Central and ambivalent role of hydrogen peroxide during intercellular induction of apoptosis.

TGF-beta pretreated non-transformed fibroblasts induce apoptosis selectively in transformed fibroblasts. This novel potential control step of oncogenesis has been termed intercellular induction of apoptosis. Intercellular signalling depends on target cell-derived extracellular superoxide anions that drive the efficiency of two signalling pathways. These are based on the formation of peroxynitrite through nitric oxide/superoxide anion interaction and on the generation of hypochlorous acid, followed by interaction of hypochlorous acid with superoxide anions, leading to the generation of hydroxyl radicals. This report demonstrates that exogenous hydrogen peroxide causes an overall inhibition of intercellular induction of apoptosis through blunting of the nitric oxide/peroxynitrite signalling pathway. When the HOCl/hydroxyl radical signalling pathway is studied separately (in the presence of an inhibitor of nitric oxide synthesis), exogenous hydrogen peroxide causes an enhancement of apoptosis induction. Based on the dual and adverse effects of hydrogen peroxide on intercellular induction of apoptosis, its steady state concentration seems to be one of the critical parameters that determine efficiency of apoptosis induction in transformed cells.