Calcium-Dependent Mechanisms in Drug Toxicity and Cell Killing

Summary

There is now convincing evidence that the calcium ion plays a critical role in cytotoxicity and cell death. In a variety of experimental models cell killing has been found to be preceded by intracellular Ca²⁺ accumulation, and pretreatment with Ca²⁺ entry blockers or intracellular Ca²⁺ chelators has been shown to provide protection. Further, resistance to cell killing has been reported to correlate with cellular levels of the Ca²⁺-binding protein calbindin-D_28k in neurons and thymoma cells. It is also clear that sustained increases in intracellular Ca²⁺ level can activate cytotoxic mechanisms which result in perturbations of cell structure and function. For example, the stimulation of Ca²⁺-dependent proteases can cause a disruption of cytoskeletal organization, and Ca²⁺-mediated phospholipase activation can result in an impairment of mitochondrial function and cessation of ATP synthesis. The activation of Ca²⁺, Mg²⁺-dependent endonuclease(s) is associated with characteristic chromatin cleavage which is a hallmark of apoptotic cell killing in the immune system and other tissues. The aim of this overview is to discuss some recent advances in our knowledge of the role of the calcium ion in cytotoxicity.