Doxorubicin induces cell death mainly by:
Doxorubicin, anthracycline antibiotic isolated from Streptomyces peucetius subsp. caesius, induces cytotoxicity via dual mechanisms of DNA damage and oxidative stress. Planar tetracyclic chromophore intercalates between DNA base pairs preferentially at CpG sequences increasing helical length and inhibiting topoisomerase IIalpha by trapping covalent enzyme-DNA cleavage complex preventing resealing of transient double-strand breaks introduced during replication, leading to activation of ATM kinase, phosphorylation of histone H2AX at serine139 forming gamma-H2AX foci, p53 accumulation, and mitochondrial apoptosis via Bax translocation and cytochrome c release. Quinone moiety undergoes redox cycling catalyzed by NADPH cytochrome P450 reductase, nitric oxide synthases, and mitochondrial complex I generating superoxide anion, hydrogen peroxide, and hydroxyl radicals via Fenton reaction with iron. Reactive oxygen species oxidize membrane lipids, proteins, and cause oxidative DNA lesions 8-oxo-guanine. Glutathione depletion amplifies injury. Unlike specific ribosome or translation inhibitors, doxorubicin pleiotropic damage effective against proliferating cells but causes cardiotoxicity due to ROS in cardiomyocytes lacking high antioxidant defenses.
Ref: Thorn et al PharmGKB Doxorubicin topoisomerase II ROS; Gewirtz DA Biochem Pharmacol 1999 Doxorubicin DNA damage ROS mechanisms.