Figure 6.

Activation of the apoptotic pathway by adenine deoxynucleosides. An adenine deoxynucleoside, such as 2CdA, enters cells and is converted progressively to its active 2CdATP. The 2CdATP causes DNA strand break formation, activating poly(ADP ribose) polymerase and p53, with resultant depletion of NAD and adenine nucleotides, and a concomitant increase in oxidative stress. In untreated cells, the concentrations of ATP and cytochrome c (c.c.) in the cytoplasm are insufficient to trigger the caspase cascade. However, the binding of Apaf-1 to caspase-9, in the presence of 2CdATP and small amounts of released cytochrome c leads to the cleavage of caspase-3, converting it to an active autocatalytic protease, in a process analogous to the blood clotting. The active caspase-3 then stimulates, in turn, the CAD endonuclease that irreversibly degrades DNA.