UNSYMMETRICALLY SUBSTITUTED POLYAMINE ANALOG INDUCES CASPASE-INDEPENDENT PROGRAMMED CELL-DEATH IN BCL-2-OVEREXPRESSING CELLS

The polyamine analogue, thyl-N-11-[(cycloheptyl)methyl]-4,8-diaza-unde cane (CHENSpm)-induced programmed cell death in NCI H157 cells is acco mpanied by cytochrome c release, the loss of mitochondrial membrane po tential, activation of caspase-3, caspase-mediated poly(ADP-ribose) po lymerase cleavage, G(2)-M arrest, and DNA and nuclear fragmentation. O verexpression of Bcl-2 completely inhibits CHENSpm-induced cytochrome c release, caspase-3 activation, and poly(ADP-ribose) polymerase cleav age. However, Bcl-2 does not abrogate CHENSpm-induced programmed cell death. These results suggest that although cytochrome c release and ac tivation of the caspase-3 protease cascade contribute to the rapid and efficient execution of apoptosis, a caspase cascade-independent pathw ay also exists and can be activated by CHENSpm treatment.