Transforming growth factor (TGF)-beta pretreated nontransformed fibroblasts induce apoptosis selectively in transformed fibroblasts. This potential control step during oncogenesis has been termed intercellular induction of apoptosis. Selectivity and efficiency of intercellular induction of apoptosis depend on transformed target cell-derived superoxide anions that drive two intercellular signaling pathways--the HOCl/hydroxyl radical and the nitric oxide (NO)/peroxynitrite pathway. Other natural antitumor systems like macrophages or cells of the granulocyte lineage seem to utilize the same signaling chemistry. Our data demonstrate the existence of an alternative signaling pathway in these systems. This pathway depends on the presence of nitrite and is still effective when the two conventional signaling pathways are blocked by superoxide dismutase (SOD). Nitrite-dependent apoptosis induction is neither blocked by SOD nor by the hydroxyl radical scavenger terephthalate, but it is inhibited by the peroxidase inhibitor aminobenzoyl hydrazide and by the hypochlorous acid (HOCl) scavenger taurine. Therefore, nitrite, that is nontoxic for our cells, seems to interact with HOCl to form the apoptosis inducer nitryl chloride. Nitryl chloride-mediated apoptosis induction might be relevant for apoptosis induction in tumor cells that release SOD and thus escape the two classical signaling pathways.