Role of Nitric Oxide Synthases in Doxorubicin-Induced Cardiomyopathy

Since the discovery of Doxorubicin (Dox), its safe use is under intense discussion due to its cardiotoxic side effects manifested in patients at different times during the treatment or even after years of treatment. Several therapeutic approaches to replace conventional Dox or use of other drugs in combination have exhausted the clinicians and researchers without much success. When the replacement strategies failed to show any rigor, a better understanding of Doxorubicin’s mechanism of action seemed like the only gateway to the discovery of a new targeted therapeutic approach. An increase in reactive oxygen species and the resultant oxidative stress as the mechanism of Dox-induced cardiomyopathy, proposed by us as well as others has gained some traction. However, this explanation has not been enough to alleviate concerns with Dox and we are still in search for a solution for its safe use. More recently, our laboratory and others have also shown the importance of nitrosative stress. Furthermore, we have shown that Vitamin C not only mitigates nitrosative stress but it also modulates Dox-induced cardiotoxic changes in isolated cardiomyocytes as well as in whole animals exposed to Dox. The present review chapter focusses on the mechanism of Dox-induced nitrosative stress and the role of Vitamin C in mitigating the cardiotoxic effects of Dox.