The B cell lymphoma 2 (BCL‑2) gene family encodes more than 20 proteins that have a central role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals, and are fundamental to the balance between cell survival and death [1-3].
BCL2 was initially discovered as part of the t(14;18) chromosomal translocation, which occurs in patients with follicular lymphoma and diffuse large B cell lymphoma (DLBCL), and leads to elevated BCL2 transcription [4-5]. Although originally believed to act as a classical growth-driving oncogene, it was later shown that BCL2 instead promotes malignant cell survival by attenuating apoptosis [6-7]. Members of the BCL‑2 family are grouped together, as they contain up to four conserved BCL‑2 homology (BH) regions. The multi-region (BH1–4) anti-apoptotic proteins BCL‑2, BCL‑XL (also known as BCL‑2L1), BCL‑W (also known as BCL‑2L2), myeloid cell leukaemia 1 (MCL1) and A1 (also known as BCL‑2A1) antagonize pro-apoptotic BH3‑only proteins, and they inhibit the essential apoptosis effectors BCL‑2 antagonist killer  (BAK) and BCL‑2‑associated X protein (BAX) . BCL2 dysregulation results in the overexpression of the anti-apoptotic protein BCL‑2, which alters the balance between pro-apoptotic and anti-apoptotic members of the BCL‑2 family .
Fig1. The intrinsic apoptosis pathway. 
Programmed cell death, or apoptosis, is critical to both development and maintenance of tissues, as well as to the destruction of the cell when injured. The BCL-2 family proteins and the inhibitors of apoptosis proteins (AIPs) are the major regulators of the apoptotic process, whereas caspases, a family of cysteine proteases, are the major executioners of this process . Following activation of the intrinsic pathway by cellular stress, pro-apoptotic BCL‑2 homology 3 (BH3) ‑only proteins inhibit the anti-apoptotic proteins B cell lymphoma 2 (BCL‑2), BCL‑XL, BCL‑W and myeloid cell leukaemia 1 (MCL1). The subsequent activation and oligomerization of the pro-apoptotic proteins BCL‑2 antagonist killer 1 (BAK) and BCL‑2‑associated X protein (BAX) results in mitochondrial outer membrane permeabilization (MOMP). This results in the release of cytochrome c and second mitochondria-derived activator of caspase (SMAC; also known as DIABLO) from the mitochondria. Cytochrome c forms a complex with procaspase 9 and apoptosis protease-activating factor 1 (APAF1), which leads to the activation of caspase 9. Caspase 9 then activates procaspase 3 and procaspase 7, resulting in cell death. Inhibition of this process by anti-apoptotic BCL‑2 proteins occurs via sequestration of pro-apoptotic proteins through binding to their BH3 motifs. BIM, BCL‑2‑interacting mediator of cell death; XIAP, X‑linked inhibitor of apoptosis. [15, 17]
Nowadays, studies showed that the inhibition of apoptosis related Bcl-2 family proteins is thought to lead to chemoresistance  and has been identified in many cancers, including haematological malignancies  (such as multiple myeloma, chronic lymphocytic leukaemia (CLL), acute lymphocytic leukaemia (ALL), acute myeloid leukaemia (AML), myelodysplastic syndrome and myeloproliferative neoplasms) and solid tumours (such as breast cancer , lung cancer , melanoma  and mesothelioma . Therefore, as BCL‑2‑mediated resistance to intrinsic apoptosis is a hallmark of malignancy, targeting the anti-apoptotic BCL‑2 proteins is an attractive therapeutic strategy in cancer.