MT‐102 prevents tissue wasting and improves survival in a rat model of severe cancer cachexia

Background: Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia. Methods: Young male Wistar Han rats were intraperitoneally inoculated with 108 Yoshida hepatoma AH-130 cells and once daily treated with 0.3 mg kg−1, 3 mg kg−1 MT-102, or placebo by gavage. Results: Three mg kg−1d−1 MT-102 not only prevented progressive loss of fat mass (−6 ± 2 g vs -12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. −37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. −60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg−1d−1 MT-102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg-1d-1 MT-102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16–0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase-6 activity or Western blot analysis, respectively. Conclusions: The present study shows that 3 mg kg−1 MT-102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival