TY - JOUR
T1 - 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
AU - Koike, Naoyoshi
AU - Kota, Ryuichi
AU - Naito, Yoshiko
AU - Hayakawa, Noriyo
AU - Matsuura, Tomomi
AU - Hishiki, Takako
AU - Onishi, Nobuyuki
AU - Fukada, Junichi
AU - Suematsu, Makoto
AU - Shigematsu, Naoyuki
AU - Saya, Hideyuki
AU - Sampetrean, Oltea
N1 - Funding Information:
H.S. has received commercial research grants from POLA Pharma Inc. and Nihon Noyaku Co. Ltd. O.S. has received research support from Nihon Noyaku Co. Ltd. The findings of this study are the subject of a Japanese patent application as follows: Applicants: Keio University and POLA Pharma Inc. Inventors: H.S., O.S., N.K., and N. Kubota. Application no.: PCT/JP2018/036792. Status: international publication. Specific aspects of the study covered in the application: radiosensitizing effect of dor-anidazole on GSCs as well as its effects on mitochondrial complexes and ROS. Dor-anidazole used in this study was provided by POLA Pharma Inc. All other authors declare no competing interests.
Funding Information:
We thank I. Ishimatsu for preparing the histopathology samples, M. Sato and M. Kobori for help in preparation of the paper, and Collaborative Research Resources of Keio University School of Medicine for technical assistance. Funding: This work was supported by KAKENHI Grants-in Aid for Scientific Research (C) to O.S. (nos. 16K07124 and 19K07671) and a Grant-in Aid for Early Career Scientists to N.K. (no. 18K15602) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-020-01165-z
DO - 10.1038/s42003-020-01165-z
M3 - Article
C2 - 32807853
AN - SCOPUS:85089502715
SN - 2399-3642
VL - 3
JO - Communications biology
JF - Communications biology
IS - 1
M1 - 450
ER -
