Figure 7.

PAC-1 enhances the apoptotic signal as induced by cytotoxins such as doxorubicin. (a) Doxorubicin inhibits topoisomerase II, resulting in canonical intrinsic pathway apoptosis. (b) PAC-1 induces apoptosis through chelation of labile inhibitory zinc from procaspase-3, and PAC-1 also relieves zinc-mediated inhibition of caspase-3 activity. (c) The combination of PAC-1 and doxorubicin induces amplified levels of apoptosis due a primed (nonzinc inhibited) population of procaspase-3 that is more responsive to upstream proteolysis (see data in Figure 3b and Supporting Figures 5b and 6). In addition, PAC-1 enables any caspase-3 generated by doxorubicin to be more active, through chelation of inhibitory zinc from caspase-3 (see data in Figure 3c and Supporting Figure 5c). Elevated caspase-3 activity leads to enhanced cleavage of the endogenous protein substrate PARP-1 (Figure 3b,e and Supporting Figures 5b and 6), and higher levels of apoptotic cell death (Figure 3a and Supporting Figure 5a).