FIG. 1.

Currently understood mechanism for the iron-mediated generation of ROS by doxorubicin. The anthracycline doxorubicin undergoes a one-electron reduction of the C ring, leading to the formation of a semiquinone free radical metabolite. In the presence of oxygen, its unpaired electron is donated to oxygen forming superoxide radicals. Flavoproteins and glutathione (GSH/GSSG) catalyze the formation of a reduced semiquinone by accepting electrons from NADH or NADPH. SOD can catalyze the dismutation of superoxide into oxygen and H₂O₂ and provide an antioxidant defense, along with catalase and other antioxidant enzymes. A detailed description of the Fenton and Haber–Weiss reactions and the pathways labeled as Mechanism I or II are provided in the text. The iron-mediated generation of hydroxyl radicals can damage lipids, proteins, and DNA. The outcome of oxidative damage on critical cellular components could include apoptosis, autophagy, and/or necrosis. Modified with permission from Thomas Simunek (Charles University in Prague) (237). GSH, glutathione; GSSG, oxidized glutathione; H₂O₂, hydrogen peroxide; NADH, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; SOD, superoxide dismutase.