(P12-031-25) A Protective Effect of Piceatannol on Cancer-Associated Wasting

Objectives: Cancer-associated cachexia (CAC) is a debilitating wasting syndrome characterized by active adipose lipolysis and severe fat loss followed by muscle atrophy in cancer patients, leading to reduced chemotherapy tolerance and decreased survival rates. Among the mechanisms driving this condition, IL-6-mediated STAT3 (Signal Transducer and Activator of Transcription 3) pathway is a key regulator that mediates muscle protein degradation in CAC. Piceatannol (Pic), a natural stilbene commonly found in blueberries and passion fruit, exhibits diverse bioactivities, including antioxidant, anti-inflammatory, and anti-obesity properties. We previously demonstrated that intraperitoneal administration of Pic mitigated CAC largely through suppression of adipose lipolysis. However, the role of orally administrated Pic in cancer-associated wasting and its direct impact on CAC-related muscle atrophy remains unclear.

Methods: In vitro, C2C12 myoblasts were differentiated for 5 days, then treated with piceatannol (Pic) and C26 colon cancer-conditioned medium (CCM) for 24h. In vivo, BALB/c mice received Pic 2 weeks pre- and post-C26 cell injection, ending at >10% body weight loss.

Results: In the present study, the effects of Pic on muscle atrophy in CAC were observed both in vitro and in vivo using C2C12 myotube atrophy cell model and C26 tumor-bearing CAC mice model. We found that Pic alleviated myotubes atrophy of C2C12 cells induced by conditioned medium of C26 colon cancer cells (CCM) by decreasing the expression of Murf-1, Atrogin-1 and phosphorylated STAT3 proteins. In vivo, oral administration of Pic alleviated body weight loss, as well as the reduction of adipose and muscle tissue mass through inhibition of tumor-induced ATGL and CGI-58, and Murf-1, Atrogen-1 and pSTAT3 respectively. This resulted in preserving cross-sectional area of muscle fibers in C26 tumor-bearing mice. Notably, Pic treatment significantly suppressed tumor-induced plasma IL-6 levels and IL-6 mRNA in CCM-treated C2C12 myotubes.

Conclusions: These findings reveal that oral Pic prevents cancer-induced muscle atrophy by modulating tumor-induced IL-6 expression, while also reducing CAC-induced adipose loss. This suggests that Pic could be a promising treatment for CAC. 

Funding Sources: This activity was funded by USDA NIFA National Needs Fellowship (NNF).