Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
Eur J Pharmacol. 2021 Oct 5;908:174344. doi: 10.1016/j.ejphar.2021.174344. Epub 2021 Jul 13.
Considering the fact that cancer cells can switch among various molecular pathways and mechanisms to ensure their progression, chemotherapy is no longer effective enough in cancer therapy. As an anti-tumor agent, doxorubicin (DOX) is derived from Streptomyces peucetius and can induce cytotoxicity by binding to topoisomerase enzymes to suppress DNA replication, leading to apoptosis and cell cycle arrest. However, efficacy of DOX in suppressing cancer progression is restricted by development of drug resistance. Cancer cells elevate their metastasis in triggering DOX resistance. The epithelial-to-mesenchymal transition (EMT) mechanism participates in transforming epithelial cells into mesenchymal cells that have fibroblast-like features. The EMT diminishes intercellular adhesion and enhances migration of cells that are necessary for carcinogenesis. Various oncogenic molecular pathways stimulate EMT in cancer. EMT can induce DOX resistance, and in this way, upstream mediators such as ZEB proteins, microRNAs, Twist1 and TGF-β play a significant role. Identification of molecular pathways involved in EMT regulation and DOX resistance has resulted in using gene therapy such as microRNA transfection and siRNA in overcoming chemoresistance. Furthermore, curcumin and formononetin, owing to their cytotoxicity against cancer cells, can suppress EMT in mediating DOX sensitivity. For promoting efficacy in DOX sensitivity, nanoparticles have been developed for boosting ability in EMT inhibition.
考虑到癌细胞可以切换各种分子途径和机制来确保其进展，化疗在癌症治疗中不再足够有效。多柔比星（DOX）作为一种抗肿瘤药物，来源于链霉菌属，通过与拓扑异构酶结合抑制 DNA 复制，从而诱导细胞毒性，导致细胞凋亡和细胞周期停滞。然而，DOX 抑制癌症进展的功效受到耐药性发展的限制。癌细胞通过触发 DOX 耐药性来提高其转移能力。上皮-间质转化（EMT）机制参与将上皮细胞转化为具有成纤维细胞样特征的间充质细胞。EMT 降低了细胞间的黏附性，并增强了细胞的迁移能力，这对于癌变是必需的。各种致癌分子途径刺激癌细胞中的 EMT。EMT 可以诱导 DOX 耐药性，因此，ZEB 蛋白、microRNA、Twist1 和 TGF-β 等上游介质在其中发挥重要作用。鉴定 EMT 调控和 DOX 耐药性涉及的分子途径，导致使用基因治疗（如 microRNA 转染和 siRNA）来克服化疗耐药性。此外，姜黄素和芒柄花素由于对癌细胞的细胞毒性，可以抑制 EMT 来介导 DOX 敏感性。为了提高 DOX 敏感性的疗效，已经开发了纳米颗粒来增强 EMT 抑制能力。
