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Cyclophosphamide Induces the Ferroptosis of Tumor Cells Through Heme Oxygenase-1

Ferroptosis has been implicated in the therapeutic responses of various types of tumors. Cyclophosphamide (CTX), one of the most successful antitumor agents, is widely used to treat both hematopoietic and solid tumors. In this study, we revealed the ferroptosis pathway targeted by CTX treatment in t...

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Autores principales: Shi, Hezhan, Hou, Bo, Li, Huifeng, Zhou, Hui, Du, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899725/
https://www.ncbi.nlm.nih.gov/pubmed/35264971
http://dx.doi.org/10.3389/fphar.2022.839464
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author Shi, Hezhan
Hou, Bo
Li, Huifeng
Zhou, Hui
Du, Bin
author_facet Shi, Hezhan
Hou, Bo
Li, Huifeng
Zhou, Hui
Du, Bin
author_sort Shi, Hezhan
collection PubMed
description Ferroptosis has been implicated in the therapeutic responses of various types of tumors. Cyclophosphamide (CTX), one of the most successful antitumor agents, is widely used to treat both hematopoietic and solid tumors. In this study, we revealed the ferroptosis pathway targeted by CTX treatment in tumor cells and clarified its mechanisms. Cell viability was remarkably suppressed by CTX, accompanied by the accumulation of intracellular iron and reactive oxygen species (ROS), reduced glutathione levels, deformed mitochondria and a loss of the mitochondrial membrane potential. These effects were impeded by the ferroptosis inhibitors ferrostatin-1 (Fer1) and deferoxamine (DFO). Moreover, CTX treatment obviously upregulated nuclear factor E2 related factor 2 (NRF2) and heme oxygenase-1 (HMOX-1) expression. Additionally, the HMOX-1 inducer Hemin notably enhanced CTX-mediated tumor inhibition in vitro and in vivo through a mechanism that involved interfering with the ferroptosis process. Therefore, our findings indicated ferroptosis induction by CTX through the activation of the NRF2/HMOX-1 pathway, which might provide a potential strategy for tumor chemotherapy.
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spelling pubmed-88997252022-03-08 Cyclophosphamide Induces the Ferroptosis of Tumor Cells Through Heme Oxygenase-1 Shi, Hezhan Hou, Bo Li, Huifeng Zhou, Hui Du, Bin Front Pharmacol Pharmacology Ferroptosis has been implicated in the therapeutic responses of various types of tumors. Cyclophosphamide (CTX), one of the most successful antitumor agents, is widely used to treat both hematopoietic and solid tumors. In this study, we revealed the ferroptosis pathway targeted by CTX treatment in tumor cells and clarified its mechanisms. Cell viability was remarkably suppressed by CTX, accompanied by the accumulation of intracellular iron and reactive oxygen species (ROS), reduced glutathione levels, deformed mitochondria and a loss of the mitochondrial membrane potential. These effects were impeded by the ferroptosis inhibitors ferrostatin-1 (Fer1) and deferoxamine (DFO). Moreover, CTX treatment obviously upregulated nuclear factor E2 related factor 2 (NRF2) and heme oxygenase-1 (HMOX-1) expression. Additionally, the HMOX-1 inducer Hemin notably enhanced CTX-mediated tumor inhibition in vitro and in vivo through a mechanism that involved interfering with the ferroptosis process. Therefore, our findings indicated ferroptosis induction by CTX through the activation of the NRF2/HMOX-1 pathway, which might provide a potential strategy for tumor chemotherapy. Frontiers Media S.A. 2022-02-21 /pmc/articles/PMC8899725/ /pubmed/35264971 http://dx.doi.org/10.3389/fphar.2022.839464 Text en Copyright © 2022 Shi, Hou, Li, Zhou and Du. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Shi, Hezhan
Hou, Bo
Li, Huifeng
Zhou, Hui
Du, Bin
Cyclophosphamide Induces the Ferroptosis of Tumor Cells Through Heme Oxygenase-1
title Cyclophosphamide Induces the Ferroptosis of Tumor Cells Through Heme Oxygenase-1
title_full Cyclophosphamide Induces the Ferroptosis of Tumor Cells Through Heme Oxygenase-1
title_fullStr Cyclophosphamide Induces the Ferroptosis of Tumor Cells Through Heme Oxygenase-1
title_full_unstemmed Cyclophosphamide Induces the Ferroptosis of Tumor Cells Through Heme Oxygenase-1
title_short Cyclophosphamide Induces the Ferroptosis of Tumor Cells Through Heme Oxygenase-1
title_sort cyclophosphamide induces the ferroptosis of tumor cells through heme oxygenase-1
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899725/
https://www.ncbi.nlm.nih.gov/pubmed/35264971
http://dx.doi.org/10.3389/fphar.2022.839464
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