Effect of Doxorubicin on Cardiac Myocytes: Role of Apoptosis, Autophagy and other Proteolytic Pathways

Abstract

Doxorubicin is a very effective chemotherapeutic agent. However, its use is limited by serious cardiac side effects, including long-term irreversible cardiac failure which is often fatal. These effects are related to the cumulative dose but other factors also play a role. Through a systematic search in an electronic database, manuscripts dealing with this matter were included. Exposure of the heart to doxorubicin s result in three types of stress: 1] genotoxic, 2] energetic and 3] oxidative stress. These effects are closely related with the dependence of the heart on oxidative phosphorylation, its low defenses against reactive oxygen species and with the peculiarities of mitochondria, which are abundantly present in cardiac tissue. In most manuscripts, the cellular effects of doxorubicin are documented by changes in enzymatic pathways within cardiomyocytes. These pathways have mutual influences, which complicate the interpretation of results. These pathways often result in proteolysis, cellular damage and apoptotic cell death. Necrosis and autophagy are also involved as mechanisms. Most of the included manuscripts deal with in-vitro experiments with anti-oxidant agents, using cardiomyoblasts and H9c2 cell lines as well as in-vivo short-term murine models. However, long-term animal models are lacking. Clinical articles and experiments with cells other than cardiomyocytes are few. The effects of doxorubicin on the extracellular matrix also needs further exploration. These areas need further exploration.