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Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy

Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-typ...

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Autores principales: Hoare, Joseph I., Osmani, Bleona, O’Sullivan, Emily A., Browne, Ashley, Campbell, Nicola, Metcalf, Stephen, Nicolini, Francesco, Saxena, Jayeta, Martin, Sarah A., Lockley, Michelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8813932/
https://www.ncbi.nlm.nih.gov/pubmed/35115660
http://dx.doi.org/10.1038/s42003-022-03041-4
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author Hoare, Joseph I.
Osmani, Bleona
O’Sullivan, Emily A.
Browne, Ashley
Campbell, Nicola
Metcalf, Stephen
Nicolini, Francesco
Saxena, Jayeta
Martin, Sarah A.
Lockley, Michelle
author_facet Hoare, Joseph I.
Osmani, Bleona
O’Sullivan, Emily A.
Browne, Ashley
Campbell, Nicola
Metcalf, Stephen
Nicolini, Francesco
Saxena, Jayeta
Martin, Sarah A.
Lockley, Michelle
author_sort Hoare, Joseph I.
collection PubMed
description Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947. Synergy is not due to β-adrenergic blockade but is dependent on β-arrestins and is reversed by β-arrestin CRISPR gene editing. Co-treatment with dl922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via β-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment.
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spelling pubmed-88139322022-02-10 Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy Hoare, Joseph I. Osmani, Bleona O’Sullivan, Emily A. Browne, Ashley Campbell, Nicola Metcalf, Stephen Nicolini, Francesco Saxena, Jayeta Martin, Sarah A. Lockley, Michelle Commun Biol Article Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947. Synergy is not due to β-adrenergic blockade but is dependent on β-arrestins and is reversed by β-arrestin CRISPR gene editing. Co-treatment with dl922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via β-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment. Nature Publishing Group UK 2022-02-03 /pmc/articles/PMC8813932/ /pubmed/35115660 http://dx.doi.org/10.1038/s42003-022-03041-4 Text en © The Author(s) 2022 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
Hoare, Joseph I.
Osmani, Bleona
O’Sullivan, Emily A.
Browne, Ashley
Campbell, Nicola
Metcalf, Stephen
Nicolini, Francesco
Saxena, Jayeta
Martin, Sarah A.
Lockley, Michelle
Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy
title Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy
title_full Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy
title_fullStr Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy
title_full_unstemmed Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy
title_short Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy
title_sort carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8813932/
https://www.ncbi.nlm.nih.gov/pubmed/35115660
http://dx.doi.org/10.1038/s42003-022-03041-4
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