Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy

Abstract

Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic pathway. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins. Overexpression of anti-apoptotic Bcl-2 family members has been associated with chemotherapy resistance in various human cancers, and preclinical studies have shown that agents targeting anti-apoptotic Bcl-2 family members have preclinical activity as single agents and in combination with other antineoplastic agents. Clinical trials of several investigational drugs targeting the Bcl-2 family (oblimersen sodium, AT-101, ABT-263, GX15-070) are ongoing. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.

Fig. 1

The apoptotic pathway to cell death from the perspective of the Bcl-2 family of proteins.1, The intrinsic pathway is initiated by various signals, principally extracellular stimuli. 2, The extrinsic pathway is activated by Fas ligand or TRAIL, subsequently activating caspase-8. Caspase-8 transforms Bid into truncated Bid. In addition, caspase-8 initiates a cascade of caspase activation. 3, BH3-only proteins (Bim, Bid, Bad, Noxa, Puma) engage with anti-apoptotic Bcl-2 family proteins to relieve their inhibition of Bax and Bak to activate them. 4, Next, Bax and Bak are oligomerized and activated, leading to mitochondrial outer membrane permeabilization. 5, Once mitochondrial membranes are permeabilized, cytochrome c and/or Smac/DIABLO is released into the cytoplasm, wherein they combine with an adaptor molecule, apoptosis protease-activating factor 1, and an inactive initiator caspase, procaspase-9, within a multiprotein complex called the apoptosome. Smac/DIABLO inhibits inhibitors of apoptosis proteins to activate caspase-9. 6, Caspase-9 activates caspase-3, which is the initiation step for the cascade of caspase activation. Intrinsic and extrinsic pathways converge on caspase-3. Bcl-2 family proteins are also found on the endoplasmic reticulum and the perinuclear membrane in hematopoietic cells, but they are predominantly localized to mitochondria.