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Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoat...

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Autores principales: Castoldi, Francesca, Vacchelli, Erika, Zitvogel, Laurence, Maiuri, Maria Chiara, Pietrocola, Federico, Kroemer, Guido
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287785/
https://www.ncbi.nlm.nih.gov/pubmed/30546941
http://dx.doi.org/10.1080/2162402X.2018.1498285
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author Castoldi, Francesca
Vacchelli, Erika
Zitvogel, Laurence
Maiuri, Maria Chiara
Pietrocola, Federico
Kroemer, Guido
author_facet Castoldi, Francesca
Vacchelli, Erika
Zitvogel, Laurence
Maiuri, Maria Chiara
Pietrocola, Federico
Kroemer, Guido
author_sort Castoldi, Francesca
collection PubMed
description The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient (Becn1(±) or Atg4b(−/-)) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, Becn1(+/-) and Atg4b(−/-) mice, we observed an increase in the toxicity of MTX on Atg4b(−/-) mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy.
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spelling pubmed-62877852018-12-13 Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy Castoldi, Francesca Vacchelli, Erika Zitvogel, Laurence Maiuri, Maria Chiara Pietrocola, Federico Kroemer, Guido Oncoimmunology Original Research The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient (Becn1(±) or Atg4b(−/-)) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, Becn1(+/-) and Atg4b(−/-) mice, we observed an increase in the toxicity of MTX on Atg4b(−/-) mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy. Taylor & Francis 2018-10-01 /pmc/articles/PMC6287785/ /pubmed/30546941 http://dx.doi.org/10.1080/2162402X.2018.1498285 Text en © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Original Research
Castoldi, Francesca
Vacchelli, Erika
Zitvogel, Laurence
Maiuri, Maria Chiara
Pietrocola, Federico
Kroemer, Guido
Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy
title Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy
title_full Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy
title_fullStr Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy
title_full_unstemmed Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy
title_short Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy
title_sort systemic autophagy in the therapeutic response to anthracycline-based chemotherapy
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287785/
https://www.ncbi.nlm.nih.gov/pubmed/30546941
http://dx.doi.org/10.1080/2162402X.2018.1498285
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