RETARDATION OF CHEMICAL HYPOXIA-INDUCED NECROTIC CELL-DEATH BY BCL-2 AND ICE INHIBITORS - POSSIBLE INVOLVEMENT OF COMMON MEDIATORS IN APOPTOTIC AND NECROTIC SIGNAL TRANSDUCTIONS

Inhibition of the respiratory chain reaction by cyanide, rotenone or a ntimycin A (chemical hypoxia) induces necrotic cell death characterize d by apparently intact chromatin, remarkable mitochondrial swelling wi th loss of crista structure, and loss of plasma membrane integrity, Th e treatments induce no apoptotic cell death, as defined by fragmented nuclei with condensed chromatin, fragmented or condensed cytoplasm, Th e anti-apoptotic proteins Bcl-2 and Bcl-x(L) effectively retard the ch emical hypoxia-induced necrotic cell death, The necrotic cell death is also retarded by inhibitors of ICE(-like) proteases, including interl eukin-1 beta converting enzyme (ICE), which are common mediators of ap optosis, These results indicate that Bcl-2/Bcl-x(L) and ICE(-like) pro teases modulate apoptotic and at least some forms of necrotic cell dea th, Both cell death pathways appear to involve some common mediators; however necrotic or apoptotic cell death signals might be transduced t hrough multiple pathways, because Bcl-2/Bcl-x(L) or inhibitors of ICE( -like) proteases are relatively less potent in blocking necrotic cell death than in preventing apoptosis.