Atovaquone impedes muscle wasting in pancreatic cancer by AMPK modulation.

Cancer-induced cachexia is a multifactorial syndrome characterized by systemic inflammation and progressive skeletal muscle and fat wasting. More than 80% pancreatic cancer patients exhibit a cachectic phenotype, which significantly contributes to the overall mortality of cancer patients.

Till now, there is no FDA-approved therapy for cancer-associated cachexia that has been developed. In the present study, we have demonstrated the anti-cachectic potential of an anti-malarial compound, atovaquone.

We observed that atovaquone inhibits cancer cell-conditioned media-induced myotube atrophy in a dose-dependent manner. Atovaquone treatments lead to reduced cachectic markers expression in conditioned media-treated myotubes.

Further, we observed that atovaquone treatment results in reduced reactive oxygen species levels in conditioned media-treated myotubes. Mechanistically, we observed that atovaquone treatment of myotubes enhances the glycolytic capacity of conditioned-media-treated myotubes by upregulating Glut4 expression.

Furthermore, we established that increased Glut4 expression is primarily driven by atovaquone-induced AMPK activation. By utilizing a syngeneic orthotopic implantation model of pancreatic cancer, we have observed that atovaquone can inhibit cachectic phenotype in tumor-bearing mice, without impacting the overall tumour growth.

Overall, we have demonstrated that atovaquone exhibits anti-cachectic properties in both in vitro and in vivo model systems of pancreatic cancer-associated cachexia by modulating glycolytic capacity.