B-cell lymphoma 2 family and caspase-mediated apoptosis regulators (BCL2/Caspase pathway)

The B-cell lymphoma 2 (BCL2) family and caspase-mediated apoptosis regulators are the primary controllers of programmed cell death in multicellular organisms [1, 2]. The BCL2 family consists of pro-apoptotic and anti-apoptotic proteins that regulate mitochondrial outer membrane permeabilization (MOMP), which is considered the point of no return in the intrinsic apoptotic pathway [3, 5]. Anti-apoptotic members like BCL2, BCL-XL, and MCL1 are frequently overexpressed in various cancers, allowing malignant cells to survive despite oncogenic stress or chemotherapy [5, 6]. Caspases are a family of cysteine-aspartic proteases that act as the executioners of apoptosis, activated downstream of MOMP or through extrinsic death receptor signaling [3]. Therapeutic intervention in this pathway has been highly successful with the development of BH3 mimetics, such as venetoclax, which selectively inhibit BCL2 to induce rapid apoptosis in hematologic malignancies [4, 6]. Conversely, caspase inhibitors are being explored to prevent pathological cell death in conditions like liver disease and neurodegeneration [3]. Sources: [1] UniProt P10415; [2] NCBI Gene ID 596; [3] StatPearls: Apoptosis; [4] PubChem CID 49846579; [5] Nature Reviews Molecular Cell Biology (2019) 20:175-193; [6] NEJM (2016) 374:311-322.

Other names

Apoptosis regulatorsBCL2 family proteinsCaspase cascade componentsIntrinsic and extrinsic apoptotic regulatorsProgrammed cell death machinery

Drugs targeting this pathway primarily act as BH3 mimetics that bind to the hydrophobic groove of anti-apoptotic BCL2 family members, displacing pro-apoptotic proteins to trigger mitochondrial outer membrane permeabilization and subsequent caspase activation [1, 4, 5]. Alternatively, caspase inhibitors bind to the active site of cysteine proteases to block the execution phase of cell death [3].