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

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.

Molecular Mechanisms of Cachexia: A Review

“…As such, the potential therapeutic application of IGF-1 in the treatment of cancer cachexia should also be considered. It is important to note, however, that there are certain side effects associated with IGF-1 administration [7,37], including toxicity resulting from elevated blood glucose levels due to the action of IGF-1, as well as the promotion of tumor growth induced by hormone involvement, which may restrict the effectiveness of IGF-1 in preventing cachexia [147,148].…”

“…Cachexia is a paraneoplastic syndrome that can occur during any stage of cancer and is generally associated with a poor prognosis. Specifically, cancer cachexia has been associated with a higher risk of surgical complications, chemotherapy toxicity, functional limitations, respiratory challenges, and fatigue-all of which can have detrimental effects on patient quality of life and overall survival [1,7]. Cachexia has been described as an "auto-cannibalism condition", which occurs when tumors utilize the host's resources to support their own growth.…”

Investigating the crosstalk between chronic stress and immune cells: implications for enhanced cancer therapy

“…Propranolol has also exhibited efficacy in alleviating immune suppression facilitated by IFN-γ-induced PD-L1 expression in ovarian cancer ( Falcinelli et al, 2023 ). Additional β1-AR blockers such as Nebivolol, Bisoprolol, and Landiolol have similarly exhibited potential in bolstering antitumor immune responses across various cancer categories, thereby potentially enhancing patient prognoses ( Niu et al, 2021 ; Farhoumand et al, 2023 ; Jin et al, 2023 ; Li F. et al, 2023 ; Shahid et al, 2023 ; Springer et al, 2023 ; Yuan et al, 2023 ).…”

“…Decreasing the expression of ELK1, C-FOS, NF-κB (Kawahara et al, 2016;Nagata et al, 2020) α1a-AR Silodosin Glioma, OSCC Upregulation of Autophagy (Liu B. et al, 2021;Xing et al, 2023) α1a-AR Doxazosin PCa, AML, Inhibiting the PI3K/Akt/mTOR pathway Sun et al, 2020;Liu D. et al, 2021) α1a-AR Prazosin PCa, BCa, carcinoma, OC, CCRCC Regulation of Bcl-2 (Shimizu et al, 2020;Florent et al, 2020a,b;Zhong et al, 2021) α1a-AR Naproxen Melanoma, NSCLC, BC Boosting Caspase-3/7; ActivityFBXL2-Grp94-EGFR (Niu et al, 2021;Farhoumand et al, 2023; β1-AR Nebivolol Hepatoma, PCa, NSCLC Inhibition of (FBXL10, TRAF6) (Springer et al, 2023;Yuan et al, 2023) β1-AR Bisoprolol NSCLC Inhibiting β1-AR (Jin et al, 2023) β1-AR Landiolol NSCLC Blocking ELK-1, AhR, NF-κB Activities (Shahid et al, 2023) β1-AR Carvedilol Melanoma, CRC, BC, OC, PCa Inhibiting AKT/MAPK; β-ARs and COX-2 Inhibition; CD8 T-cell Priming Suppression; IFN-γ and PD-L1 Reduction; Decrease EMT (Sorski et al, 2016;Shaashua et al, 2017;Haldar et al, 2018Haldar et al, , 2020Daher et al, 2019;Ricon et al, 2019;Hiller et al, 2020;Liao et al, 2020;Liang et al, 2021;Li et al, 2022;Falcinelli et al, 2023) β-ARs Propranolol GC, LUAD, melanoma, hepatoma Suppression of the ERK1/2-JNK-MAPK pathway; β2-ARs/CCL2 axis (Zhang et al, 2019;Zhang B. et al, 2020;Liu C. et al, 2021;Ji et al, 2022) β2-AR ICI118551 BC, NB, melanoma IFN-γ, PD-1/PD-L1; SK2/S1P2 Hemato-differentiation enhancement Calvani et al, 2020;Bruno et al, 2023) β3-AR SR59230A Additionally, α 1-AR blockers have the potential to mitigate adverse effects and enhance the efficacy of CAR-T cell therapy…”