Abstract
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.
Footnotes
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This work was supported by a Ph.D. Scholarship (to J.C.K.) and grant (D.R.R.) from the National Heart Foundation and by a fellowship and grants from the National Health and Medical Research Council (to D.R.R.).
- Abbreviations:
- DOX
- doxorubicin
- DFO
- desferrioxamine
- Tf
- transferrin
- TfR1
- transferrin receptor 1
- IRP
- iron-regulatory protein
- BSO
- buthionine sulfoximine
- FAC
- ferric ammonium citrate
- NAC
- N-acetylcysteine
- SOD
- superoxide dismutase
- MnTBAP
- Mn(III) tetrakis (4-benzoic acid) porphyrin complex
- DAU
- daunorubicin
- EPI
- epirubicin
- ICRF-187
- dexrazoxane [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane]
- PCIH
- 2-pyridylcarboxaldehyde isonicotinoyl hydrazone
- 311
- 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone
- PAGE
- polyacrylamide gel electrophoresis
- GSH
- glutathione
- ferritin-H
- ferritin heavy chain
- ferritin-L
- ferritin light chain
- Received November 11, 2002.
- Accepted January 13, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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