Protection against doxorubicin-induced cardiotoxicity by ergothioneine

Abstract Anthracyclines such as doxorubicin remain the first line of treatment for haematological malignancies, and breast cancers. However, the potential risk of cardiac injury by anthracyclines, which may lead to severe myopathy or heart failure, severely limits their application, and remains a challenge to ensuring curative chemotherapy. While the complex interplay between pathological pathways of anthracycline cardiotoxicity is yet to be fully understood, oxidative damage, iron overload-mediated formation of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation are all believed to be involved. The unique dietary thione, ergothioneine, while not produced in animals and humans, can be avidly absorbed and accumulated in tissues including the heart. Amongst other cytoprotective properties ergothioneine has been shown to scavenge various ROS, decrease proinflammatory mediators, chelate metal cations such as Fe 2+ , preventing them from partaking in redox activities, and may protect against mitochondrial damage and dysfunction. Moreover, low plasma ergothioneine levels are also strongly correlated to risk of cardiovascular events in humans, suggestive of a cardioprotective role. Taken together this highlights the potential for ergothioneine to counteract anthracycline cardiotoxicity. Here we investigate the potential of ergothioneine supplementation to protect against cardiac dysfunction in mice models of doxorubicin-induced cardiotoxicity and found that it had significant protective effects. Moreover, ergothioneine administration in a mouse breast cancer model did not exacerbate the growth of the tumour and did not interfere with the chemotherapeutic efficacy of doxorubicin. These results suggest that ergothioneine could be a viable co-therapy to alleviate the cardiotoxic effects of anthracyclines in the treatment of cancers.