Effects of S‐pindolol in mouse pancreatic and lung cancer cachexia models

Abstract

Background It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals. Methods Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC). Results Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (À0.9 ± 1.0 vs. À2.2 ± 1.4 g for S-pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour-bearing controls (À0.4 ± 1.0 vs. À1.5 ± 1.5 g for S-pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01). Conclusions S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.

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…”