Potentiation of Doxorubicin Cardiotoxicity by Iron Loading in a Rodent Model

Gurusher S. Panjrath, Virender Patel, Carolina I. Valdiviezo, Navneet Narula, Jagat Narula, Diwakar Jain

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Objectives: The role of iron toward doxorubicin (DOX) cardiotoxicity was studied using a rodent model of dietary carbonyl iron loading. Background: Doxorubicin, a commonly used anticancer drug, is known to cause serious and potentially life-threatening cardiotoxicity. Doxorubicin cardiotoxicity is thought to be mediated through free-radical injury. Methods: Male Sprague Dawley rats fed iron-rich chow (n = 8) and regular chow (n = 8) were treated with DOX or saline (4 animals in each arm). Cardiotoxicity was assessed using mortality, weight changes, Tc-99m annexin-V imaging, histopathology, and immunohistochemistry. Results: Animals fed iron-rich chow showed significantly higher DOX cardiotoxicity as evidenced by greater weight loss (107 ± 14 g vs. 55 ± 10 g weight loss, p < 0.05), higher annexin uptake (0.14 ± 0.01% vs. 0.08 ± 0.01% injected dose/g of myocardium, p < 0.05), more severe myocyte injury on electron microscopy, and significantly higher cleaved caspase-3 staining compared with regular chow fed rats given DOX. Feeding iron-rich chow alone did not result in any cardiotoxicity. Conclusions: Dietary iron loading resulted in a substantially increased DOX cardiotoxicity in rats. Body iron stores as well as its bioavailability in tissue may be important independent predictors of susceptibility to DOX cardiotoxicity in man. Further clinical studies are warranted.

Original languageEnglish (US)
Pages (from-to)2457-2464
Number of pages8
JournalJournal of the American College of Cardiology
Issue number25
StatePublished - Jun 26 2007
Externally publishedYes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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