and the pharmacokinetics and metabolism of the drugs is also covered. Other types of resistance that are addressed include detoxification of drugs within the cancer cell and blockade of apoptosis, post-translational modifications of microtubules and other protein pathways, micro-RNAs, induction of oncogenes, and cancer stem cells, which, taken together, offer particularly multifold possibilities for preventing drug activity. The use of biomarkers for the prediction of clinical outcome and for the direction of future therapy is also addressed.
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