Model for targeting cancer cells with sensitizer BH3 mimetics. (A) Mitochondrion from a normal cell has some Bax/Bak and Bcl-2. Bcl-2 is unoccupied; normal cell behavior is provoking no death signals. (B–D) Mitochondria from cancer cells have equal Bax/Bak and overexpress Bcl-2 in this model. Antiapoptotic reserve is defined as the number of unoccupied antiapoptotic Bcl-2 family member binding pockets per cell. Compared with normal mitochondria, those that overexpress Bcl-2 may provide decreased (B), equal (C), or increased (D) antiapoptotic reserve. Because of genomic instability, oncogene activation, cell cycle checkpoint violation, or perhaps cancer-specific response to cytotoxic chemotherapy, activator BH3 domains have been triggered and are sequestered by Bcl-2. After exposure to a sensitizer BH3 mimetic (a protein, peptide, or small molecule), activator BH3 domains are displaced from cancer cells, but not normal cells, activating Bax/Bak and allowing selective cancer cell killing, perhaps even as a single agent. It can be seen why sensitizer mimetics might offer a greater therapeutic window than an activator, as an activator molecule would provide selective killing only at low doses and only for cancer cells in condition 1 (Cancer 1). At higher doses, or if the cancer cells were in condition 2 or 3, there would be killing of normal and cancer cells. It is unclear whether activator- or sensitizer-type BH3-only family members predominate in the response to conventional chemotherapy agents, and it is likely that a mixture is present. These models also speculate why certain cancers, such as follicular lymphoma and chronic lymphocytic leukemia, despite expressing higher levels of Bcl-2, are more prone to apoptosis than normal cells after DNA-damaging chemotherapy.