2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
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DOI：
10.1038/s42003-020-01165-z
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发表时间：
2020-08-17
影响因子：
5.9
通讯作者：
Sampetrean, Oltea
中科院分区：
文献类型：
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作者：
Koike, Naoyoshi;Kota, Ryuichi;Sampetrean, Oltea
在低氧条件下，硝基咪唑类化合物可取代氧作为电子受体，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。然而，这些效应是否适用于癌症干细胞尚未得到充分研究。在这里，我们表明，2-硝基咪唑doranidazole加强辐射诱导的DNA损伤在缺氧胶质瘤干细胞（GSC），并赋予一个显着的生存优势，在小鼠窝藏GSC衍生的肿瘤在放疗设置。此外，多拉硝唑和米索硝唑（而不是甲硝唑）对缺氧GSC表现出辐射非依赖性细胞毒性，这是由部分通过阻断线粒体复合物I和II诱导的铁细胞凋亡以及由此产生的氧化应激反应代谢改变介导的。Doranidazole还限制了GSC衍生的皮下肿瘤和原位脑切片中肿瘤的生长。因此，我们的研究结果揭示了2-硝基咪唑作为铁凋亡诱导剂的治疗诊断潜力，其能够在其缺氧生态位中靶向GSC。Koike等人表明，2-硝基咪唑doranidazole增加了缺氧神经胶质瘤干细胞（GSC）中辐射诱导的DNA损伤。他们进一步证明，2-硝基咪唑的额外辐射非依赖性细胞毒性是由于通过阻断线粒体复合物I和II导致氧化应激反应中的代谢变化而发生的铁凋亡。
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. Koike et al. show that the 2-nitroimidazole doranidazole increases radiation-induced DNA damage in hypoxic glioma stem cells (GSCs). They further demonstrate that additional radiation-independent cytotoxicity of 2-nitroimidazoles is due to ferroptosis that occurs through blockade of mitochondrial complexes I and II leading to metabolic changes in the oxidative stress response.