Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer
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 dysregulation of the anti-anti-apoptotic Bcl-2 family members is one of the defining features of cancer cells in comparison to nor...
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irk-123456789-1390832018-06-20T03:04:49Z Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer Weyhenmeyer, B. Murphy, A.C. Prehn, J.H.M. Murphy, B.M. Reviews 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 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. This anti-apoptotic subfamily of proteins is now a major target in the development of new methods to improve treatment outcomes 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. 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. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. 2012 Article Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer / B. Weyhenmeyer, A.C. Murphy, J.H.M. Prehn, B.M. Murphy // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 192-199. — Бібліогр.: 108 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/139083 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Reviews Reviews Weyhenmeyer, B. Murphy, A.C. Prehn, J.H.M. Murphy, B.M. Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer Experimental Oncology |
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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 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. This anti-apoptotic subfamily of proteins is now a major target in the development of new methods to improve treatment outcomes 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. 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. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. |
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Weyhenmeyer, B. Murphy, A.C. Prehn, J.H.M. Murphy, B.M. |
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Weyhenmeyer, B. Murphy, A.C. Prehn, J.H.M. Murphy, B.M. |
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Weyhenmeyer, B. |
| title |
Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer |
| title_short |
Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer |
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Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer |
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Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer |
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Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer |
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targeting the anti-apoptotic bcl-2 family members for the treatment of cancer |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer / B. Weyhenmeyer, A.C. Murphy, J.H.M. Prehn, B.M. Murphy // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 192-199. — Бібліогр.: 108 назв. — англ. |
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Experimental Oncology |
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192 Experimental Oncology 34, 192–199, 2012 (September)
TARGETING THE ANTI-APOPTOTIC BCL-2 FAMILY MEMBERS FOR
THE TREATMENT OF CANCER
B. Weyhenmeyer, A.C. Murphy, J.H.M. Prehn, B.M. Murphy*
Centre for Systems Medicine, Department of Physiology and Medical Physics, St. Stephen’s Green, Dublin 2, Ireland
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 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. This anti-apoptotic subfamily of proteins is now a major target in the development of new methods to improve treatment
outcomes 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. This Review presents the current knowledge of the role of the anti-apoptot-
ic 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. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
Key Words: apoptosis, Bcl-2 family, cancer, BH3 mimetics.
INTRODUCTION
The term apoptosis originates from the Greek ex-
pression “the falling of leaves from a tree” and refers
to an evolutionary preserved mechanism of controlled
cell deletion. It was first introduced into scientific litera-
ture in 1972, when John Kerr et al. published a detailed
description of the distinct morphological features
of dying cells; chromatin condensation, nuclear
fragmentation and cell shrinkage [1]. Cell death via
apoptosis plays a role in many diverse fundamental
processes. Apoptosis enables the removal of super-
fluous or damaged cells from the body of multicellular
organisms during embryogenesis and contributes
to cellular homeostasis [2–4]. Apoptosis is also essen-
tial in the defence against infectious microorganisms
and the removal of cancerous cells [5].
The demolition of a cell during apoptosis is primarily
achieved through the cleavage of numerous cellular
proteins by the proteolytic caspase (cysteinyl aspar-
tate proteinases) enzymes [6]. Two major pathways
lead to caspase activation in mammalian cells: the
extrinsic or death receptor pathway and the intrinsic
mitochondrial pathway [7]. 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]. Such association results in the recruitment
of adaptor proteins and either procaspase-8 or pro-
caspase-10 to form the death inducing signalling com-
plex (DISC) [8]. 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]. 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].
The intrinsic apoptotic pathway is primarily induced
by developmental cues and diverse cytotoxic events
including DNA damage and exposure to drugs or ra-
diation during cancer treatment, leading to changes
in Bcl-2 family interactions, which converge on the
outer mitochondrial membrane culminating in pore
formation [14]. Mitochondrial outer membrane per-
meabilisation (MOMP) results in the release of various
mitochondrial intermembrane space proteins, such
as cytochrome c [7]. 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]. In the presence
of (d)ATP, initiator procaspase-9 is recruited to the
complex and activated [16]. 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].
The majority of anti-cancer treatments act by in-
ducing stress signals that can activate the intrinsic mi-
tochondrial pathway of apoptosis in tumour cells [17].
