Schematic representation of both major apoptosis signaling pathways. Chemotherapy causes DNA damage, inducing p53-controlled cytochrome c release from mitochondria, which then binds to apoptosis-activating factor-1 (Apaf-1), resulting in the activation of caspase 9, followed by the activation of effector caspases including caspase 3. Bcl-2 inhibits apoptosis at the level of cytochrome c release, whereas XIAP exerts its antiapoptotic effect through interaction with active caspase 9 and with active caspase 3.6 After ligation, death receptors signal cell death by inducing a death-inducing signaling complex (DISC) composed of the cytoplasmic adapter protein Fas-associated death domain (FADD) and caspase 8. Activated caspase 8 can activate caspase 3 directly and indirectly by the truncation of Bid. The truncated form of Bid (tBid) translocates to mitochondria leading to cytochrome c release and activation of the caspase 9-mediated pathway. c-Flip inhibits caspase 8 activation by interfering with the recruitment and the processing of pro-caspases within the DISC.7
