Cellular macromolecules (DNA, lipids, and proteins)

Cellular macromolecules, including genomic DNA, membrane lipids, and functional proteins, serve as indirect targets of doxorubicin through the generation of reactive oxygen species (ROS) (PubChem: Doxorubicin, CID 31703). Doxorubicin undergoes enzymatic redox cycling, where its quinone moiety is reduced to a semiquinone radical by enzymes such as NADPH oxidase and mitochondrial complex I. This radical subsequently reacts with molecular oxygen to produce superoxide anions, which can further convert into highly reactive hydroxyl radicals (Octavia et al., 2012). These ROS cause extensive damage by inducing lipid peroxidation in cell membranes, oxidative modifications to proteins, and DNA strand breaks (Mizutani et al., 2005). While this oxidative stress contributes to the drug's anti-tumor efficacy by promoting apoptosis in malignant cells, it is also the primary driver of doxorubicin-induced cardiotoxicity (StatPearls: Doxorubicin, 2023). The heart is particularly vulnerable to this damage due to its high mitochondrial density and relatively low levels of antioxidant enzymes like catalase and superoxide dismutase (Octavia et al., 2012).

Other names

Reactive oxygen species targetsOxidative stress substratesDoxorubicin-induced ROS targetsCellular macromolecules

Doxorubicin undergoes one-electron reduction by intracellular oxidoreductases to form a semiquinone radical, which then reacts with molecular oxygen to generate superoxide anions and other reactive oxygen species (ROS), leading to the oxidative degradation of DNA, lipids, and proteins (StatPearls: Doxorubicin, 2023; Octavia et al., 2012).