Artikel ; Online: The atypical β-blocker S-oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model.
Journal of cachexia, sarcopenia and muscle
2022 Band 14, Heft 1, Seite(n) 653–660
Abstract: 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 ... ...
| Abstract | 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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| Mesh-Begriff(e) | Mice ; Rats ; Humans ; Animals ; Cachexia/drug therapy ; Cachexia/etiology ; Cachexia/metabolism ; Oxprenolol/therapeutic use ; Rats, Wistar ; Quality of Life ; Rats, Inbred Lew ; Adrenergic beta-Antagonists/therapeutic use ; Liver Neoplasms ; Pindolol |
| Chemische Substanzen | Oxprenolol (519MXN9YZR) ; ACM-001 COVID-19 vaccine ; Adrenergic beta-Antagonists ; Pindolol (BJ4HF6IU1D) |
| Sprache | Englisch |
| Erscheinungsdatum | 2022-11-08 |
| Erscheinungsland | Germany |
| Dokumenttyp | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2586864-0 |
| ISSN | 2190-6009 ; 2190-5991 |
| ISSN (online) | 2190-6009 |
| ISSN | 2190-5991 |
| DOI | 10.1002/jcsm.13116 |
| Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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