Doxorubicin-induced reactive oxygen species redox cycling

Doxorubicin-induced redox cycling is a fundamental biochemical mechanism primarily responsible for the cytotoxic and cardiotoxic effects of anthracycline antibiotics. In this process, doxorubicin is reduced by intracellular oxidoreductases, such as NADH dehydrogenase or NADPH-cytochrome P450 reductase, into a highly reactive semiquinone radical intermediate (PMID: 17511402). This radical then donates an electron to molecular oxygen, generating superoxide anions and regenerating the original doxorubicin molecule, thereby initiating a self-sustaining cycle of reactive oxygen species (ROS) production (PMID: 25108287). The resulting oxidative stress leads to extensive damage to DNA, proteins, and membrane lipids, which triggers apoptotic pathways in both malignant cells and healthy cardiomyocytes. Because the heart possesses limited antioxidant defenses and high mitochondrial density, this redox cycling is a major cause of dose-dependent, irreversible cardiomyopathy (StatPearls: NBK459232). Clinical management often involves the use of dexrazoxane, an iron chelator that reduces the formation of ROS-generating iron-anthracycline complexes (PubChem: CID 31703). Understanding this redox cycle is crucial for developing next-generation anthracyclines with reduced cardiotoxicity and for monitoring patients undergoing chemotherapy.

Other names

Anthracycline redox cyclingDoxorubicin semiquinone redox cycleDoxorubicin-induced oxidative stressROS-mediated cardiotoxicity

Doxorubicin undergoes enzymatic one-electron reduction by intracellular oxidoreductases (e.g., NADH dehydrogenase) to form a semiquinone radical; this radical rapidly reacts with molecular oxygen to generate superoxide anions and other reactive oxygen species (ROS) while regenerating the parent doxorubicin molecule to continue the cycle (PMID: 17511402).