New insight towards development of paclitaxel and docetaxel resistance in cancer cells: EMT as a novel molecular mechanism and therapeutic possibilities
New insight towards development of paclitaxel and docetaxel resistance in cancer cells: EMT as a novel molecular mechanism and therapeutic possibilities
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DOI：
10.1016/j.biopha.2021.111824
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发表时间：
2021-06-25
影响因子：
7.5
通讯作者：
Samarghandian, Saeed
中科院分区：
文献类型：
--
作者：
Ashrafizadeh, Milad;Mirzaei, Sepideh;Samarghandian, Saeed
上皮细胞向间质细胞转化（EMT）机制负责癌细胞向邻近细胞和组织的转移和迁移。在形态学上，上皮细胞转化为间充质细胞，并且在分子水平上，E-cadherin经历下调，而N-cadherin和vimentin水平增加。越来越多的证据表明EMT在介导癌细胞耐药性中的作用。另一方面，紫杉醇（PTX）和多西他赛（DTX）是属于紫杉烯家族的两种化疗药物，能够通过阻止微管解聚来诱导癌细胞的细胞周期停滞。由EMT介导的转移导致的癌细胞的侵袭行为可导致PTX和DTX抗性。EMT的上游介质如ZEB 1/2、TGF-11、microRNA等参与调节癌细胞对PTX和DTX的反应。肿瘤抑制因子抑制EMT，从而促进癌细胞对PTX和DTX的敏感性。此外，已经开发了三种不同的策略，包括使用抗肿瘤化合物、基因治疗和递送系统来抑制EMT，并增强PTX和DTX对癌细胞的细胞毒性，这些策略在目前的综述中进行了机理上的讨论。
Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis and migration of cancer cells to neighboring cells and tissues. Morphologically, epithelial cells are transformed to mesenchymal cells, and at molecular level, E-cadherin undergoes down-regulation, while an increase occurs in N-cadherin and vimentin levels. Increasing evidence demonstrates role of EMT in mediating drug resistance of cancer cells. On the other hand, paclitaxel (PTX) and docetaxel (DTX) are two chemotherapeutic agents belonging to taxene family, capable of inducing cell cycle arrest in cancer cells via preventing microtubule depolymerization. Aggressive behavior of cancer cells resulted from EMT-mediated metastasis can lead to PTX and DTX resistance. Upstream mediators of EMT such as ZEB1/2, TGF-ll, microRNAs, and so on are involved in regulating response of cancer cells to PTX and DTX. Tumor-suppressing factors inhibit EMT to promote PTX and DTX sensitivity of cancer cells. Furthermore, three different strategies including using anti-tumor compounds, gene therapy and delivery systems have been developed for suppressing EMT, and enhancing cytotoxicity of PTX and DTX against cancer cells that are mechanistically discussed in the current review.