Figure 7. Model for major components of cisplatin-induced cytotoxicity.

Cellular exposure to cisplatin causes direct damage to mtDNA resulting in a reduction of mitochondrial protein synthesis, impairment of electron transport chain function, and subsequently, increases in intracellular ROS levels. ROS ultimately promotes cell death, resulting in a significant enhancement of the cytotoxic effect exerted by cisplatin through the generation of nDNA damage. Mitochondrial dysfunction, increased ability to scavenge mitochondrial ROS and glycolytic metabolism reduce cellular sensitivity to the mitochondrial-ROS mediated component of cisplatin cytotoxicity. Reduction in cellular sensitivity to cisplatin can also be achieved by increased DNA repair capacity. Additional, minor components not illustrated in this model may also affect cisplatin cytotoxicity.