We have previously reported that
calcium ionophore A23187 differentially induces
necrosis in CEM cells, a T-
lymphoblastic leukemia cell line, and apoptosis in HL60 cells, a promyelocytic
leukemia cell line. Stimulation with
VP16, however, induces typical apoptosis in both cell lines.
Necrosis in CEM cells, characterized by cell shrinkage and clustering, began within 5 min of treatment. Swelling of the mitochondria, lumpy
chromatin condensation and intact plasma membranes were evident by electron microscopy. These A23187-mediated changes in CEM cells were suppressed by
clonazepam or
CGP37157, inhibitors of the mitochondrial
Na(+)/Ca(2+) exchanger. The changes, however, were not affected by
cyclosporin A, an inhibitor of the
mitochondrial permeability transition pore. In both CEM and HL60 cells, intra-cellular
calcium increased with similar amplitude within 1 min of treatment with 2 microM
A23187. Intra-mitochondrial
calcium increased with
clonazepam pre-treatment alone in both CEM and HL60 cells. However, intra-mitochondrial
calcium did not change drastically in response to
A23187 in CEM or HL60 cells, either untreated or pre-treated with
clonazepam.
A23187 induces
necrosis in CEM cells concurrent with
mitochondrial dysfunction, which is independent of the mitochondrial permeability transition, but affected by intra-mitochondrial
calcium, while HL60 cells lack these early changes. Differences in the responses to
A23187 between these two cell lines might derive from differences in the susceptibility of the mitochondrial membrane to rapid increases in intra-cellular
calcium.