Anthracyclines induce accumulation of iron in ferritin in myocardial and neoplastic cells: inhibition of the ferritin iron mobilization pathway.
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 (59)Fe donated from transferrin was incorporated into ferritin. Over longer incubation periods up to 18 to 24 h, (59)Fe was subsequently mobilized from ferritin into other compartments in control cells. However, anthracyclines inhibited ferritin-(59)Fe redistribution during the 18- to 24-h period, resulting in a significant (p < 0.0003) 3- to 5-fold accumulation of ferritin-(59)Fe compared with control cells. The increase in ferritin-(59)Fe after a 24-h incubation with DOX could not be correlated with increased ferritin expression, suggesting that (59)Fe accumulation occurred in pre-existing ferritin. In addition to DOX, other redox-cycling agents (i.e., menadione and paraquat) also increased ferritin-(59)Fe 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-(59)Fe 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.
Kwok
J C
JC
The Heart Research Institute, Iron Metabolism and Chelation Group, Sydney, New South Wales, Australia.
Richardson
D R
DR
D018943:Anthracyclines / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001692:Biological Transport; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005293:Ferritins / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D014168:Transferrin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D002614:Chelating Agents; D014168:Transferrin; D004317:Doxorubicin; D005293:Ferritins; D007501:Iron; D002945:Cisplatin