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PRECLINICAL STUDY

Potentiation of Doxorubicin Cardiotoxicity by Iron Loading in a Rodent Model

Gurusher S. Panjrath, MD^_*, Virender Patel, MD^_*, Carolina I. Valdiviezo, MD, Navneet Narula, MD, Jagat Narula, MD, PhD, FACC^_* and Diwakar Jain, MD, FACC^_*,_*

^_* Division of Cardiology, Drexel University College of Medicine, Philadelphia, Pennsylvania
Pathology Department, University of Pennsylvania, Philadelphia, Pennsylvania
Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, New York, New York.

Manuscript received December 4, 2006; revised manuscript received January 24, 2007, accepted February 6, 2007.

^_* Reprint requests and correspondence: Dr. Diwakar Jain, Drexel University College of Medicine, 245 North 15 Street, MS 470, Philadelphia, Pennsylvania 19102. (Email: Diwakar.Jain{at}drexelmed.edu).

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.

Abbreviations and Acronyms   DOX = doxorubicin   HFE = iron regulatory gene

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