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The atypical β‐blocker S‐oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model

BACKGROUND: Beta‐blockers and selected stereoisomers of beta‐blockers, like bisoprolol and S‐pindolol (ACM‐001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia—the Yoshida...

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Autores principales: Yuan, Luping, Springer, Jochen, Palus, Sandra, Busquets, Silvia, Jové, Queralt, Alves de Lima Junior, Edson, Anker, Markus S., von Haehling, Stephan, Álvarez Ladrón, Natalia, Millman, Oliver, Oosterlee, Annemijn, Szymczyk, Agata, López‐Soriano, Francisco Javier, Anker, Stefan D., Coats, Andrew J.S., Argiles, Josep M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891926/
https://www.ncbi.nlm.nih.gov/pubmed/36346141
http://dx.doi.org/10.1002/jcsm.13116
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author Yuan, Luping
Springer, Jochen
Palus, Sandra
Busquets, Silvia
Jové, Queralt
Alves de Lima Junior, Edson
Anker, Markus S.
von Haehling, Stephan
Álvarez Ladrón, Natalia
Millman, Oliver
Oosterlee, Annemijn
Szymczyk, Agata
López‐Soriano, Francisco Javier
Anker, Stefan D.
Coats, Andrew J.S.
Argiles, Josep M.
author_facet Yuan, Luping
Springer, Jochen
Palus, Sandra
Busquets, Silvia
Jové, Queralt
Alves de Lima Junior, Edson
Anker, Markus S.
von Haehling, Stephan
Álvarez Ladrón, Natalia
Millman, Oliver
Oosterlee, Annemijn
Szymczyk, Agata
López‐Soriano, Francisco Javier
Anker, Stefan D.
Coats, Andrew J.S.
Argiles, Josep M.
author_sort Yuan, Luping
collection PubMed
description BACKGROUND: Beta‐blockers and selected stereoisomers of beta‐blockers, like bisoprolol and S‐pindolol (ACM‐001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia—the Yoshida AH‐130 rat model and the Lewis lung carcinoma (LLC) mouse model. METHODS AND RESULTS: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S‐oxprenolol (HR: 0.49, 95% CI: 0.28–0.85, P = 0.012) was superior to 50 mg/kg/d R‐oxprenolol (HR: 0.83, 95% CI 0.38–1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S‐oxprenolol groups vs the same combination of the R‐oxprenolol groups lead to a significantly improved survival of S‐oxprenolol vs R‐oxprenolol (HR: 1.61, 95% CI: 1.08–2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S‐oxprenolol‐treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R‐oxprenolol. A dose‐dependent attenuation of weight and lean mass loss by S‐oxprenolol was seen in the Yoshida rat model, whereas R‐oxprenolol had only had a significant effect on fat mass. S‐oxprenolol also non‐significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S‐oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S‐oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R‐oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF‐1 receptor, Akt) and catabolic signalling is inhibited (FXBO‐10, TRAF‐6) by S‐pindolol, but not he R‐enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK. CONCLUSIONS: S‐oxprenolol is superior to R‐oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.
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spelling pubmed-98919262023-02-02 The atypical β‐blocker S‐oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model Yuan, Luping Springer, Jochen Palus, Sandra Busquets, Silvia Jové, Queralt Alves de Lima Junior, Edson Anker, Markus S. von Haehling, Stephan Álvarez Ladrón, Natalia Millman, Oliver Oosterlee, Annemijn Szymczyk, Agata López‐Soriano, Francisco Javier Anker, Stefan D. Coats, Andrew J.S. Argiles, Josep M. J Cachexia Sarcopenia Muscle Short Report BACKGROUND: Beta‐blockers and selected stereoisomers of beta‐blockers, like bisoprolol and S‐pindolol (ACM‐001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia—the Yoshida AH‐130 rat model and the Lewis lung carcinoma (LLC) mouse model. METHODS AND RESULTS: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S‐oxprenolol (HR: 0.49, 95% CI: 0.28–0.85, P = 0.012) was superior to 50 mg/kg/d R‐oxprenolol (HR: 0.83, 95% CI 0.38–1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S‐oxprenolol groups vs the same combination of the R‐oxprenolol groups lead to a significantly improved survival of S‐oxprenolol vs R‐oxprenolol (HR: 1.61, 95% CI: 1.08–2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S‐oxprenolol‐treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R‐oxprenolol. A dose‐dependent attenuation of weight and lean mass loss by S‐oxprenolol was seen in the Yoshida rat model, whereas R‐oxprenolol had only had a significant effect on fat mass. S‐oxprenolol also non‐significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S‐oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S‐oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R‐oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF‐1 receptor, Akt) and catabolic signalling is inhibited (FXBO‐10, TRAF‐6) by S‐pindolol, but not he R‐enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK. CONCLUSIONS: S‐oxprenolol is superior to R‐oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia. John Wiley and Sons Inc. 2022-11-08 /pmc/articles/PMC9891926/ /pubmed/36346141 http://dx.doi.org/10.1002/jcsm.13116 Text en © 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Short Report
Yuan, Luping
Springer, Jochen
Palus, Sandra
Busquets, Silvia
Jové, Queralt
Alves de Lima Junior, Edson
Anker, Markus S.
von Haehling, Stephan
Álvarez Ladrón, Natalia
Millman, Oliver
Oosterlee, Annemijn
Szymczyk, Agata
López‐Soriano, Francisco Javier
Anker, Stefan D.
Coats, Andrew J.S.
Argiles, Josep M.
The atypical β‐blocker S‐oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model
title The atypical β‐blocker S‐oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model
title_full The atypical β‐blocker S‐oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model
title_fullStr The atypical β‐blocker S‐oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model
title_full_unstemmed The atypical β‐blocker S‐oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model
title_short The atypical β‐blocker S‐oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model
title_sort atypical β‐blocker s‐oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model
topic Short Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891926/
https://www.ncbi.nlm.nih.gov/pubmed/36346141
http://dx.doi.org/10.1002/jcsm.13116
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