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Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor
No approved therapy exists for cancer‐associated cachexia. The colon‐26 mouse model of cancer cachexia mimics recent late‐stage clinical failures of anabolic anti‐cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM)...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005646/ https://www.ncbi.nlm.nih.gov/pubmed/31930715 http://dx.doi.org/10.15252/emmm.201809910 |
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author | Liva, Sophia G Tseng, Yu‐Chou Dauki, Anees M Sovic, Michael G Vu, Trang Henderson, Sally E Kuo, Yi‐Chiu Benedict, Jason A Zhang, Xiaoli Remaily, Bryan C Kulp, Samuel K Campbell, Moray Bekaii‐Saab, Tanios Phelps, Mitchell A Chen, Ching‐Shih Coss, Christopher C |
author_facet | Liva, Sophia G Tseng, Yu‐Chou Dauki, Anees M Sovic, Michael G Vu, Trang Henderson, Sally E Kuo, Yi‐Chiu Benedict, Jason A Zhang, Xiaoli Remaily, Bryan C Kulp, Samuel K Campbell, Moray Bekaii‐Saab, Tanios Phelps, Mitchell A Chen, Ching‐Shih Coss, Christopher C |
author_sort | Liva, Sophia G |
collection | PubMed |
description | No approved therapy exists for cancer‐associated cachexia. The colon‐26 mouse model of cancer cachexia mimics recent late‐stage clinical failures of anabolic anti‐cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx‐024. The histone deacetylase inhibitor (HDACi) AR‐42 exhibited anti‐cachectic activity in this model. We explored combined SARM/AR‐42 therapy as an improved anti‐cachectic treatment paradigm. A reduced dose of AR‐42 provided limited anti‐cachectic benefits, but, in combination with GTx‐024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR‐42 suppressed the IL‐6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx‐024‐mediated β‐catenin target gene regulation was apparent in cachectic mice only when combined with AR‐42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx‐024 therapy and a blockade of GTx‐024‐mediated anabolic signaling. AR‐42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx‐024. Combining GTx‐024, a clinically established anabolic therapy, with AR‐42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients. |
format | Online Article Text |
id | pubmed-7005646 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70056462020-02-13 Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor Liva, Sophia G Tseng, Yu‐Chou Dauki, Anees M Sovic, Michael G Vu, Trang Henderson, Sally E Kuo, Yi‐Chiu Benedict, Jason A Zhang, Xiaoli Remaily, Bryan C Kulp, Samuel K Campbell, Moray Bekaii‐Saab, Tanios Phelps, Mitchell A Chen, Ching‐Shih Coss, Christopher C EMBO Mol Med Articles No approved therapy exists for cancer‐associated cachexia. The colon‐26 mouse model of cancer cachexia mimics recent late‐stage clinical failures of anabolic anti‐cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx‐024. The histone deacetylase inhibitor (HDACi) AR‐42 exhibited anti‐cachectic activity in this model. We explored combined SARM/AR‐42 therapy as an improved anti‐cachectic treatment paradigm. A reduced dose of AR‐42 provided limited anti‐cachectic benefits, but, in combination with GTx‐024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR‐42 suppressed the IL‐6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx‐024‐mediated β‐catenin target gene regulation was apparent in cachectic mice only when combined with AR‐42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx‐024 therapy and a blockade of GTx‐024‐mediated anabolic signaling. AR‐42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx‐024. Combining GTx‐024, a clinically established anabolic therapy, with AR‐42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients. John Wiley and Sons Inc. 2020-01-13 2020-02-07 /pmc/articles/PMC7005646/ /pubmed/31930715 http://dx.doi.org/10.15252/emmm.201809910 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Liva, Sophia G Tseng, Yu‐Chou Dauki, Anees M Sovic, Michael G Vu, Trang Henderson, Sally E Kuo, Yi‐Chiu Benedict, Jason A Zhang, Xiaoli Remaily, Bryan C Kulp, Samuel K Campbell, Moray Bekaii‐Saab, Tanios Phelps, Mitchell A Chen, Ching‐Shih Coss, Christopher C Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor |
title | Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor |
title_full | Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor |
title_fullStr | Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor |
title_full_unstemmed | Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor |
title_short | Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor |
title_sort | overcoming resistance to anabolic sarm therapy in experimental cancer cachexia with an hdac inhibitor |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005646/ https://www.ncbi.nlm.nih.gov/pubmed/31930715 http://dx.doi.org/10.15252/emmm.201809910 |
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