There are two proposed mechanisms by which doxorubicin acts in the cancer cell: (i) intercalation into DNA and disruption of topoisomerase-II-mediated DNA repair and (ii) generation of free radicals and damage to cellular membranes, DNA, and proteins. In brief, doxorubicin is oxidized to semiquinone, an unstable metabolite, which is converted back to doxorubicin in a process that releases reactive oxygen species. Reactive oxygen species can lead to lipid peroxidation and membrane damage, DNA damage, oxidative stress, and trigger apoptotic pathways of cell death. Candidate genes that may modulate this pathway involve those capable of the oxidation reaction (NADH dehydrogenases, nitric oxide synthases, xanthine oxidase) and those capable of deactivating the free radicals such as glutathione peroxidase, catalase, and superoxide dismutase. Alternatively, doxorubicin can enter the nucleus and poison topoisomerase-II, resulting in DNA damage and cell death.
