Bcl-2-regulated anti-apoptotic pathway

The Bcl-2-regulated anti-apoptotic pathway, also known as the intrinsic or mitochondrial apoptotic pathway, is a fundamental cellular process that regulates programmed cell death in response to internal stress signals such as DNA damage or growth factor deprivation [1, 2]. This pathway is governed by the B-cell lymphoma 2 (Bcl-2) family of proteins, which consists of three functional groups: anti-apoptotic members (e.g., Bcl-2, Bcl-xL, Mcl-1), pro-apoptotic effectors (Bax and Bak), and pro-apoptotic BH3-only initiators (e.g., Bim, Bad, Puma) [2, 7]. In healthy cells, anti-apoptotic proteins maintain survival by sequestering pro-apoptotic members, preventing them from forming pores in the mitochondrial outer membrane [1, 13]. However, in many cancers, the overexpression of anti-apoptotic proteins allows malignant cells to evade death and develop resistance to therapy [4, 12]. Drugs targeting this pathway, known as BH3-mimetics, function by binding to the hydrophobic grooves of anti-apoptotic proteins, thereby releasing pro-apoptotic factors to trigger mitochondrial outer membrane permeabilization (MOMP) and subsequent cell death [1, 15]. Venetoclax is a highly successful clinical example of a selective Bcl-2 inhibitor used to treat hematological malignancies [4, 13].

Other names

Intrinsic apoptotic pathwayMitochondrial apoptotic pathwayBcl-2 family-regulated pathwayPro-survival Bcl-2 pathway

BH3-mimetics that bind to and inhibit anti-apoptotic BCL-2 family proteins, thereby inducing mitochondrial outer membrane permeabilization and apoptosis.