title: Doxorubicin induced heart failure: Phenotype and molecular mechanisms.
abstract: Long term survival of childhood cancers is now more than 70%. Anthracyclines, including doxorubicin, are some of the most efficacious anticancer drugs available. However, its use as a chemotherapeutic agent is severely hindered by its dose-limiting toxicities. Most notably observed is cardiotoxicity, but other organ systems are also degraded by doxorubicin use. Despite the years of its use and the amount of information written about this drug, an understanding of its cellular mechanisms is not fully appreciated. The mechanisms by which doxorubicin induces cytotoxicity in target cancer cells have given insight about how the drug damages cardiomyocytes. The major mechanisms of doxorubicin actions are thought to be as an oxidant generator and as an inhibitor of topoisomerase 2. However, other signaling pathways are also invoked with significant consequences for the cardiomyocyte. Further the interaction between oxidant generation and topoisomerase function has only recently been appreciated and the consequences of this interaction are still not fully understood. The unfortunate consequences of doxorubicin within cardiomyocytes have promoted the search for new drugs and methods that can prevent or reverse the damage caused to the heart after treatment in cancer patients. Alternative protocols have lessened the impact on newly diagnosed cancer patients. However the years of doxorubicin use have generated a need for monitoring the onset of cardiotoxicity as well as understanding its potential long-term consequences. Although a fairly clear understanding of the short-term pathologic mechanisms of doxorubicin actions has been achieved, the long-term mechanisms of doxorubicin induced heart failure remain to be carefully delineated.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY, United States.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Mitry
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY, United States.
authors.forename: John G
authors.initials: JG
authors.lastname: Edwards
keywords: Cancer; Cardiomyopathy; DNA damage; Doxorubicin; Heart failure; Mitochondria; Oxidant stress; Topoisomerase