Superoxide-dependent and -independent mitochondrial signaling during apoptosis in multiple myeloma cells

Superoxide (O-2(-)) radicals have been linked to apoptosis. Here, we show that 2-methoxyestradiol (2ME2)-induced apoptosis in multiple myeloma ( MM) cells is associated with O-2(-) generation, whereas dexamethasone (Dex)induced apoptosis occurs without concurrent increase in O-2(-). In contrast, both these agents decrease mitochondrial transmembrane potential (Deltapsi(m)). Treatment of MM cells with an antioxidant N-acetyl-L-cysteine blocks 2ME2, but not Dex-induced apoptosis as well as release of mitochondrial proteins cytochrome c (cyto c) and Smac. Taken together, these results demonstrate that there are at least two distinct apoptotic pathways: one dependent on O-2(-), which is induced by 2ME2 and is associated with release of cyto c and Smac; and the other an independent of O-2(-), which is triggered by Dex and associated with Smac release.