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Dehydroascorbic acid sensitizes cancer cells to system x(c)(-) inhibition-induced ferroptosis by promoting lipid droplet peroxidation

Since the discovery of ferroptosis, it has been postulated that this type of cell death could be utilized in treatments for cancer. Unfortunately, several highly aggressive tumor models are resistant to the pharmacological induction of ferroptosis. However, with the use of combined therapies, it is...

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Autores principales: Ferrada, Luciano, Barahona, María José, Vera, Matías, Stockwell, Brent R., Nualart, Francisco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522586/
https://www.ncbi.nlm.nih.gov/pubmed/37752118
http://dx.doi.org/10.1038/s41419-023-06153-9
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author Ferrada, Luciano
Barahona, María José
Vera, Matías
Stockwell, Brent R.
Nualart, Francisco
author_facet Ferrada, Luciano
Barahona, María José
Vera, Matías
Stockwell, Brent R.
Nualart, Francisco
author_sort Ferrada, Luciano
collection PubMed
description Since the discovery of ferroptosis, it has been postulated that this type of cell death could be utilized in treatments for cancer. Unfortunately, several highly aggressive tumor models are resistant to the pharmacological induction of ferroptosis. However, with the use of combined therapies, it is possible to recover sensitivity to ferroptosis in certain cellular models. Here, we discovered that co-treatment with the metabolically stable ferroptosis inducer imidazole ketone erastin (IKE) and the oxidized form of vitamin C, dehydroascorbic acid (DHAA), is a powerful therapy that induces ferroptosis in tumor cells previously resistant to IKE-induced ferroptosis. We determined that DHAA and IKE + DHAA delocalize and deplete GPX4 in tumor cells, specifically inducing lipid droplet peroxidation, which leads to ferroptosis. Moreover, in vivo, IKE + DHAA has high efficacy with regard to the eradication of highly aggressive tumors such as glioblastomas. Thus, the use of IKE + DHAA could be an effective and safe therapy for the eradication of difficult-to-treat cancers.
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spelling pubmed-105225862023-09-28 Dehydroascorbic acid sensitizes cancer cells to system x(c)(-) inhibition-induced ferroptosis by promoting lipid droplet peroxidation Ferrada, Luciano Barahona, María José Vera, Matías Stockwell, Brent R. Nualart, Francisco Cell Death Dis Article Since the discovery of ferroptosis, it has been postulated that this type of cell death could be utilized in treatments for cancer. Unfortunately, several highly aggressive tumor models are resistant to the pharmacological induction of ferroptosis. However, with the use of combined therapies, it is possible to recover sensitivity to ferroptosis in certain cellular models. Here, we discovered that co-treatment with the metabolically stable ferroptosis inducer imidazole ketone erastin (IKE) and the oxidized form of vitamin C, dehydroascorbic acid (DHAA), is a powerful therapy that induces ferroptosis in tumor cells previously resistant to IKE-induced ferroptosis. We determined that DHAA and IKE + DHAA delocalize and deplete GPX4 in tumor cells, specifically inducing lipid droplet peroxidation, which leads to ferroptosis. Moreover, in vivo, IKE + DHAA has high efficacy with regard to the eradication of highly aggressive tumors such as glioblastomas. Thus, the use of IKE + DHAA could be an effective and safe therapy for the eradication of difficult-to-treat cancers. Nature Publishing Group UK 2023-09-27 /pmc/articles/PMC10522586/ /pubmed/37752118 http://dx.doi.org/10.1038/s41419-023-06153-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ferrada, Luciano
Barahona, María José
Vera, Matías
Stockwell, Brent R.
Nualart, Francisco
Dehydroascorbic acid sensitizes cancer cells to system x(c)(-) inhibition-induced ferroptosis by promoting lipid droplet peroxidation
title Dehydroascorbic acid sensitizes cancer cells to system x(c)(-) inhibition-induced ferroptosis by promoting lipid droplet peroxidation
title_full Dehydroascorbic acid sensitizes cancer cells to system x(c)(-) inhibition-induced ferroptosis by promoting lipid droplet peroxidation
title_fullStr Dehydroascorbic acid sensitizes cancer cells to system x(c)(-) inhibition-induced ferroptosis by promoting lipid droplet peroxidation
title_full_unstemmed Dehydroascorbic acid sensitizes cancer cells to system x(c)(-) inhibition-induced ferroptosis by promoting lipid droplet peroxidation
title_short Dehydroascorbic acid sensitizes cancer cells to system x(c)(-) inhibition-induced ferroptosis by promoting lipid droplet peroxidation
title_sort dehydroascorbic acid sensitizes cancer cells to system x(c)(-) inhibition-induced ferroptosis by promoting lipid droplet peroxidation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522586/
https://www.ncbi.nlm.nih.gov/pubmed/37752118
http://dx.doi.org/10.1038/s41419-023-06153-9
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