Abstract

Cardiotoxicity from the antitumor anthracycline doxorubicin correlates with doxorubicin cardiac levels, redox activation to superoxide anion (O₂^._) and hydrogen peroxide (H₂O₂), and formation of the long-lived secondary alcohol metabolite doxorubicinol. Cardiotoxicity may first manifest during salvage therapy with other drugs, such as the anthracenedione mitoxantrone. Minimal evidence for cardiotoxicity in anthracycline-pretreated patients with refractory-relapsed non-Hodgkin lymphoma was observed with the novel anthracenedione pixantrone. We characterized whether pixantrone and mitoxantrone caused different effects on doxorubicin levels, redox activation, and doxorubicinol formation. Pixantrone and mitoxantrone were probed in a validated ex vivo human myocardial strip model that was either doxorubicin-naïve or preliminarily subjected to doxorubicin loading and washouts to mimic doxorubicin treatment and elimination in the clinical setting. In doxorubicin-naïve strips, pixantrone showed higher uptake than mitoxantrone; however, neither drug formed O₂^._ or H₂O₂. In doxorubicin-pretreated strips, neither pixantrone nor mitoxantrone altered the distribution and clearance of residual doxorubicin. Mitoxantrone showed an unchanged uptake and lacked effects on doxorubicin levels, but synergized with doxorubicin to form more O₂^._ and H₂O₂, as evidenced by O₂^._-dependent inactivation of mitochondrial aconitase or mitoxantrone oxidation by H₂O₂-activated peroxidases. In contrast, pixantrone uptake was reduced by prior doxorubicin exposure; moreover, pixantrone lacked redox synergism with doxorubicin, and formed an N-dealkylated product that inhibited metabolism of residual doxorubicin to doxorubicinol. Redox inactivity and inhibition of doxorubicinol formation correlate with the cardiac safety of pixantrone in doxorubicin-pretreated patients. Redox inactivity in the face of high cardiac uptake suggests that pixantrone might also be safe in doxorubicin-naïve patients.