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

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...

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Autores principales: Koike, Naoyoshi, Kota, Ryuichi, Naito, Yoshiko, Hayakawa, Noriyo, Matsuura, Tomomi, Hishiki, Takako, Onishi, Nobuyuki, Fukada, Junichi, Suematsu, Makoto, Shigematsu, Naoyuki, Saya, Hideyuki, Sampetrean, Oltea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431527/
https://www.ncbi.nlm.nih.gov/pubmed/32807853
http://dx.doi.org/10.1038/s42003-020-01165-z
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author Koike, Naoyoshi
Kota, Ryuichi
Naito, Yoshiko
Hayakawa, Noriyo
Matsuura, Tomomi
Hishiki, Takako
Onishi, Nobuyuki
Fukada, Junichi
Suematsu, Makoto
Shigematsu, Naoyuki
Saya, Hideyuki
Sampetrean, Oltea
author_facet Koike, Naoyoshi
Kota, Ryuichi
Naito, Yoshiko
Hayakawa, Noriyo
Matsuura, Tomomi
Hishiki, Takako
Onishi, Nobuyuki
Fukada, Junichi
Suematsu, Makoto
Shigematsu, Naoyuki
Saya, Hideyuki
Sampetrean, Oltea
author_sort Koike, Naoyoshi
collection PubMed
description 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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spelling pubmed-74315272020-08-27 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche Koike, Naoyoshi Kota, Ryuichi Naito, Yoshiko Hayakawa, Noriyo Matsuura, Tomomi Hishiki, Takako Onishi, Nobuyuki Fukada, Junichi Suematsu, Makoto Shigematsu, Naoyuki Saya, Hideyuki Sampetrean, Oltea Commun Biol Article 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. Nature Publishing Group UK 2020-08-17 /pmc/articles/PMC7431527/ /pubmed/32807853 http://dx.doi.org/10.1038/s42003-020-01165-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Koike, Naoyoshi
Kota, Ryuichi
Naito, Yoshiko
Hayakawa, Noriyo
Matsuura, Tomomi
Hishiki, Takako
Onishi, Nobuyuki
Fukada, Junichi
Suematsu, Makoto
Shigematsu, Naoyuki
Saya, Hideyuki
Sampetrean, Oltea
2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
title 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
title_full 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
title_fullStr 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
title_full_unstemmed 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
title_short 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
title_sort 2-nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431527/
https://www.ncbi.nlm.nih.gov/pubmed/32807853
http://dx.doi.org/10.1038/s42003-020-01165-z
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