Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
Department of Radiology, Keio University School of Medicine, Tokyo, Japan.
Commun Biol. 2020 Aug 17;3(1):450. doi: 10.1038/s42003-020-01165-z.
Under hypoxic conditions, nitroimidazoles can replace oxygen as electron acceptors, thereby enhancing the effects of radiation on malignant cells. These compounds also accumulate in hypoxic cells, where they can act as cytotoxins or imaging agents. However, whether these effects apply to cancer stem cells has not been sufficiently explored. Here we show that the 2-nitroimidazole doranidazole potentiates radiation-induced DNA damage in hypoxic glioma stem cells (GSCs) and confers a significant survival benefit in mice harboring GSC-derived tumors in radiotherapy settings. Furthermore, doranidazole and misonidazole, but not metronidazole, manifested radiation-independent cytotoxicity for hypoxic GSCs that was mediated by ferroptosis induced partially through blockade of mitochondrial complexes I and II and resultant metabolic alterations in oxidative stress responses. Doranidazole also limited the growth of GSC-derived subcutaneous tumors and that of tumors in orthotopic brain slices. Our results thus reveal the theranostic potential of 2-nitroimidazoles as ferroptosis inducers that enable targeting GSCs in their hypoxic niche.
在缺氧条件下，硝基咪唑类药物可以替代氧作为电子受体，从而增强辐射对恶性细胞的作用。这些化合物也在缺氧细胞中积累，在那里它们可以作为细胞毒素或成像剂发挥作用。然而，这些作用是否适用于癌症干细胞尚未得到充分探讨。在这里，我们表明 2-硝基咪唑多拉唑增强了缺氧神经胶质瘤干细胞（GSCs）中辐射诱导的 DNA 损伤，并在放射治疗环境中携带 GSC 衍生肿瘤的小鼠中赋予了显著的生存益处。此外，多拉唑和米索硝唑，但不是甲硝唑，对缺氧 GSCs 表现出辐射非依赖性细胞毒性，这是通过阻断线粒体复合物 I 和 II 以及由此导致的氧化应激反应中的代谢改变部分介导的。多拉唑还限制了 GSC 衍生的皮下肿瘤和原位脑切片肿瘤的生长。因此，我们的研究结果揭示了 2-硝基咪唑类药物作为铁死亡诱导剂的治疗潜力，使其能够靶向其缺氧生态位中的 GSCs。