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
Received: June 22, 2012
*Correspondence: Fax: 353 1 402 2447;
E-mail: bronamurphy@rcsi.ie
Abbreviations used: A1 — Bcl-2-related gene A1; Apaf-1 — apop-
totic protease-activating factor 1; Bad — Bcl-2-associated death
promoter; Bak — Bcl-2 homologuous agonist killer; Bax — Bcl-
2-associated-x protein; Bcl-2 — B cell lymphoma-2; Bcl-xL — Bcl-
2-related gene long isoform; BH — Bcl-2 homology; Bid — BH3 in-
teracting-domain death agonist; Bik — Bcl-2-interacting killer;
Bim — Bcl-2 interacting mediator of cell death; Bmf — Bcl-2 modi-
fying factor; Bok — Bcl-2 related ovarian killer; caspase — cys-
teinyl aspartate proteinase; DISC — death inducing signalling
complex; FasL — Fas ligand; Hrk — Harakiri; Mcl-1 — myeloid cell
leukemia-1; MOMP — mitochondrial outer membrane permeabili-
sation; PUMA — p53-upregulated modulator of apoptosis; tBid —
truncated Bid; TNF — tumour necrosis factor; TNF-R1 — tumour
necrosis factor-receptor 1.
Exp Oncol 2012
34, 3, 192–199
INVITED REVIEW
Experimental Oncology 34, 192–199, 2012 (September) 193
future perspectives on targeting the anti-apoptotic
Bcl-2 family of proteins for therapeutic intervention
in human malignancies.
Fig. 1. Caspase Activation Pathways. (A) Engagement of plasma
membrane-associated death receptors results in recruitment
and activation of procaspase-8 via the adaptor molecule
FADD. In type I cells, active caspase-8 can directly activate
procaspase-3. Active caspase-3 can then initiate a caspase
activation cascade. In type II cells, the reduced level of activated
caspase-8 cleaves the BH3-only protein Bid. This 15 kDa frag-
ment, tBid, activates the mitochondrial pathway by stimulating
cytochrome c release via Bax and/or Bak oligomerization and
insertion into the outer mitochondrial membrane. Once in the
cytoplasm cytochrome c promotes apoptosome assembly and
thus caspase activation. (B) Diverse forms of cellular stress,
(DNA damage, cytotoxic drugs, cytokine withdrawal), may
trigger the release of cytochrome c from mitochondria via the
death-promoting Bcl-2 family members, such as Bax and/
or Bak, oligomerization and insertion into the outer mitochondrial
membrane. Cytochrome c release from mitochondria is inhibited
by the death inhibitory Bcl-2 family members, such as Bcl-2 and
Bcl-xL. (Adapted from [110])
THE CLASSIFICATION OF THE
BCL-2 FAMILY OF PROTEINS
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]. Unsurpris-
ingly 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].
The name of this diverse family originates from their
first identified member, Bcl-2, an oncoprotein that was
activated via chromosome translocation in human fol-
licular lymphoma [21, 22]. 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]. 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). These anti-apoptotic proteins have
similar 3D structures, possess four BH domains,
and all promote cell survival by inactivating their pro-
apoptotic Bcl-2 family counterparts and preserving
outer mitochondrial membrane integrity [23]. The pro-
apoptotic Bcl-2 family members may be subdivided
into 2 classes: the multidomain effector proteins and
the BH3-only proteins. The multidomain members
include Bcl-2-associated-x protein (Bax), Bcl-2 ho-
mologuous 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]. Once activated,
the effector proteins, Bax and Bak promote apoptosis
by enabling pore formation within the mitochondrial
outer membrane [25].
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).
Fig. 2. Schematic representation of Bcl-2 family members.
Bcl-2 family members are the key regulators of cytochrome
c release from the mitochondria. As is illustrated, all members
of the family contain at least one of 4 BH domains, designated
BH1, BH2, BH3 and BH4. Some members also contain a trans-
membrane domain that tethers these proteins to intracellular
membranes. The anti-apoptotic members most similar to Bcl-2,
such as Bcl-xL contain all 4 BH domains. There are 2 very distinct
pro-apoptotic sub-families: the multidomain effectors and the
BH3-only subgroup. The multidomain effectors, Bax, Bak and
Bok are very similar to Bcl-2 and contain structural features
of all 4 BH domains. The “BH3-only” proteins such as Bad, Bid
and Bim contain a central BH3 domain that is essential for their
killing activity. The “BH3-only” proteins are a very diverse family.
(Adapted from [110])
BH3-only group members include, Bcl-2-as-
sociated 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).
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].
194 Experimental Oncology 34, 192–199, 2012 (September)
THE INTERACTIONS BETWEEN THE
BCL-2 FAMILY OF PROTEINS
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 exact mechanisms
of how Bcl-2 proteins interconnect to regulate MOMP
and apoptosis has been controversially discussed.
The “direct activation” model proposes that BH3-only
proteins Bim, truncated Bid (tBid) and maybe PUMA
act as “direct activators” of Bak/Bax and the rest of the
BH3-only proteins act as “sensitisers” or decoys but
do not directly activate Bax/Bak. 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]. 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 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. 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]. The more
recently proposed “embedded together” model
combines features of both. Under this model, BH3-
only sensitisers are thought to displace Bax and the
BH3-only activators from the anti-apoptotic proteins.
