PMC

(A) Cell death signals trigger BID and BIM to activate BAX and BAK, which in turn initiate mitochondrial outer membrane permeabilization (MOMP) and lead to apoptosis. (B) Anti-apoptotic molecules, including BCL-2, antagonize both activator and effector molecules and block the apoptotic cascade. (C) Cell death signals also activate sensitizer molecules, which antagonize anti-apoptotic molecules and release the block on apoptosis. This physiologic role is pharmacologically recapitulated by BH3-mimetic drugs such as venetoclax.

(A) In an apoptotically primed cell, BCL-2 or other anti-apoptotic molecules sequester BIM (or BID) and prevent interaction with effector molecules such as BAK or BAX. (B) Binding of VCX to BCL-2 displaces BIM, allowing it to interact with BAX (or BAK), which then oligomerizes and allows efflux of cytochrome C from the mitochondrion. (C) A cell with a low degree of apoptotic priming has relatively little BIM or BID. In this case, treatment with VCX (D) has little effect in and of itself, though this might not preclude synergy with additional chemotherapy.