The small molecule ACM-001 improves cardiac function in a rat model of severe cancer cachexia.

Abstract

Cachexia, a common manifestation of malignant cancer, is not only associated with weight loss, but also with severe cardiac atrophy and impaired cardiac function. Here, we investigated the effects of ACM-001 (0.3 or 3mg/kg/d) in comparison to carvedilol (3 or 30mg/kg/d), metropolol (50 or 100mg/kg/d), nebivolol (1 or 10mg/kg/d) and tertatolol (0.5 or 5 mg/kg/d) on cardiac mass and function in a rat cancer cachexia model. Young male Wistar Han rats were inoculated with 108 Yoshida hepatoma AH-130 cells ip and treated once daily with verum or placebo by gavage. Cardiac function (echocardiography), body weight and body composition (NMR-Scans) were assessed. The hearts of animals were euthanized on day 11 (placebo and 3 mg/kg/d ACM-001) were used for signaling studies. Beta-blockers had no effect on tumour burden. ACM-001 reduced body weight loss (placebo: -34±2.4g vs 3mg/kg/d ACM-001: -14.8±8.4g, p=0.033). Lean mass wasting was attenuated (placebo: -16.5±2.34g vs 3mg/kg/d ACM-001: -2.4±6.7g, p=0.037), while fat loss was similar (p=0.4) on day 11. Placebo animals lost LVmass (-101±14mg), which was prevented only by 3mg/kg/d ACM-001 (7±25mg, 0<0.01 vs placebo). ACM-001 improved the EF (ΔEF: placebo: -24.3±2.6, 3mg/kg/d ACM-001: 0.1±2.9, p<0.001). Cardiac output was 50% lower in the placebo group (-41±4mL/min) compared to baseline, while 3mg/kg/d ACM-001 preserved cardiac output (-5±8, p<0.01). The molecular mechanisms involve inhibition of protein degradation and activation of protein synthesis pathways. This study shows that 3mg/kg/d ACM-001 restores the anabolic/catabolic balance in cardiac muscle leading to improved function. Moreover, not all beta-blockers have similar effects. This article is protected by copyright. All rights reserved.