Fig. 6. The roles of the Bcl-2 family and IAPs in apoptosis regulation.

Apoptosis is a highly complex and tightly regulated cell death program¹⁰. In recent years two classes of proteins have come increasingly into the focus of potential therapeutic interventions, the Bcl-2 family and IAPs. The Bcl-2 family (red) comprises proteins that contain at least one Bcl-2 homology (BH) domain and fall into three subgroups: the BH3-only, the pro-survival and the proapoptotic proteins. Cellular stress stimulates BH3-only proteins which then alter the balance between pro- and anti-apoptotic Bcl-2 family proteins leading to BAX and BAK-forming pores and thus initiating mitochondrial apoptosis⁶⁵. The most promising approach with regards to this protein family are BH3 mimetics that have a function similar to that of BH3-only proteins. While BH3 mimetics on their own can be sufficient to induce apoptosis, generally some form of additional stress is needed for optimal efficacy⁶⁵. Interestingly, in a preclinical setting, successes with BH3 mimetics could be achieved particularly in the high-risk groups of ALL and neuroblastoma³. It is tempting to speculate that within particularly aggressive tumours, be it due to the high proliferation rate or the fact that invasive cells more frequently encounter a hostile environment, the intrinsic cellular stress is already at a higher level, so that less extrinsic force is needs to be combined with the mimetics. While the Bcl-2 family contribute to apoptosis resistance directly prior to/at the mitochondria, there is a second class of proteins (green) that mediate cell death resistance at the stages following mitochondrial involvement. Of the eight mammalian Inhibitor of Apoptosis Proteins (IAPs), three are ubiquitously expressed, XIAP, c-IAP 1 and 2⁶⁵. XIAP binds and thereby inhibits Caspases-3, -7 and -9, while the role of the c-IAPs seems slightly more complex; while there is considerable functional overlap with XIAP, they also have a crucial role in RIP1-dependent necrosis or necroptosis^98,99. Therapeutically, mimetics of the naturally occurring IAP inhibitor, Smac/DIABOLO have shown great promise. Unlike BH3 mimetics which can either sensitise for, or induce cell death in a tumour-dependent manner⁶⁵, Smac mimetics are generally considered as sensitisers and not inducers of apoptosis⁹⁹. Their potency was first demonstrated using an orthotopic human glioblastoma model, where the combination of Smac mimetic and death ligand Apo2-L/TRAIL de facto cured the mice, while the individual substances had no or little effect on overall survival¹⁰⁰