Anthracycline degradation in cardiomyocytes: a journey to oxidative survival.
The clinical use of doxorubicin (DOX) and other quinone-hydroquinone antitumor anthracyclines is limited by dose-related cardiotoxicity. One-electron redox cycling of the quinone moiety has long been known to form reactive oxygen species (ROS) in excess of the limited antioxidant defenses of cardiomyocytes; therefore, anthracycline cardiotoxicity was perceived as a one-way process in which redox cycling of the quinone always primed cardiomyocytes to oxidant stress and death. The past few years witnessed a growing interest in an alternative process in which peroxidases and quinone-derived hydrogen peroxide were able to oxidize the hydroquinone moiety of anthracyclines. Such a process was initially thought to amplify the cardiotoxicity induced by anthracyclines. Here, we briefly review how oxyferrous myoglobin could be subsequently identified as the primary catalyst of anthracycline oxidation in cardiomyocytes and be shown to induce an anthracycline chemical degradation that diminished the cellular levels and toxicity of active parent compounds. Many aspects of anthracycline degradation remain obscure or only partially understood; nevertheless, it is not too naive to conclude that anthracyclines are degraded and inactivated as a result of ROS production from their own redox cycling. Anthracycline redox reactions might therefore be viewed as two-way processes in which oxidative stress mediated both the death and survival of cardiomyocytes.
Menna
Pierantonio
P
University Campus Bio-Medico, Fondazione Alberto Sordi-Research Institute on Aging, Rome, Italy.
Salvatorelli
Emanuela
E
Minotti
Giorgio
G
D018943:Anthracyclines / Q000378:metabolism* / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000633:toxicity; D017209:Apoptosis; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009211:Myoglobin / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D009211:Myoglobin; D017382:Reactive Oxygen Species; D004317:Doxorubicin