Potentiation of Doxorubicin Cardiotoxicity by Iron Loading in a Rodent Model

ObjectivesThe role of iron toward doxorubicin (DOX) cardiotoxicity was studied using a rodent model of dietary carbonyl iron loading.BackgroundDoxorubicin, 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.MethodsMale 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.ResultsAnimals 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.ConclusionsDietary 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.