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Abiraterone In Vitro Is Superior to Enzalutamide in Response to Ionizing Radiation
Abiraterone acetate and Enzalutamide are novel anti-androgens that are key treatments to improve both progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. In this study, we aimed to determine whether combinations of AR inhibitors with radia...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335570/ https://www.ncbi.nlm.nih.gov/pubmed/34367984 http://dx.doi.org/10.3389/fonc.2021.700543 |
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author | Wright, Timothy C. Dunne, Victoria L. Alshehri, Ali H. D. Redmond, Kelly M. Cole, Aidan J. Prise, Kevin M. |
author_facet | Wright, Timothy C. Dunne, Victoria L. Alshehri, Ali H. D. Redmond, Kelly M. Cole, Aidan J. Prise, Kevin M. |
author_sort | Wright, Timothy C. |
collection | PubMed |
description | Abiraterone acetate and Enzalutamide are novel anti-androgens that are key treatments to improve both progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. In this study, we aimed to determine whether combinations of AR inhibitors with radiation are additive or synergistic, and investigated the underlying mechanisms governing this. This study also aimed to compare and investigate a biological rationale for the selection of Abiraterone versus Enzalutamide in combination with radiotherapy as currently selection is based on consideration of side effect profiles and clinical experience. We report that AR suppression with Enzalutamide produces a synergistic effect only in AR-sensitive prostate models. In contrast, Abiraterone displays synergistic effects in combination with radiation regardless of AR status, alluding to potential alternative mechanisms of action. The underlying mechanisms governing this AR-based synergy are based on the reduction of key AR linked DNA repair pathways such as NHEJ and HR, with changes in HR potentially the result of changes in cell cycle distribution, with these reductions ultimately resulting in increased cell death. These changes were also shown to be conserved in combination with radiation, with AR suppression 24 hours before radiation leading to the most significant differences. Comparison between Abiraterone and Enzalutamide highlighted Abiraterone from a mechanistic standpoint as being superior to Abiraterone for all endpoints measured. Therefore, this provides a potential rationale for the selection of Abiraterone over Enzalutamide. |
format | Online Article Text |
id | pubmed-8335570 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83355702021-08-05 Abiraterone In Vitro Is Superior to Enzalutamide in Response to Ionizing Radiation Wright, Timothy C. Dunne, Victoria L. Alshehri, Ali H. D. Redmond, Kelly M. Cole, Aidan J. Prise, Kevin M. Front Oncol Oncology Abiraterone acetate and Enzalutamide are novel anti-androgens that are key treatments to improve both progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. In this study, we aimed to determine whether combinations of AR inhibitors with radiation are additive or synergistic, and investigated the underlying mechanisms governing this. This study also aimed to compare and investigate a biological rationale for the selection of Abiraterone versus Enzalutamide in combination with radiotherapy as currently selection is based on consideration of side effect profiles and clinical experience. We report that AR suppression with Enzalutamide produces a synergistic effect only in AR-sensitive prostate models. In contrast, Abiraterone displays synergistic effects in combination with radiation regardless of AR status, alluding to potential alternative mechanisms of action. The underlying mechanisms governing this AR-based synergy are based on the reduction of key AR linked DNA repair pathways such as NHEJ and HR, with changes in HR potentially the result of changes in cell cycle distribution, with these reductions ultimately resulting in increased cell death. These changes were also shown to be conserved in combination with radiation, with AR suppression 24 hours before radiation leading to the most significant differences. Comparison between Abiraterone and Enzalutamide highlighted Abiraterone from a mechanistic standpoint as being superior to Abiraterone for all endpoints measured. Therefore, this provides a potential rationale for the selection of Abiraterone over Enzalutamide. Frontiers Media S.A. 2021-07-21 /pmc/articles/PMC8335570/ /pubmed/34367984 http://dx.doi.org/10.3389/fonc.2021.700543 Text en Copyright © 2021 Wright, Dunne, Alshehri, Redmond, Cole and Prise 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 | Oncology Wright, Timothy C. Dunne, Victoria L. Alshehri, Ali H. D. Redmond, Kelly M. Cole, Aidan J. Prise, Kevin M. Abiraterone In Vitro Is Superior to Enzalutamide in Response to Ionizing Radiation |
title | Abiraterone In Vitro Is Superior to Enzalutamide in Response to Ionizing Radiation |
title_full | Abiraterone In Vitro Is Superior to Enzalutamide in Response to Ionizing Radiation |
title_fullStr | Abiraterone In Vitro Is Superior to Enzalutamide in Response to Ionizing Radiation |
title_full_unstemmed | Abiraterone In Vitro Is Superior to Enzalutamide in Response to Ionizing Radiation |
title_short | Abiraterone In Vitro Is Superior to Enzalutamide in Response to Ionizing Radiation |
title_sort | abiraterone in vitro is superior to enzalutamide in response to ionizing radiation |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335570/ https://www.ncbi.nlm.nih.gov/pubmed/34367984 http://dx.doi.org/10.3389/fonc.2021.700543 |
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