Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress

Figure 2

Schematic representation of DOX-induced apoptosis and the involvement of ROS. DOX-derived ROS could affect the regulation of calcium homeostasis, resulting in cytosolic calcium (Ca²⁺) overload that can activate calcineurin and increase the transcription of Fas ligand (FasL). DOX-derived ROS could also inhibit the expression of caspase-8 (C8, also known as FLICE) inhibitory protein FLIP, rendering cells to apoptosis. Additionally, DOX-derived ROS could act as an intrinsic stress that activates mitogen activated protein kinases (MAPK) p38 and JNK and NF-κB pathways as well as intracellular p53 accumulation, leading to an alteration in the ratio of proapoptotic proteins to antiapoptotic proteins (e.g., Bax to Bcl-2), cytochrome C (Cyto C) release, and caspase-9 and -3 (C9/C3) activation.