B-cell lymphoma 2 family proteins (Bcl-2 family)

The B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of the intrinsic (mitochondrial) apoptotic pathway, acting as a molecular rheostat to determine cell survival or death (Youle & Strasser, 2008). This family is categorized into three functional groups: anti-apoptotic members (e.g., Bcl-2, Bcl-xL, Mcl-1), pro-apoptotic effectors (Bax, Bak), and pro-apoptotic BH3-only initiators (e.g., Bim, Puma, Bid) (Czabotar et al., 2014). In many cancers, particularly hematologic malignancies, the overexpression of anti-apoptotic proteins allows cells to evade death signals and develop resistance to therapy (Montero & Letai, 2018). Therapeutic strategies focus on BH3 mimetics, small molecules that bind to the hydrophobic grooves of anti-apoptotic proteins to release pro-apoptotic effectors and trigger mitochondrial outer membrane permeabilization (MOMP) (Roberts et al., 2016). Venetoclax, a selective Bcl-2 inhibitor, has achieved significant clinical success in treating chronic lymphocytic leukemia and acute myeloid leukemia (Shamas-Din et al., 2013). However, targeting this machinery requires careful management of toxicities such as tumor lysis syndrome and lineage-specific cytopenias like thrombocytopenia (Kvansakul et al., 2014).

Other names

Bcl-2 familyB-cell CLL/lymphoma 2 familyMitochondrial apoptotic pathway proteinsBcl-2 family of apoptosis regulators

BH3 mimetics bind to the hydrophobic groove of anti-apoptotic Bcl-2 family proteins (such as Bcl-2, Bcl-xL, or Mcl-1), preventing them from sequestering pro-apoptotic proteins like Bax and Bak. This leads to the oligomerization of Bax/Bak, mitochondrial outer membrane permeabilization (MOMP), release of cytochrome c, and subsequent activation of the caspase cascade resulting in programmed cell death.