Therapeutic Potential of Polydatin Against Cancer Cachexia by Regulating the STAT3 Signaling Pathway

Background/Objectives: Cancer cachexia is a wasting syndrome with significant loss of body weight and muscle mass caused by inflammation and abnormal metabolism in advanced cancers. Despite its detrimental effects on patients, no standard treatment has been established for this syndrome. Thus, finding new treatments will broaden the remedy for cancer cachexia, resulting in increased survival in patients with terminal cancer. Methods: In this study, we assessed the therapeutic effects of the natural compound polydatin on cancer cachexia in vitro and in vivo using C2C12 myoblasts and CT26-bearing mice to elucidate the mechanisms of how it ameliorates muscle atrophy. At the same time, molecular docking analysis of polydatin with the IL6/STAT3 signaling pathway was conducted to demonstrate their interaction. Results: Our data showed that polydatin treatment at 100 mg/kg could attenuate symptoms of cancer cachexia including body weight loss, muscle strength and severe inflammation. Muscle mass reduction—with the shrinking of muscle fibers, an increase in the expression levels of two E3 ubiquitin ligases (MuRF1 and Atrogin-1) and interleukin-6, and a downregulation of MyHC—observed in CT26-bearing mice was reversed by polydatin at 100 mg/kg. On C2C12 myotubes, polydatin also ameliorated muscle atrophy induced by the CT26 conditioned medium and suppressed STAT3 phosphorylation at the concentration of 200 µM. Structural features of polydatin in the proteins in the STAT3 pathway were identified through molecular docking simulations. Conclusions: Taken together, polydatin significantly attenuated muscle atrophy in a cancer cachexia model by inhibiting the STAT3 signaling pathway; thus, it might be a promising compound in the development of drug candidates for cancer cachexia therapy.