Ursolic Acid Alleviates Cancer Cachexia and Prevents Muscle Wasting via Activating SIRT1

SIMPLE SUMMARY: Cancer cachexia is a multifactorial condition characterized by body weight loss and skeletal muscle wasting that negatively impacts the quality of life and survival of cancer patients. In this paper, we found that ursolic acid (UA) alleviated cancer cachexia and prevented muscle wasting via activating SIRT1, and thence inhibiting phosphorylation levels of NF-κB and STAT3. Furthermore, UA remained effective in the advanced stages of cancer cachexia. This is significant because no approved drug for the treatment of cancer-related muscle atrophy is available. UA may be a potential drug for cancer cachexia and has the possibility of translational application to clinical treatment. ABSTRACT: Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. However, there are currently no effective drugs against cancer cachexia. Ursolic acid (UA) is a lipophilic pentacyclic triterpene that has been reported to alleviate muscle atrophy and reduce muscle decomposition in some disease models. This study aimed to explore the role and mechanisms of UA treatment in cancer cachexia. We found that UA attenuated Lewis lung carcinoma (LLC)-conditioned medium-induced C2C12 myotube atrophy and muscle wasting of LLC tumor-bearing mice. Moreover, UA dose-dependently activated SIRT1 and downregulated MuRF1 and Atrogin-1. Molecular docking results revealed a good binding effect on UA and SIRT1 protein. UA rescued vital features wasting without impacting tumor growth, suppressed the elevated spleen weight, and downregulated serum concentrations of inflammatory cytokines in vivo. The above phenomena can be attenuated by Ex-527, an inhibitor of SIRT1. Furthermore, UA remained protective against cancer cachexia in the advanced stage of tumor growth. The results revealed that UA exerts an anti-cachexia effect via activating SIRT1, thereby downregulating the phosphorylation levels of NF-κB and STAT3. UA might be a potential drug against cancer cachexia.