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A new clinical trial in which cancer patients are given a chemotherapy drug delivered directly into their tumors is giving hope to people with a highly aggressive type of brain cancer.Chris Amundsen is one of them. The term apoptosis originates from the Greek expression “the falling of leaves from a tree” and refers to an evolutionary preserved mechanism of controlled cell deletion.
The demolition of a cell during apoptosis is primarily achieved through the cleavage of numerous cellular proteins by the proteolytic caspase (cysteinyl aspartate proteinases) enzymes [6]. The majority of anti-cancer treatments act by inducing stress signals that can activate the intrinsic mitochondrial pathway of apoptosis in tumour cells [17].
The rapid and irreversible release of cytochrome c from mitochondria is generally recognised as the “point of no return” in the life of a cell [18]. Structurally, the BH3-only proteins are homologous to the rest of the Bcl-2 family members in only one small sequence, the BH3 domain (Fig. 2).
BH3-only group members include, Bcl-2-associated death promoter (Bad), BH3 interacting-domain death agonist (Bid), Bcl-2-interacting killer (Bik), Bcl-2 interacting mediator of cell death (Bim), Bcl-2 modifying factor (Bmf), Harakiri (Hrk), Noxa and p53-upregulated modulator of apoptosis (PUMA). Most cells express a variety of both anti-apoptotic and pro-apoptotic Bcl-2 proteins and the interaction between proteins within this family dictates whether a cell survives or dies [20].
The discovery that Bcl-2 did not drive cell proliferation, as for previously characterized oncogenes, but rather promoted cell survival, led to the realisation that the inhibition of apoptotic pathways was a critical step in tumourigenesis [35]. The outcome of these collective observations from over three decades of research on Bcl-2 family proteins is that these family members are now extremely attractive targets for the treatment of numerous cancers. The first drug developed to pharmacologically inhibit Bcl-2 was Oblimersen sodium (G3139, Genasense), an 18-mer antisense oligonucleotide designed to target the first six codons of BCL-2 mRNA [56].
HA-141 was identified via in silico screens for compounds that bound the hydrophobic groove of Bcl-2 [62]. Gossypol, a polyphenol derived from the cottonseed plant, was the first natural compound discovered that demonstrated inhibition of Bcl-2, Bcl-xL and Mcl-1 [66]. Gossypol has toxicity problems however, most likely due to two reactive aldehyde groups [76] and as a result many derivatives of gossypol have been generated, ranging from Apogossypol, the first derivative designed, to the more recent BI-97C1 (Sabutoclax).
The two Bcl-2 inhibitor drugs furthest in clinical development are obatoclax (GX-15-70) from Gemin X Biotechnologies and ABT-737 from Abbott. ABT-737 was developed using nuclear magnetic resonance to screen a chemical library for BH3-like analogues that bound with high efficiency to the hydrophobic groove of Bcl-xL [94]. BH3 profiling was designed as a tool to understand addiction to Bcl-2 family proteins [105].
The observations that being dependent on, or addicted to an anti-apoptotic Bcl-2 family member can lead to a cancer phenotype has resulted in the development of many BH3 mimetics to treat a broad range of haematological malignancies and solid tumors. We thank our colleagues, Caoimhin Concannon and Sean Kilbride for their helpful comments in the preparation of this review. The 37-year-old and his wife Laura sped up their wedding after he received the devastating news that has an often fatal brain cancer called glioblastoma.Chris and Laura Amundsen on their wedding day. Two major pathways lead to caspase activation in mammalian cells: the extrinsic or death receptor pathway and the intrinsic mitochondrial pathway [7]. This Review presents the current knowledge of how cancer cells overcome such treatment strategies, with particular reference to the role of the anti-apoptotic Bcl-2 family in this process, as well as current and future perspectives on targeting the anti-apoptotic Bcl-2 family of proteins for therapeutic intervention in human malignancies. Unsurprisingly therefore, the process of cytochrome c release from mitochondria is tightly controlled, primarily by the B cell lymphoma-2 (Bcl-2) family of proteins [19, 20].
BH3-only protein signalling is essential for the initiation of the mitochondrial apoptotic pathway, but MOMP requires the presence of either Bax or Bak [25–27].