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. These important interactions occur at the
mitochondrial outer membrane [32, 33]. Although fur-
ther work is required to more thoroughly elucidate the
intricate interactions between the Bcl-2 family of pro-
teins, 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].
THE ROLE OF THE ANTI-APOPTOTIC
BCL-2 FAMILY PROTEINS IN CANCER
DEVELOPMENT AND MAINTENANCE
The discovery that Bcl-2 did not drive cell prolifera-
tion, 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]. 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]. BCL-2 transgenic mice develop
spontaneous tumours [37] and BCL-2 gene and
protein amplification has been discovered in vari-
ous malignancies, including chronic lymphocytic
leukaemias [38], small cell lung cancers [39], breast
carcinomas [40], non-Hodgkin’s lymphoma [41] and
glioblastomas [42]. Mcl-1 overexpression predisposes
mice to B-cell lymphomas [43]. In humans, Mcl-1 ex-
pression is markedly high in many cases of acute my-
eloid leukaemia and multiple myeloma, and diverse
cancers demonstrate overexpression of Mcl-1 and
BCL-x genes [44, 45]. Pertinently, it has also been
demonstrated that not only does the overexpression
of the anti-apoptotic members of the Bcl-2 fami-
ly play a role in cancer development; their elevated
expression can also be correlated with resistance
to cancer therapeutics, including chemotherapy and
radiotherapy [23, 46]. Miyashita and colleagues first
demonstrated the link between Bcl-2 and resistance
to DNA-damaging agents in various lymphoid cell
lines [47, 48]. 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]. More recent studies
have extended these observations even further with
evidence of “oncogene addiction”. This concept,
based on work from the laboratories of the late Stan-
ley 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. Under these circumstances, the upregula-
tion 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].
ANTI-APOPTOTIC BCL-2 FAMILY
MEMBERS AS TARGETS FOR THE
TREATMENT OF CANCERS
The outcome of these collective observations from
over three decades of research on Bcl-2 family pro-
teins is that these family members are now extremely
attractive targets for the treatment of numerous
cancers. 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]. Thus, treatment with molecules that
mimic the BH3 domain of the pro-apoptotic proteins
may potentially overcome the increase in anti-apop-
totic Bcl-2 proteins and thus induce cancer cell death.
The first drug developed to pharmacologically
inhibit Bcl-2 was Oblimersen sodium (G3139, Genas-
ense), an 18-mer antisense oligonucleotide designed
to target the first six codons of BCL-2 mRNA [56].
Initial preclinical and clinical studies showed that the
combination treatment of Oblimersen with a given
anti-cancer drug increased the chemotherapeutic
Experimental Oncology 34, 192–199, 2012 (September) 195
effect in various types of cancers [57–60]. 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]. Factors considered
as contributory to the failure of this drug included the
sole targeting of Bcl-2 by Oblimersen and the po-
tential increased expression of other anti-apoptotic
Bcl-2 family members as a result of the downregulation
in Bcl-2 expression. To circumvent these difficulties
efforts were next directed at neutralizing a broader
range of the anti-apoptotic Bcl-2 family members.
HA-141 was identified via in silico screens for
compounds that bound the hydrophobic groove
of Bcl-2 [62]. 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]. Additionally, in combination with
etoposide, HA14-1 has been demonstrated to slow
the growth of glioblastoma in vivo [64]. 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].
Gossypol, a polyphenol derived from the cotton-
seed plant, was the first natural compound discov-
ered that demonstrated inhibition of Bcl-2, Bcl-xL and
Mcl-1 [66]. Originally gossypol was studied as a male
contraceptive [67], but was later shown to have po-
tent anti-cancer effects [68, 69]. 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]. In preclinical
studies many groups have shown gossypol’s potent
pro-apoptotic activity [71, 72]. 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 can-
cer (SCLC) were disappointing [73]. More promising
results were achieved in a PhaseI/II trial, evaluating
AT-101 in prostate cancer [74] and when AT-101 was
administered in combination with docetaxel, in a Phase
II trial of non-small cell lung cancer [75]. Further
Phase I and II trials are ongoing to further evaluate
AT-101 in combination with conventional chemothera-
peutics across a range of malignancies, including small
and non-small cell lung cancers, chronic lymphocytic
leukaemia, prostate cancers and glioblastoma multi-
fome (AT-101, http://clinicaltrials.gov).
