Mechanism of alpha-tocopheryl succinate-induced apoptosis of promyelocyticleukemia cells

Selective induction of apoptosis in tumor cells is important for treating p atients with cancer. Because oxidative stress plays an important role in th e process of apoptosis, we studied the effect of alpha-tocopheryl succinate (VES) on the fate of cultured human promyelocytic leukemia cells (HL-60). The presence of fairly low concentrations of VES inhibited the growth and D NA synthesis of HL-60 cells, and also induced their apoptosis via a mechani sm that was inhibited by z-VAD-fluoromethylketone (z-VAD-fmk), an inhibitor of pan-caspases. VES activated various types of caspases, including caspas e-3, 6, 8, and 9, but not caspase-1. VES triggered the reaction leading to the cleavage of Bid, a member of the death agonist Bcl-2 family, and releas ed cytochrome c (Cyt.c) from the mitochondria into the cytosol by a z-VAD-f mk-inhibitable mechanism. VES transiently increased the intracellular calci um level [Ca2+](i) and stimulated the release of Cyt.c in the presence of i norganic phosphate (Pi). However, high concentrations of VES (similar to 10 0 mu M) hardly induced swelling of isolated mitochondria but depolarized th e mitochondrial membrane potential by a cyclosporin A (CsA)-insensitive mec hanism. These results indicate that VES-induced apoptosis of HL-60 cells mi ght be caused by activation of the caspase cascade coupled with modulation of mitochondrial membrane function.