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Vol. 62, Issue 4, 888-900, October 2002
The Heart Research Institute, the Iron Metabolism and Chelation
Group, Sydney, New South Wales, Australia
Anthracyclines are effective antineoplastic agents. However, the
interaction of these drugs with iron (Fe) is an important cause of
myocardial toxicity, limiting their therapeutic use (J Lab
Clin Med 122:245-251, 1993). To overcome this
limitation, it is crucial to understand how anthracyclines interact
with the Fe metabolism of myocardial and neoplastic cells.
Iron-regulatory proteins (IRPs) play vital roles in regulating cellular
Fe metabolism via their mRNA-binding activity. We showed that
doxorubicin (DOX) and its analogs interfere with tumor and myocardial
cell Fe metabolism by affecting the RNA-binding activity of IRPs.
Unexpectedly, experiments with the free radical scavengers, catalase,
superoxide dismutase, ebselen, and Mn(III) tetrakis (4-benzoic acid)
porphyrin complex, suggested that the effects of DOX on
IRP-RNA-binding activity were not due to anthracycline-mediated free
radical production. In contrast to previous studies, we showed that the
DOX metabolite, doxorubicinol, had no effect on IRP-RNA-binding
activity. Rather, the anthracycline-Fe and -copper (Cu) complexes
decreased IRP-RNA-binding activity, indicating that formation of
anthracycline-metal complexes may affect cellular Fe metabolism. In
addition, anthracyclines prevented the response of IRPs to the
depletion of intracellular Fe by chelators. This information may be
useful in designing novel therapeutic strategies against tumor cells by
combining chelators and anthracyclines. Interestingly, the effect of
DOX on primary cultures of cardiomyocytes was similar to that observed
using neoplastic cells, and particularly notable was the decrease in IRP2-RNA-binding activity. Our results add significant new information regarding the effects of anthracyclines on Fe metabolism that may lead
to the design of more effective treatments.
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