Adriamycin-induced oxidative mitochondrial cardiotoxicity.
The anticancer agent Adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity. Numerous studies have attempted to characterize and elucidate the mechanism(s) behind its cardiotoxic effect. Despite a wealth of data covering a wide-range of effects mediated by the drug, the definitive mechanism remains a matter of debate. However, there is consensus that this toxicity is related to the induction of reactive oxygen species (ROS). Induction of ROS in the heart by ADR occurs via redox cycling of the drug at complex I of the electron transport chain. Many studies support the theory that mitochondria are a primary target of ADR-induced oxidative stress, both acutely and long-term. This review focuses on the effects of ADR redox cycling on the mitochondrion, which support the hypothesis that these organelles are indeed a major factor in ADR cardiotoxicity. This review has been constructed with particular emphasis on studies utilizing cardiac models with clinically relevant doses or concentrations of ADR in the hope of advancing our understanding of the mechanisms of ADR toxicity. This compilation of current data may reveal valuable insights for the development of therapeutic strategies better tailored to minimizing the dose-limiting effect of ADR.
Berthiaume
J M
JM
Toxicology Graduate Program, Medical School, University of Minnesota, Duluth, Minnesota 55812, USA.
Wallace
K B
KB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000633:toxicity; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D008955:Models, Cardiovascular; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D042967:Electron Transport Complex I