The exact mechanisms of how Bcl-2 proteins interconnect to regulate MOMP and apoptosis has been controversially discussed. Indeed many studies have since highlighted that the dysregulation of Bcl-2 and other anti-anti-apoptotic family members is one of the key defining features of cancer cells in comparison to normal cells [36]. As previously mentioned, structural studies have elucidated a hydrophobic groove on the surface of anti-apoptotic Bcl-2 family proteins that binds the BH3 dimerization domain of pro-apoptotic family members [20]. Initial preclinical and clinical studies showed that the combination treatment of Oblimersen with a given anti-cancer drug increased the chemotherapeutic effect in various types of cancers [57–60]. In preclinical studies it has been shown to inhibit the binding of Bcl-2 and Bcl-x to Bax and Bak [63, 64] and induce apoptosis in a wide variety of cancer cells, including glioma cells [64] and colon cancer cells [65]. Originally gossypol was studied as a male contraceptive [67], but was later shown to have potent anti-cancer effects [68, 69].
These compounds bind with even greater efficiency to the anti-apoptotic Bcl-2 family members but do not confer the same level of toxicity [77, 78]. Obatoclax was discovered as a result of a high-throughput screen of natural compounds that disrupted protein interactions in the Bcl-2 family and was the first pan anti-apoptotic Bcl-2 protein inhibitor to be described [85].
ABT-737 does not inhibit Mcl-1 but binds to and inhibits Bcl-2, Bcl-xL and Bcl-w with nanomolar affinities, closely resembling the BH3 domain of Bad and representing a far greater potency of action than for the previously discussed compounds [80]. Thrombocytopenia, attributable to the high-affinity inhibition of Bcl-xL in platelets, has been recognised as a dose-limiting side effect of ABT-263 in preclinical studies [98] and in Phase I trials [102–104].
Using this technique cell lines were divided into three classes based on their specific anti-apoptotic block to the intrinsic pathway of apoptosis. As discussed above clinical data has revealed some to be more successful than others when trialed in patients.
Most cells express a variety of both anti-apoptotic and pro-apoptotic Bcl-2 proteins and the interaction within this family dictates whether a cell survives or dies. The extrinsic apoptotic pathway can be induced by the association of death receptors belonging to the tumour necrosis factor (TNF) receptor superfamily, such as Fas or TNF-R1 and their respective ligands, FasL and TNF-alpha [8, 9]. The name of this diverse family originates from their first identified member, Bcl-2, an oncoprotein that was activated via chromosome translocation in human follicular lymphoma [21, 22]. BCL-2 transgenic mice develop spontaneous tumours [37] and BCL-2 gene and protein amplification has been discovered in various malignancies, including chronic lymphocytic leukaemias [38], small cell lung cancers [39], breast carcinomas [40], non-Hodgkin’s lymphoma [41] and glioblastomas [42].
Thus, treatment with molecules that mimic the BH3 domain of the pro-apoptotic proteins may potentially overcome the increase in anti-apoptotic Bcl-2 proteins and thus induce cancer cell death.
However, after failing to result in survival differences in a pivotal melanoma trial this agent did not obtain US Food and Drug Administration approval [61]. Additionally, in combination with etoposide, HA14-1 has been demonstrated to slow the growth of glioblastoma in vivo [64]. Natural gossypol is a racemic mixture and studies have found that the levo enantiomer (l-gossypol) has more potent pro-apoptotic effects than d-gossypol [70]. While preclinical results are promising [79], at present there are no reports on clinical trials using such derivatives but it is expected that these derivatives will enter trials soon. This small molecule bipyrrole compound has been shown to bind to Bcl-2, Bcl-x, Bcl-w and Mcl-1 in vitro [86].
ABT-737 is extremely effective at enhancing the response to radiation as well as a variety of chemotherapy agents in many different cancer cell lines in vitro, and displayed significant activity as a monotherapeutic in two small-cell lung cancer xenograft models [94, 95].
Due to encouraging results of these Phase I trials, Phase II trials are proceeding [102–104].
A “class A” block was defined as one that arose from insufficient levels of BH3-only proteins.
Evidence also indicates that a single BH3 mimetic may not be sufficient as a monotherapeutic to cure cancer patients and the best results may be achieved by appropriate drug combinations.
Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.
Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.
Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.

Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.
Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). In vivo patterns of Bcl-2 family protein expression in breast carcinomas in relation to apoptosis. BCL2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma.
BCL-2 family protein expression in initial and recurrent glioblastomas: modu­lation by radiochemotherapy. MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Bcl-xL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice. Mcl-1, a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia.
A Phase I pharmacokinetic and biological correlative study of oblimersen sodium (genasense, g3139), an antisense oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer. A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer.
Oblimersen: Augmerosen, BCL-2 antisense oligonucleotide — Genta, G 3139, GC 3139, oblimersen sodium. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells.
The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis is inhibited by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human colon cancer cells.
Gossypol and some other terpenoids, flavonoids and phenols that affect quality of cottonseed protein. Biochemical correlates of the antitumor and antimitochondrial properties of gossypol enantiomers. Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells. Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-x(L) [(-)-gossypol] against diffuse large cell lymphoma. A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer.
Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048).
The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Crystal structure of the Bcl-xL -Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein.
Modulating the bcl-2 family of apoptosis suppressors for potential therapeutic benefit in cancer. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Experience with obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma. A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance.
Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo.
Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Synergistic antitumor activity of gemcitabine and ABT-737 in vitro and in vivo through disrupting the interaction of USP9X and Mcl-1. Actinomycin D decreases Mcl-1 expression and acts synergistically with ABT-737 against small cell lung cancer cell lines. Mcl-1 phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B cells.
Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour acti­vity.
Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. BH3 profiling — Measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. They found an experimental drug treatment program at Lenox Hill Hospital in New York City directed by Dr. The dysregulation of the anti-anti-apoptotic Bcl-2 family members is one of the defining features of cancer cells in comparison to normal cells, and significantly contributes to the resistance of cancer cells to current treatment modalities. Such association results in the recruitment of adaptor proteins and either procaspase-8 or procaspase-10 to form the death inducing signalling complex (DISC) [8].
To date, there are 25 known proteins in the Bcl-2 family that can be subdivided into 3 groups, according to their pro- and anti-apoptotic effects and the presence of Bcl-2 homology (BH) domains [23]. As is illustrated, all members of the family contain at least one of 4 BH domains, designated BH1, BH2, BH3 and BH4. Such “sensitisers” prevent the antiapoptotic Bcl-2-like proteins from binding to the activators, thus freeing these proteins to interact with and activate Bak and Bax, leading to MOMP and cytochrome c release [28, 29]. Factors considered as contributory to the failure of this drug included the sole targeting of Bcl-2 by Oblimersen and the potential increased expression of other anti-apoptotic Bcl-2 family members as a result of the downregulation in Bcl-2 expression. However, the binding affinity of this compound for Bcl-2 is quite high and is significantly higher than affinities of other inhibitors for Bcl-2 [62].
In preclinical studies many groups have shown gossypol’s potent pro-apoptotic activity [71, 72]. Finally and of special interest are the observations by Vogler and colleagues that gossypol and its derivatives may kill even in the absence of Bak and Bax, indicating that the mechanisms of action of these drugs may in fact be independent of the intrinsic mitochondrial pathway [80]. Preclinical experiments showed that Obatoclax has pro-apoptotic effects when used alone and enhances the in vitro efficacy of bortezomib in human multiple myeloma [87] and mantle cell lymphoma cell lines [88]. However, drug delivery is problematic for ABT-737 and resistance is observed in cells that express Mcl-1 [96, 97].
Identifying the most suitable drug combinations may be achieved by using techniques such as BH3 profiling or a systems modelling approach examining Bcl-2 family interactions.
John Boockvar, and Amundsen soon enrolled."So this clinical trial is novel because we're giving a high dose of the medication that we normally give by mouth directly into the tumor," Boockvar said.

This anti-apoptotic subfamily of proteins is now a major target in the development of new methods to improve treatment outcomes for cancer patients.
