Research Center of Artemisinin, China Academy of Chinese Medical Sciences, Beijing 100700, China; Tang Center for Herbal Medicine Research, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China.
Biomed Pharmacother. 2022 Apr;148:112742. doi: 10.1016/j.biopha.2022.112742. Epub 2022 Feb 26.
The activation of artemisinin and its derivatives (ARTs) to generate ROS and other free radicals is mainly heme- or ferrous iron-dependent. ARTs induce ferroptosis in tumor cells, although the involvement of ferroptosis in malaria remains unclear. We found that three typical inducers of ferroptosis (erastin, RSL3 and sorafenib) could effectively mimic DHA inhibition on the growth of blood-stage parasites, which exhibited synergistic or nearly additive interactions in vitro with DHA, while the combination of DHA with ferroptosis inhibitors (deferoxamine, liproxstatin-1) had an obvious antagonistic effect. DHA, similar to ferroptosis inducers, can simultaneously induce the accumulation of ferroptosis-associated cellular labile iron and lipid peroxide. However, deferoxamine and liproxstatin-1 reduced the increase in ferrous iron and lipid peroxide caused by DHA. These results suggested that ferroptosis might be an effective way to induce cell death in parasites and could be a primary mechanism by which DHA kills parasites, with almost 50% contribution at low concentrations. These results provide a new strategy for antimalarial drug screening and clinical medication guidance.
青蒿素及其衍生物（ARTs）的激活产生 ROS 和其他自由基主要依赖于血红素或亚铁离子。ARTs 在肿瘤细胞中诱导铁死亡，尽管铁死亡在疟疾中的作用仍不清楚。我们发现三种典型的铁死亡诱导剂（erastin、RSL3 和 sorafenib）可以有效地模拟 DHA 对血期寄生虫生长的抑制作用，它们在体外与 DHA 具有协同或近乎相加的相互作用，而 DHA 与铁死亡抑制剂（去铁胺、liproxstatin-1）的组合则表现出明显的拮抗作用。DHA 与铁死亡诱导剂相似，可同时诱导铁死亡相关细胞不稳定铁和脂质过氧化物的积累。然而，去铁胺和 liproxstatin-1 降低了 DHA 引起的亚铁离子和脂质过氧化物的增加。这些结果表明，铁死亡可能是诱导寄生虫细胞死亡的有效途径，并且可能是 DHA 杀死寄生虫的主要机制之一，在低浓度时几乎有 50%的贡献。这些结果为抗疟药物筛选和临床用药指导提供了新的策略。
