FIGURE 9.

Multiple molecular targets are simultaneously involved in the pro-apoptotic effect of AD0157 on human myeloid leukemia cells. On the one hand, in the control of intrinsic pathway of apoptosis, inhibition of Akt phosphorylation by AD0157 could lead to dephosphorylation of pro-apoptotic Bad, causing a drop in the mitochondrial membrane potential and triggering the release of cytochrome c into the cytosol. This could facilitate the formation of apoptosome, which activates the initiator caspase-9 that would cause an activation of executioner caspases-3/-7, ultimately leading to apoptosis. On the other hand, the effect of AD0157 on the extrinsic pathway of apoptosis is suggested by the increase in the caspase-8 activity, which could then prompt the activation of the effector caspases. In addition, caspase-8 could initiate a mitochondrial amplification loop, mediated by the cleavage of the BH3-only protein Bid. In the scheme, targets of AD0157 are indicated with a red star.