Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer center, Xianning Center Hospital, Xianning, China.
Cancer Res Treat. 2018 Apr;50(2):445-460. doi: 10.4143/crt.2016.572. Epub 2017 May 10.
Ferroptosis is a new mode of regulated cell death, which is completely distinct from other cell death modes based on morphological, biochemical, and genetic criteria. This study evaluated the therapeutic role of ferroptosis in classic chemotherapy drugs, including the underlying mechanism.
Cell viabilitywas detected by using the methylthiazoltetrazlium dye uptake method. RNAiwas used to knockout iron-responsive element binding protein 2, and polymerase chain reaction, western blot was used to evaluate the efficiency. Intracellular reduced glutathione level and glutathione peroxidases activitywere determined by related assay kit. Intracellularreactive oxygen species levelswere determined by flowcytometry. Electron microscopywas used to observe ultrastructure changes in cell.
Among five chemotherapeutic drugs screened in this study, cisplatin was found to be an inducer for both ferroptosis and apoptosis in A549 and HCT116 cells. The depletion of reduced glutathione caused by cisplatin and the inactivation of glutathione peroxidase played the vital role in the underlying mechanism. Besides, combination therapy of cisplatin and erastin showed significant synergistic effect on their anti-tumor activity.
Ferroptosis had great potential to become a new approach in anti-tumor therapies and make up for some classic drugs, which open up a new way for their utility in clinic.
铁死亡是一种新的细胞程序性死亡方式，根据形态学、生化和遗传学标准，它与其他细胞死亡方式完全不同。本研究评估了铁死亡在经典化疗药物中的治疗作用，包括潜在的机制。
采用噻唑蓝染料摄取法检测细胞活力。利用 RNAi 敲除铁反应元件结合蛋白 2，通过聚合酶链反应和蛋白质印迹法评估敲除效率。通过相关试剂盒测定细胞内还原型谷胱甘肽水平和谷胱甘肽过氧化物酶活性。通过流式细胞术测定细胞内活性氧水平。利用电子显微镜观察细胞超微结构变化。
在本研究筛选的五种化疗药物中，顺铂被发现可诱导 A549 和 HCT116 细胞发生铁死亡和细胞凋亡。顺铂引起的还原型谷胱甘肽耗竭和谷胱甘肽过氧化物酶失活在其潜在机制中起关键作用。此外，顺铂和 erastin 的联合治疗对其抗肿瘤活性表现出显著的协同作用。
铁死亡很有可能成为抗肿瘤治疗的新方法，并弥补一些经典药物的不足，为其在临床中的应用开辟了新途径。
