Most cancer drugs are general cytotoxins that kill cells by means of an undefined mechanism. By studying the ways in which different BCL2 family members regulate the commitment to programmed cell death, Stanley Korsmeyer's group discovered two specific pathways by which a subset of this family, known as the 'BCL2 homology (BH)3-only'proteins, promote apoptosis. In the September issue of Cancer Cell, they report that mimetics of regions of these proteins might be some of the first reagents that have been developed to initiate cancer-cell death through genetically defined pathways.

The pro-apoptotic members of the BCL2 family comprise two classes — those that share homology in up to three conserved regions, known as BH 1–3 domains, and the BH3-only proteins, which only share sequence homology with the amphipathic α-helical BH3 domain. The BH3 domain is required for apoptosis induction, and mediates binding of the BH3-only proteins (BID, NOXA, PUMA, BIK, BIM and BAD) to other BCL2-family members.

Letai et al. synthesized BH3 peptides from representative BH3-only molecules to test whether these domains, when removed from the context of the intact protein, could induce cell death. Surprisingly, they found that different BH3 domains possessed distinct functions, and could be further categorized into two subgroups. One group, called the 'BID-like' subgroup, bound and activated oligomerization of the pro-apoptotic mitochondrial proteins BAK and BAX, leading to cytochrome c release and cell death. This BID-like subgroup also bound to the anti-apoptotic protein BCL2, however, where these peptides were sequestered and unable to function. The other group, known as the 'BAD-like' subgroup, did not activate BAK or BAX, but instead bound BCL2. This binding displaced the sequestered BID-like peptides, freeing them to mediate cytochrome c release and apoptosis.

So can these peptides be used to kill cancer cells, which possess many alterations in this entire pathway? The authors linked the peptides to an eight-amino-acid polyarginine chain stretch, to facilitate transport of the peptides across the plasma membrane, and showed that the BID-like peptide induced apoptosis in cultured leukaemia cells. The BAD-like peptide could not kill cells on its own, but seemed to sensitize cells to apoptosis, lowering the concentration of BID-like peptide that is required to induce cell death. These peptides might be used to increase the apoptotic susceptibility of other types of cancer cells, which frequently protect themselves from death by upregulating BCL2.