Caspase-independent cell death without generation of reactive oxygen species in irradiated MOLT-4 human leukemia cells

To improve our understanding of ionizing radiation effects on immune cells, we investigated steps leading to radiation-induced cell death in MOLT-4, a thymus-derived human leukemia cell. After exposure of MOLT-4 cells to 4 Gy of X-rays, irradiated cells sequentially showed increase in intracellular Reactive Oxygen Species (ROS), decrease in mitochondrial membrane potential, and eventually apoptotic cell death. In the presence of the Caspase Inhibitor z-VAD-fmk, irradiated cells exhibited necrotic characteristics such as mitochondrial swelling instead of Apoptosis. ROS generation was not detected during this necrotic cell death process. These results indicate that radiation-induced Apoptosis in MOLT-4 cells requires elevation of intracellular ROS as well as activation of a series of caspases, whereas the cryptic necrosis program--which is independent of intracellular ROS generation and Caspase activation--is activated when the Apoptosis pathway is blocked.