BIH Center for Regenerative Therapies, Charité-University Medical Center Berlin, Berlin, Germany.
German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin Berlin, Berlin, Germany.
J Cachexia Sarcopenia Muscle. 2023 Feb;14(1):653-660. doi: 10.1002/jcsm.13116. Epub 2022 Nov 8.
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.
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.
S-oxprenolol is superior to R-oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.
β受体阻滞剂和β受体阻滞剂的某些立体异构体，如比索洛尔和 S-吲哚洛尔（ACM-001），已被证明在癌症恶病质的临床前模型中有效。在这里，我们测试了氧烯洛尔立体异构体在两种临床前癌症恶病质模型中的疗效-吉田 AH-130 大鼠模型和 Lewis 肺癌（LLC）小鼠模型。
在吉田 AH130 肝癌大鼠癌症恶病质模型中，与安慰剂相比，50mg/kg/d S-氧烯洛尔（HR：0.49，95%CI：0.28-0.85，P=0.012）优于 50mg/kg/d R-氧烯洛尔（HR：0.83，95%CI 0.38-1.45，P=0.51）在降低死亡率（=达到伦理终点）方面。在 S-氧烯洛尔组体重减轻有显著影响的三种剂量（12.5、25 和 50mg/kg/d）与 R-氧烯洛尔组相同剂量的组合相比，S-氧烯洛尔的存活明显改善（HR：1.61，95%CI：1.08-2.39，P=0.0185）。有趣的是，在 S-氧烯洛尔治疗组（5、12.5、25 和 50mg/kg/d）中观察到明显的剂量依赖性，而在 R-氧烯洛尔治疗组中则没有观察到这种依赖性。在吉田大鼠模型中，S-氧烯洛尔呈剂量依赖性减轻体重和瘦肉量的损失，而 R-氧烯洛尔仅对脂肪量有显著影响。S-氧烯洛尔也非显著减少 LLC 模型中的体重减轻，并改善肌肉功能（握力为 428±25 和 539±37g/100g 体重，分别为安慰剂和 S-氧烯洛尔）。然而，在吉田模型中，对生活质量指标（食物摄入和自发活动）只有较小的影响（25mg/kg/S-氧烯洛尔：11.9±2.5g vs 安慰剂：4.9±0.8g，P=0.013，也与 25mg/kg/d R-氧烯洛尔：7.5±2.6g，P=0.025）。在本研究中使用的剂量下，两种对映体对心脏大小和功能均无影响。涉及合成代谢/分解代谢同平衡的蛋白质的 Western 印迹表明，合成代谢信号被保留（IGF-1 受体，Akt），分解代谢信号被抑制（FXBO-10，TRAF-6）由 S-普萘洛尔，但不是 R-对映体。所有组的葡萄糖转运蛋白 Glut1 和 Glut4 的表达相似，AMPK 也是如此。
S-氧烯洛尔在癌症恶病质动物模型中优于 R-氧烯洛尔，并为癌症恶病质的人类应用提供了希望。