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 de-
rivative designed, to the more recent BI-97C1 (Sabu-
toclax). These compounds bind with even greater ef-
ficiency to the anti-apoptotic Bcl-2 family members but
do not confer the same level of toxicity [77, 78]. 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. Finally and of special interest are the observa-
tions 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 mi-
tochondrial pathway [80]. Autophagy has been sug-
gested as the mechanism by which gossypol induces
death in cells with very high levels of Bcl-2 [81]. While
not a direct focus of this review, autophagy is a sec-
ond process of cell death in which the Bcl-2 family
have also been described to play a role. Briefly, the
BH3-only protein, Beclin-1 is essential for the initiation
of autophagy and can be inhibited by binding to Bcl-2/
Bcl-xL at the endoplasmic reticulum [82–84]. Gossypol
has been shown to induce autophagy by blocking this
Bcl-2-Beclin 1 interaction [81].
The two Bcl-2 inhibitor drugs furthest in clinical
development are obatoclax (GX-15-70) from Gemin
X Biotechnologies and ABT-737 from Abbott. Obato-
clax 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]. This small molecule bipyrrole compound
has been shown to bind to Bcl-2, Bcl-x, Bcl-w and
Mcl-1 in vitro [86]. Preclinical experiments showed
that Obatoclax has pro-apoptotic effects when used
alone and enhances the in vitro efficacy of bortezo-
mib in human multiple myeloma [87] and mantle cell
lymphoma cell lines [88]. Obatoclax has been tested
in Phase I clinical trials in patients with haematological
and myeloid malignancies and was well tolerated [89,
90]. 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 eto-
poside in patients with extensive-stage small cell lung
cancer [92]. Again, the mechanism of action of this
putative anti-apoptotic Bcl-2 family inhibitor is not
fully understood as it has been shown to induce cell
death in the absence of Bax/Bak and caspase-9 [80].
Similar to gossypol, autophagy has also been sug-
gested as an alternative method of inducing cell death
which Obatoclax may utilize to kill cells under certain
circumstances [93].
ABT-737 was developed using nuclear magnetic
resonance to screen a chemical library for BH3-like
analogues that bound with high efficiency to the hy-
drophobic groove of Bcl-xL [94]. 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]. ABT-737 is extremely effective at en-
hancing 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]. However, drug delivery
is problematic for ABT-737 and resistance is observed
196 Experimental Oncology 34, 192–199, 2012 (September)
in cells that express Mcl-1 [96, 97]. To overcome the
delivery problems, ABT-263 (Navitoclax) was deve-
loped by Abbott for use in the clinic. 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 pro-
teins as ABT-737 [98]. 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]. Several strategies are also be-
ing developed to complement the activity of ABT-737,
by neutralizing Mcl-1 [99–101].
A number of Phase I and Phase II trials are currently
underway or have recently been completed evaluat-
ing the efficacy of ABT-263 as both a montherapeutic
and in combination with other chemotherapeutics
in patients with malignancies of lymphoid origin and
solid tumours (ABT-263, http://clinicaltrials.gov).
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 preclini-
cal studies [98] and in Phase I trials [102–104]. Due
to encouraging results of these Phase I trials, Phase
II trials are proceeding [102–104]. Importantly, unlike
the other BH3 mimetics discussed, ABT-737 has been
shown to act in a similar manner to other BH3-only
proteins and requires the presence of Bax/Bak and
caspase-9 to induce apoptosis which it is hoped will
lead to increased selectivity in its cytotoxicity towards
cancer cells [80, 97].
PREDICTING RESPONSES
TO BH3 MIMETICS
BH3 profiling was designed as a tool to understand
addiction to Bcl-2 family proteins [105]. Using this tech-
nique cell lines were divided into three classes based
on their specific anti-apoptotic block to the intrinsic
pathway of apoptosis. A “class A” block was defined
as one that arose from insufficient levels of BH3-only
proteins. A “class B” inhibition block developed after
significant loss of Bax and Bak. Finally, a “class C” block
occurred when the cells overexpressed anti-apoptotic
proteins [106, 107]. 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]. Such
experiments suggest that BH3 profiling could be a use-
ful 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].
CONCLUSIONS AND PERSPECTIVES
The observations that being dependent on, or ad-
dicted to an anti-apoptotic Bcl-2 family member can
lead to a cancer phenotype has resulted in the devel-
opment of many BH3 mimetics to treat a broad range
of haematological malignancies and solid tumors.
As discussed above clinical data has revealed some
to be more successful than others when trialed in pa-
tients. 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. Identifying the most
suitable drug combinations may be achieved by using
techniques such as BH3 profiling or a systems mod-
elling approach examining Bcl-2 family interactions.
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.
ACKNOWLEDGEMENTS
We thank our colleagues, Caoimhin Concannon
and Sean Kilbride for their helpful comments in the
preparation of this review.
FINANCIAL SUPPORT
This research was generously supported by grants
from the Health Research Board (RP/2008/69) and
the RCSI Research Committee (GR 08-0155) to BMM.
CONFLICT OF INTEREST
No conflicts to disclose.
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