Apoptosis enables the removal of superfluous or damaged cells from the body of multicellular organisms during embryogenesis and contributes to cellular homeostasis [2–4]. Depending on the cell type, extrinsic apoptotic signalling can proceed via two pathways: in type I cells, active caspase-8 cleaves and activates executioner caspase-3, directly leading to nuclear fragmentation and ultimately cell death [10, 11]. The anti-apoptotic Bcl-2-like proteins, comprise 1 group and has amongst its members Bcl-2, Bcl-2-related gene long isoform (Bcl-xL), Bcl-w, myeloid cell leukemia-1 (Mcl-1) and Bcl-2-related gene A1 (A1).
Some members also contain a transmembrane domain that tethers these proteins to intracellular membranes.
The second “derepression” model suggests that Bax and Bak are always active and the anti-apoptotic proteins prevent cell death by binding to them.
In humans, Mcl-1 expression is markedly high in many cases of acute myeloid leukaemia and multiple myeloma, and diverse cancers demonstrate overexpression of Mcl-1 and BCL-x genes [44, 45]. To circumvent these difficulties efforts were next directed at neutralizing a broader range of the anti-apoptotic Bcl-2 family members. However, the results of a Phase II clinical trial in which, L-gossypol (AT-101, Ascenta) was tested in patients with recurrent chemosensitive extensive-stage small cell lung cancer (SCLC) were disappointing [73]. Autophagy has been suggested as the mechanism by which gossypol induces death in cells with very high levels of Bcl-2 [81]. Obatoclax has been tested in Phase I clinical trials in patients with haematological and myeloid malignancies and was well tolerated [89, 90]. To overcome the delivery problems, ABT-263 (Navitoclax) was deve­loped by Abbott for use in the clinic. Finally, a “class C” block occurred when the cells overexpressed anti-apoptotic proteins [106, 107].
Undoubtedly further understanding of this subfamily of proteins is needed to exploit the potential offered by their successful targeting and ultimately deliver improved therapies for cancer patients.
Several drugs directed at inhibiting Bcl-2 and related anti-apoptotic proteins have been developed with some showing considerable promise in the clinic. Apoptosis is also essential in the defence against infectious microorganisms and the removal of cancerous cells [5]. In type II cells, active caspase-8 cleaves the BH3-only protein Bid to fom truncated Bid (tBid), which activates the intrinsic mitochondrial apoptotic pathway [12, 13]. In type II cells, the reduced level of activated caspase-8 cleaves the BH3-only protein Bid. These anti-apoptotic proteins have similar 3D structures, possess four BH domains, and all promote cell survival by inactivating their proapoptotic Bcl-2 family counterparts and preserving outer mitochondrial membrane integrity [23]. In this model the role of the BH3-only proteins is to target and bind the anti-apoptotic Bcl-2 family members to release active Bak and Bax. Pertinently, it has also been demonstrated that not only does the overexpression of the anti-apoptotic members of the Bcl-2 fami­ly play a role in cancer development; their elevated expression can also be correlated with resistance to cancer therapeutics, including chemotherapy and radiotherapy [23, 46].
While not a direct focus of this review, autophagy is a second process of cell death in which the Bcl-2 family have also been described to play a role. In a more recent phase II study in patients with relapsed or refractory classical Hodgkin lymphoma, obatoclax displayed limited clinical activity [91] but more promising results were observed in a phase I trial of obatoclax in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer [92]. ABT-263 is an oral version of ABT-737 and shares a similar binding profile and affinities to purified Bcl-2, Bcl-xL and Bcl-w proteins as ABT-737 [98].
Further investigations highlighted that BH3 profiling correctly identified those cell lines that were Bcl-2 dependent based on correlation with response to the Bcl-2 antagonist ABT-737 [108]. This Review presents the current knowledge of the role of the anti-apoptotic Bcl-2 family in cancer cells, as well as current and future perspectives on targeting this subfamily of proteins for therapeutic intervention in human malignancies. The intrinsic apoptotic pathway is primarily induced by developmental cues and diverse cytotoxic events including DNA damage and exposure to drugs or radiation during cancer treatment, leading to changes in Bcl-2 family interactions, which converge on the outer mitochondrial membrane culminating in pore formation [14]. The pro-apoptotic Bcl-2 family members may be subdivided into 2 classes: the multidomain effector proteins and the BH3-only proteins. There are 2 very distinct pro-apoptotic sub-families: the multidomain effectors and the BH3-only subgroup. While certain members of the BH3-only family (Bim, PUMA and tBid) can bind to all anti-apoptotic proteins, other proteins, such as Bad and Noxa, only interact with a specific Bcl-2 protein family member to regulate MOMP [30, 31].
