Calcium chelators induce apoptosis--evidence that raised intracellular ionised calcium is not essential for apoptosis

A moderate sustained rise in intracellular ionised calcium has been observed to be associated with apoptosis occurring in many experimental systems. The application of extracellular and intracellular chelators of calcium has been reported to produce a decrease in apoptosis, while the addition of calcium ionophores often increases apoptosis. These findings, together with the observation of calcium-induced internucleosomal DNA cleavage in isolated nuclei, have suggested that DNA cleavage (and apoptosis) is a calcium-dependent process. However, a number of studies have shown that apoptosis is not always associated with a rise in the level of intracellular ionised calcium. In the present study, calcium chelators were found to induce apoptosis in cultured cells, concomitant with a decrease in both intracellular ionised calcium and total cell calcium content. Decreased intracellular ionised magnesium was also induced by extracellular chelators. These findings provide further evidence that a raised intracellular ionised calcium is not universally present during the induction of apoptosis. It is proposed that loss of calcium homeostasis, rather than a sustained rise in cytosolic calcium, is a determining factor in cell death by apoptosis.