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Vol. 63, Issue 4, 849-861, April 2003
The Heart Research Institute, Iron Metabolism and Chelation Group
and Children's Cancer Institute Australia for Medical Research, Iron
Metabolism and Chelation Program, Sydney, New South Wales, Australia
Anthracyclines are potent antitumor agents that cause cardiotoxicity at
high cumulative doses. Because anthracycline cardiotoxicity is
attributed to their ability to avidly bind iron (Fe), we examined the
effect of anthracyclines on intracellular Fe trafficking in neoplastic
cells and differentiated cardiomyocytes. In both cell types, incubation
with doxorubicin (DOX) resulted in a significant (p < 0.004) accumulation of Fe in the storage protein, ferritin. Pulse-chase experiments using control cells demonstrated that within
6 h, the majority of 59Fe donated from transferrin was
incorporated into ferritin. Over longer incubation periods up to 18 to
24 h, 59Fe was subsequently mobilized from ferritin
into other compartments in control cells. However, anthracyclines
inhibited ferritin-59Fe redistribution during the 18- to
24-h period, resulting in a significant (p < 0.0003) 3- to 5-fold accumulation of ferritin-59Fe compared
with control cells. The increase in ferritin-59Fe after a
24-h incubation with DOX could not be correlated with increased
ferritin expression, suggesting that 59Fe accumulation
occurred in pre-existing ferritin. In addition to DOX, other
redox-cycling agents (i.e., menadione and paraquat) also increased
ferritin-59Fe levels. Moreover, the intracellular
superoxide scavenger, Mn(III) tetrakis(4-benzoic acid)-porphyrin
complex, partially prevented the ability of DOX and menadione at
inducing this effect. Hence, superoxide generation by these compounds
could play a role in causing ferritin-59Fe accumulation.
This study is the first to demonstrate the effect of anthracyclines at
inhibiting Fe mobilization from ferritin, resulting in marked Fe
accumulation within the molecule. This response may have consequences
in terms of the cytotoxic effects of anthracyclines.
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