Miyashita and colleagues first demonstrated the link between Bcl-2 and resistance to DNA-damaging agents in various lymphoid cell lines [47, 48]. Furthermore, ABT-263 has demonstrated activity as a single agent in small cell lung cancer orthotopic tumour models and has been shown to enhance the activity of chemotherapy agents in cancer cell lines [98]. Such experiments suggest that BH3 profiling could be a useful in the clinic as a diagnostic tool as it could potentially be used to predict patient response to an antagonist of an anti-apoptotic protein [105, 109]. Mitochondrial outer membrane permeabilisation (MOMP) results in the release of various mitochondrial intermembrane space proteins, such as cytochrome c [7]. Once in the cytoplasm cytochrome c promotes apoptosome assembly and thus caspase activation. The multidomain members include Bcl-2-associated-x protein (Bax), Bcl-2 homologuous agonist killer (Bak) and the much less studied, Bcl-2 related ovarian killer (Bok) and contain structural features of all four BH domains, similar to the antiapoptotic proteins [24]. The multidomain effectors, Bax, Bak and Bok are very similar to Bcl-2 and contain structural features of all 4 BH domains. Since then overexpression of Bcl-2, Bcl-xL or Mcl-1 has been shown to protect against many diverse anti-cancer agents, in both mice [49–52] and humans, reviewed in [23, 53]. Gossypol has been shown to induce autophagy by blocking this Bcl-2-Beclin 1 interaction [81].
Similar to gossypol, autophagy has also been suggested as an alternative method of inducing cell death which Obatoclax may utilize to kill cells under certain circumstances [93]. Several strategies are also being developed to complement the activity of ABT-737, by neutralizing Mcl-1 [99–101].
Released cytochrome c binds to apoptotic protease-activating factor 1 (Apaf-1), thereby inducing the oligomerisation of Apaf-1 and the formation of the apoptosome [15].
Once activated, the effector proteins, Bax and Bak promote apoptosis by enabling pore formation within the mitochondrial outer membrane [25].
The “BH3-only” proteins such as Bad, Bid and Bim contain a central BH3 domain that is essential for their killing activity. Under this model, BH3-only sensitisers are thought to displace Bax and the BH3-only activators from the anti-apoptotic proteins. More recent studies have extended these observations even further with evidence of “oncogene addiction”.
In the presence of (d)ATP, initiator procaspase-9 is recruited to the complex and activated [16]. Cytochrome c release from mitochondria is inhibited by the death inhibitory Bcl-2 family members, such as Bcl-2 and Bcl-xL.
Bax is then free to oligomerise and the BH3-only activators can bind and recruit additional Bax, which also oligomerises, resulting in pore formation and MOMP. This concept, based on work from the laboratories of the late Stanley Korsmeyer and Anthony Letai, implies that even in the absence of an anti-cancer agent, many cancer cells are addicted to the presence of Bcl-2 proteins and their survival is dependent on the activity of these oncogenes. Active caspase-9 in turn triggers the activation of executioner caspases, caspase-3 and -7, leading to a cascade of caspase-mediated cleavage reactions that lead to cell death (Fig. 1) [16]. Under these circumstances, the upregulation of proapoptotic Bcl-2 family members in response to oncogenic signals in tumour cells is not sufficient to overcome the increased antiapoptotic Bcl-2 family protein signalling within the cells [54, 55]. Although further work is required to more thoroughly elucidate the intricate interactions between the Bcl-2 family of proteins, the shared theme of all proposed models is the engagement of anti-apoptotic Bcl-2 family members by the BH3-only subfamily of proteins.
Anti-apoptotic Bcl-2 family members contain a hydrophobic binding pocket, formed by the folding of their BH1, BH2 and BH3 domains and BH3-only proteins can bind into this groove via their BH3 domain [20, 26, 34].
When the abundance of active pro-apoptotic Bcl-2 family proteins exceeds the binding capacity of the anti-apoptotic Bcl-2 family proteins, MOMP occurs and the mitochondrial pathway of apoptosis proceeds [20].

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