Figure 1.

Potential signaling pathways involved in anthracycline-induced cardiomyocyte injury. Anthracycline-induced cell death is balanced by intracellular survival signaling which is linked to neuregulin/ErbB2 and Akt activation. The suggested principal mechanism of anthracycline damage is via generation of reactive oxygen species ROS by iron-anthracycline complexes, leading to lipid peroxidation and membrane damage. Oxidative stress (ROS, nitric oxide NO, and peroxynitrite ONOO–) causes activation of kinase pathways (mitogen-activated protein kinase MAPK, stress-activated protein kinase SAPK, c-Jun N-terminal kinases JNK) modulating response to anthracyclines and linking to apoptotic pathway. In mitochondria, ROS and calcium overload lead to the release of cytochrome c (cyt c) from mitochondria into cytoplasm, via mitochondrial permeability transition pore opening (mPTP), which results in membrane potential dissipation (delta psi m), activation of caspases and apoptosis. Other putative mechanisms include damage to nuclear DNA, disruption of sarcomeric protein, suppression of transcription factors (GATA-4, p300, p53) that regulate cell survival and sarcomeric protein synthesis, and disturbance of energy metabolism.