Doxorubicinol inhibits cardiac myofilament activation
Doxorubicin is one of the most effective anti-neoplastic agents, particularly against hematologic malignancies including leukemias and lymphomas. Unfortunately, its use is limited by acute and chronic cardiotoxicity. Its major metabolite has been implicated in the pathogenesis of doxorubicin-induced heart failure. The effect of doxorubicinol on myofilaments has not been characterized. The rationale for this study was that doxorubicinol had been shown to accumulate within human cardiac myocytes, depress contractility, and interact with sarcomeric proteins 'in vitro.' We hypothesized that doxorubicinol negatively impacted myofilament activation. Intramyocyte distribution, myofilament binding and effect on myofilament function were evaluated using clinically relevant concentrations. Doxorubicinol exhibited a binding pattern consistent with anisotropic bands, bound actin and myosin in isolated myofilament preparations and depressed myofilament ATPase activity and calcium sensitivity. The ATPase depressive effects were not due to inhibited thick filament strong cross bridge formation; this suggested involvement of the thin filaments in the cardiotoxic mechanism.