Impairment of programmed cell death (apoptosis) is both a key step in the development of cancer and a major barrier to its durable treatment. Understanding its control, however, is stimulating new therapeutic approaches. Commitment to apoptosis is largely regulated by interactions between three factions of the Bcl-2 protein family (Strasser et al, 2011). The initial signals, often evoked by cellular damage (e.g. chemotherapy), are conveyed by ‘BH3-only proteins’, which bind via their short BH3 interaction domain to other Bcl-2 family members. An essential step, however, is activation of Bax and Bak, which then form homo-oligomers that permeabilize the mitochondrial outer membrane, triggering a proteolytic holocaust. Until overwhelmed by BH3-only proteins, members of the pro-survival faction, e.g. Bcl-2, Bcl-xL, Mcl-1, sequester any activated Bax or Bak.
The pivotal step in commitment to apoptosis is the conversion of Bax and Bak from benign monomers into the homo-oligomers that disrupt the mitochondria. This can be initiated by the binding of certain BH3-only proteins or their BH3 peptides (e.g. Bim and Bid). Insights into the mechanism have arisen from recent structural studies on Bax lacking its C-terminal trans-membrane helix, BaxDTM (Czabotar et al, in press). Crystal structures of BaxDTM activated by Bid BH3 revealed the peptide bound into the Bax surface groove and revealed that its binding provokes a major rearrangement in Bax: its N-terminal half (alpha helices 1 - 5) separates from the remainder (alpha helices 6 - 8). Moreover, the first step of Bax oligomerization was demonstrated to form symmetric dimers where the BH3 domain (aipha helix 2) of one molecule has inserted into the surface groove of another.
Targeting the pro-survival Bcl-2 proteins with organic compounds that mimic the BH3 peptides has great promise for cancer therapy. The best characterized ‘BH3 mimetics’ are ABT-737 and its orally bioavailable relative ABT-263 (navitoclax), which bind Bcl-2, Bcl-xL and Bcl-w but not Mcl-1. In malignancies where Bcl-2 has a critical role, e.g. chronic lymphocytic leukaemia (CLL), they have shown substantial activity. However, their targeting of Bcl-xL provokes an acute drop in platelets, which is the dose-limiting toxicity in the clinic. Consequently, there are high hopes that the very recently described Bcl-2-specific mimetic ABT-199 (Souers et al, 2013), which does not cause the platelet drop, will be even more effective.