2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche

• Published in: Communications biology Vol. 3; no. 1; p. 450
• Main Authors: Koike, Naoyoshi, Kota, Ryuichi, Naito, Yoshiko, Hayakawa, Noriyo, Matsuura, Tomomi, Hishiki, Takako, Onishi, Nobuyuki, Fukada, Junichi, Suematsu, Makoto, Shigematsu, Naoyuki, Saya, Hideyuki, Sampetrean, Oltea
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.08.2020; Nature Publishing Group
• Subjects: 14/1; 14/19; 38/61; 38/77; 631/67; 631/67/1059; 631/67/1922; 631/67/2327; 631/67/71; 64/60; 82/1; 96/31; Biology; Biomedical and Life Sciences; Brain slice preparation; Brain tumors; Cytotoxicity; Cytotoxins; Deoxyribonucleic acid; DNA; DNA damage; Ferroptosis; Glioma cells; Hypoxia; Life Sciences; Metabolism; Metronidazole; Misonidazole; Mitochondria; Neuroimaging; Nitroimidazole; Oxidative stress; Radiation therapy; Stem cell transplantation; Stem cells; Tumors
• ISSN: 2399-3642; 2399-3642
• 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. 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.