The study investigates the distinct caspase cascades initiated in receptor-mediated and chemical-induced apoptosis. Both receptor-induced (CD95 and tumor necrosis factor) and chemical-induced apoptosis result in similar time-dependent activation of caspases-3, -7, -8, and -9 in Jurkat T cells and human leukemic U937 cells. In receptor-mediated apoptosis, the caspase inhibitor Z-VAD.FMK inhibits apoptosis by blocking the upstream activator caspase-8, leading to the inhibition of Bid cleavage, cytochrome c release, processing of effector caspases, loss of mitochondrial membrane potential, and externalization of phosphatidylserine. In contrast, Z-VAD.FMK inhibits chemical-induced apoptosis by targeting the initiator caspase-9, which is activated after commitment to cell death. Cleavage of Bid but not cytochrome c release is blocked by Z-VAD.FMK, indicating that cytochrome c release in chemical-induced apoptosis is caspase-independent and not mediated by Bid cleavage. The authors propose that caspases play a crucial role in the cell death-inducing mechanism in receptor-mediated apoptosis, while in chemical-induced apoptosis, they act solely as executioners of apoptosis.The study investigates the distinct caspase cascades initiated in receptor-mediated and chemical-induced apoptosis. Both receptor-induced (CD95 and tumor necrosis factor) and chemical-induced apoptosis result in similar time-dependent activation of caspases-3, -7, -8, and -9 in Jurkat T cells and human leukemic U937 cells. In receptor-mediated apoptosis, the caspase inhibitor Z-VAD.FMK inhibits apoptosis by blocking the upstream activator caspase-8, leading to the inhibition of Bid cleavage, cytochrome c release, processing of effector caspases, loss of mitochondrial membrane potential, and externalization of phosphatidylserine. In contrast, Z-VAD.FMK inhibits chemical-induced apoptosis by targeting the initiator caspase-9, which is activated after commitment to cell death. Cleavage of Bid but not cytochrome c release is blocked by Z-VAD.FMK, indicating that cytochrome c release in chemical-induced apoptosis is caspase-independent and not mediated by Bid cleavage. The authors propose that caspases play a crucial role in the cell death-inducing mechanism in receptor-mediated apoptosis, while in chemical-induced apoptosis, they act solely as executioners of apoptosis.