The Molecular Effects of Anthracyclines on Iron Metabolism : The molecular effects of anthracyclines on the iron metabolism of myocardial and neoplastic cells

Anthracyclines are potent anti-tumor agents that cause cardiotoxicity at high cumulative doses, limiting their therapeutic use. The mechanisms of anthracycline-mediated cardiotoxicity are poorly understood, but iron (Fe) has been implicated in this process. This book describes the effect of these drugs on intracellular Fe trafficking and distribution in both neoplastic and myocardial cells. The anthracycline, doxorubicin (DOX) and its analogues interfere with tumor and myocardial cell Fe metabolism by decreasing the RNA-binding activity of the iron-regulatory proteins (IRPs), that are involved in regulating cellular Fe homeostasis. Additionally, anthracyclines prevented the response of cellular IRPs to the depletion of intracellular Fe pools by Fe chelators. Incubation of DOX in both cell types resulted in the accumulation of Fe in the storage protein, ferritin, and inhibited Fe mobilisation from this protein. These studies suggested that the lysosome/proteasome pathway may be a novel target for anthracyclines, inhibiting Fe redistribution from ferritin that is essential for vital Fe-requiring processes such as DNA synthesis.