Anthracyclines are commonly used to treat a variety of solid and hematologic tumors in both adults and children. However, because they have clinically relevant dose-dependent cardiotoxicity, lower doses are used in treating childhood cancer [18
]. Anthracyclines express their anticancer effects through two major mechanisms: (1) their intercalation between base pairs of DNA prevents cancer cells from replicating and (2) their inhibition of topoisomerase-II activity prevents the uncoiling process of DNA that is necessary for replication and transcription.
However, the specific mechanisms of anthracycline cardiotoxicity are complex and, despite decades of research, remain unclear. The oxidative stress hypothesis is among the most widely studied and accepted cellular mechanism thought to cause cardiotoxicity [20
]. Once administered, anthracyclines are believed to enter cells through passive diffusion, where they can reach intracellular concentrations several hundred times higher than that in extracellular compartments. Once inside the cell, anthracyclines may form complexes with intracellular iron, leading to the production of free radicals, which can cause DNA damage and lipid peroxidation. The damage caused by free radicals, and by reactive oxygen species (ROS), can eventually lead to cell death and larger-scale organ damage.
Why the heart is particularly vulnerable to oxidative stress caused by anthracyclines is not clear, but the abundance of mitochondria found in cardiomyocytes [5
] may be involved. Increasingly, the importance of mitochondria as key mediators of anthracycline-induced cardiotoxicity has been reported [24
]. Cardiolipin, a phospholipid found in high concentrations on the inner cell membrane of cardiac mitochondria, has a high affinity for anthracyclines. This affinity allows increased concentrations to enter cardiac mitochondria [25
], which may impair membrane stability or lead to mitochondrial DNA damage by intercalation. Anthracycline effects on the mitochondria may also impair the cell's ability to produce energy and to handle the added oxidative stress of cancer and its treatments [21
]. In addition, one of the heart's key antioxidants, glutathione peroxidase, is depleted in the presence of anthracyclines [30
Several other mechanisms have been suggested for anthracycline cardiotoxicity, including the induction of apoptosis, abnormal creatine kinase activity, the production of vasoactive amines, the formation of toxic metabolites, upregulation of nitric oxide synthetase, and the inhibition of transcription and translation [31
]. Anthracyclines cause uncoupling of the electron transport chain, which creates highly reactive oxygen species, and can impair oxidative phosphorylation and adenosine triphosphate (ATP) synthesis [24
]. Anthracyclines can also impair mitochondrial calcium homeostasis, leading to the loss of stability of the mitochondrial membrane, decreased ATP, and cell death.
In addition, several other changes have been observed in anthracycline-exposed cardiomyocytes, for which the underlying mechanisms have yet to be fully explained. These changes include depleted cardiac stem cells [34
], impaired DNA synthesis [35
], impaired cell signaling that triggers cell death [36
], altered gene expression [37
], inhibited calcium release from the sarcoplasmic reticulum [38
], impaired formation of the protein titin in sarcomeres [39
], and impaired mitochondrial creatine kinase activity and function [40
]. None of these findings, however, are necessarily completely dependent or independent of an oxidative stress pathway. The fact that many of these subcellular consequences continue to progress for weeks after anthracycline exposure may provide insight into the mechanisms of chronic cardiomyopathy [41
Finally, understanding cardiovascular cell signaling proteins may prove useful by clarifying both the pathway of toxicity and the early detection of anthracycline-induced cardiotoxicity. Because of the synergistic cardiotoxic potential of anthracyclines and the ErbB2 antibody, trastuzumab, interest in the role of neuregulin (NRG-1) is growing. Neuregulin is a growth factor that is an endogenous ligand for the protein ErbB2 and is possibly involved in a signaling pathway that regulates sarcomere functioning [33
]. Neuregulin levels are decreased with anthracycline use, suggesting a potential mechanism of toxicity. However, this decrease has not been clearly associated with serum and echocardiographic markers of cardiac dysfunction [42