Targeting anti‐apoptotic BCL2 family proteins in haematological malignancies – from pathogenesis to treatment

Abstract

The B-cell lymphoma 2 (BCL2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting of BCL2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti-apoptotic functions of BCL2 proteins using structure-based design to produce specific inhibitors of protein-protein interactions has been achieved for BCL2, MCL1 and BCL-X (also termed BCL2L1), providing an armamentarium of new targeted therapies called BH3-mimetics. The first BCL2-specific inhibitor, venetoclax, has shown extraordinary single agent activity in chronic lymphocytic leukaemia (CLL), with surprisingly little toxicity given the expression of BCL2 in normal tissues. Despite success in CLL, where sensitivity to BCL2 inhibition is seen in nearly all cases, key questions have not yet been addressed. For example, responses to venetoclax in other B-cell and myeloid malignancies are heterogeneous, highlighting the need to identify biomarkers that correlate with response and, secondly, to identify/develop other specific compounds that synergise with BCL2 inhibition. In this review, we summarise the biology of BCL2 proteins, the mechanism of action of BH3-mimetics and the status of their clinical development in haematological malignancies.

MicroRNA Let-7i Is a Promising Serum Biomarker for Post-stroke Cognitive Impairment and Alleviated OGD-Induced Cell Damage in vitro by Regulating Bcl-2

“…Bcl-2 as an anti-apoptotic protein plays an important role in apoptosis regulatory (Vogler et al, 2017). In the present study, we observed the increase of Bcl-2 by the up-regulation of miRlet-7i.…”

Nonconserved miR‐608 suppresses prostate cancer progression through RAC2/PAK4/LIMK1 and BCL2L1/caspase‐3 pathways by targeting the 3′‐UTRs of RAC2/BCL2L1 and the coding region of PAK4

“…To prevent the opening of the mitochondrial outer membrane, BCL2L1 binds to Bax and Bak and inhibits their oligomerization, and thus functions as an antiapoptotic factor. 49 We demonstrated the upregulation of BCL2L1 in PCa in comparison with peritumoral tissues. MiR-608 overexpression induced significant apoptosis in PCa by directly targeting BCL2L1 through BCL2L1/ caspase-3 signaling pathway.…”

“…Next, caspase‐3 is activated by cytochrome C and initiates serial downstream apoptotic responses. To prevent the opening of the mitochondrial outer membrane, BCL2L1 binds to Bax and Bak and inhibits their oligomerization, and thus functions as an antiapoptotic factor . We demonstrated the upregulation of BCL2L1 in PCa in comparison with peritumoral tissues.…”

Effect of TW37 on the growth of H1975 EGFR‑TKI‑resistant lung cancer cells and its underlying mechanisms

“…The balance of cell survival and apoptosis signaling pathways is critical for determining the fate of cells, and multiple genes and molecules are involved in the regulation of this balance (25). Bcl-2 family proteins serve key roles in regulating cell apoptosis (26), and the results of the present study indicated that TW37 reduced the expression levels of the anti-apoptotic protein Bcl-2, as well as induced apoptosis of H1975/EGFR-TKI cells.…”