Shi Hezhan, Hou Bo, Li Huifeng, Zhou Hui, Du Bin
Department of Pathology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Pathology, School of Medicine, Jinan University, Guangzhou, China.
Front Pharmacol. 2022 Feb 21;13:839464. doi: 10.3389/fphar.2022.839464. eCollection 2022.
Ferroptosis has been implicated in the therapeutic responses of various types of tumors. Cyclophosphamide (CTX), one of the most successful antitumor agents, is widely used to treat both hematopoietic and solid tumors. In this study, we revealed the ferroptosis pathway targeted by CTX treatment in tumor cells and clarified its mechanisms. Cell viability was remarkably suppressed by CTX, accompanied by the accumulation of intracellular iron and reactive oxygen species (ROS), reduced glutathione levels, deformed mitochondria and a loss of the mitochondrial membrane potential. These effects were impeded by the ferroptosis inhibitors ferrostatin-1 (Fer1) and deferoxamine (DFO). Moreover, CTX treatment obviously upregulated nuclear factor E2 related factor 2 (NRF2) and heme oxygenase-1 (HMOX-1) expression. Additionally, the HMOX-1 inducer Hemin notably enhanced CTX-mediated tumor inhibition and through a mechanism that involved interfering with the ferroptosis process. Therefore, our findings indicated ferroptosis induction by CTX through the activation of the NRF2/HMOX-1 pathway, which might provide a potential strategy for tumor chemotherapy.
铁死亡与各类肿瘤的治疗反应有关。环磷酰胺（CTX）是最成功的抗肿瘤药物之一，广泛用于治疗造血系统肿瘤和实体瘤。在本研究中，我们揭示了CTX处理在肿瘤细胞中靶向的铁死亡途径，并阐明了其机制。CTX显著抑制细胞活力，同时伴有细胞内铁和活性氧（ROS）的积累、谷胱甘肽水平降低、线粒体形态改变以及线粒体膜电位丧失。铁死亡抑制剂铁抑素-1（Fer1）和去铁胺（DFO）可阻碍这些效应。此外，CTX处理明显上调核因子E2相关因子2（NRF2）和血红素加氧酶-1（HMOX-1）的表达。此外，HMOX-1诱导剂血红素通过干扰铁死亡过程的机制显著增强了CTX介导的肿瘤抑制作用。因此，我们的研究结果表明CTX通过激活NRF2/HMOX-1途径诱导铁死亡，这可能为肿瘤化疗提供一种潜在策略。
