Oncogene (2006) 25, 4812–4830
& 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00
www.nature.com/onc
REVIEW
Mitochondria as therapeutic targets for cancer chemotherapy
L Galluzzi, N Larochette, N Zamzami and G Kroemer
CNRS-FRE 2939, Institut Gustave Roussy, Villejuif, France
Mitochondria are vital for cellular bioenergetics and play
a central role in determining the point-of-no-return of the
apoptotic process. As a consequence, mitochondria exert a
dual function in carcinogenesis. Cancer-associated
changes in cellular metabolism (the Warburg effect)
influence mitochondrial function, and the invalidation of
apoptosis is linked to an inhibition of mitochondrial outer
membrane permeabilization (MOMP). On theoretical
grounds, it is tempting to develop specific therapeutic
interventions that target the mitochondrial Achilles’ heel,
rendering cancer cells metabolically unviable or subverting
endogenous MOMP inhibitors. A variety of experimental
therapeutic agents can directly target mitochondria,
causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds
including positively charged a-helical peptides, agents
designed to mimic the Bcl-2 homology domain 3 of Bcl-2like proteins, ampholytic cations, metals and steroid-like
compounds. Such MOMP inducers or facilitators can
induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents.
In addition, it is possible to design molecules that
neutralize inhibitor of apoptosis proteins (IAPs) or heat
shock protein 70 (HSP70). Such IAP or HSP70 inhibitors
can mimic the action of mitochondrion-derived mediators
(Smac/DIABLO, that is, second mitochondria-derived
activator of caspases/direct inhibitor of apoptosis-binding
protein with a low isoelectric point, in the case of IAPs;
AIF, that is apoptosis-inducing factor, in the case of
HSP70) and exert potent chemosensitizing effects.
Oncogene (2006) 25, 4812–4830. doi:10.1038/sj.onc.1209598
Keywords: apoptosis; Bcl-2; caspases; cell death; p53;
permeability transition
Introduction
In recent times, molecular genetic evidence in favor of a
direct implication of mitochondria in oncogenesis has
been accumulating. Some polymorphisms in mitochonCorrespondence: Dr G Kroemer, CNRS-FRE 2939, Institut Gustave
Roussy, Pavillon de Recherche 1, 39, rue Camille Desmoulins, F-94805
Villejuif, France.
E-mail: [email protected]
drial DNA influence the susceptibility to breast (Canter
et al., 2005) and prostate cancer (Petros et al., 2005).
Mitochondrial DNA transversion mutations are associated with familial medullary thyroid carcinoma (AbuAmero et al., 2005). The nucleus-encoded fumarate and
succinate dehydrogenases genes (which code for mitochondrial enzymes) have been identified as tumorsuppressor genes that inhibit the development of renal
cancer and pheochromocytoma, respectively (Isaacs
et al., 2005; Lenders et al., 2005). The targeted
disruption of frataxin in the liver has been shown to
induce hepatocellular carcinoma in mice (Thierbach
et al., 2005). These examples illustrate how mitochondrial genes and proteins can impact on oncogenesis.
Cancer cells manifest a series of metabolic changes,
one of which is the so-called Warburg effect. Accordingly, even in the presence of oxygen, cancer cells tend to
synthesize ATP mainly through anaerobic glycolysis, a
phenomenon that requires high glucose uptake and
causes local acidification owing to lactate production
(Warburg, 1930, 1956). The Warburg effect may involve
a series of metabolic defects including unregulated,
supernormal glucose uptake with upregulation of the
rate-limiting steps of glycolysis (for instance driven by
constitutive activation of the Akt pathway) (Elstrom
et al., 2004), as well as defects in mitochondrial
respiration, as they manifest in cancer cells.
Cancer cells also tend to disable the mitochondrial
pathway of apoptosis by suppressing signals that can
cause mitochondrial outer membrane permeabilization
(MOMP), which constitutes (one of) the major event(s)
sealing the cell’s fate (Ferri and Kroemer, 2001a).
Multistep tumorigenesis, as recapitulated in vitro, is
intrinsically linked to apoptosis resistance (Hahn et al.,
1999), progressive dependence on glycolytic energy
production and independence from mitochondrial energy production (Ramanathan et al., 2005). On theoretical grounds, there are two mechanisms that can link
the Warburg phenomenon to MOMP inhibition. On the
one hand, it is conceivable that the metabolic alterations
and MOMP inhibition are acquired independently. In
this scenario, mutations of mitochondrial DNA would
increase the likelihood of cancer cells to undergo
apoptosis (Kujoth et al., 2005), and only cells in which
the apoptotic pathways are suppressed might be fit
enough to participate in oncogenesis. On the other
hand, the Warburg phenomenon could be mechanistically linked to MOMP inhibition. One connection is
provided by hexokinase II, a glycolytic enzyme that may
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participate in the Warburg phenomenon and that also
can interact with mitochondrial membranes to inhibit
MOMP (Robey and Hay, 2005). Another link is given
by pathogenic mutations in the mitochondrial genome
that may reduce spontaneous apoptosis in cancer cell
lines (Shidara et al., 2005).
Here, we will consider the cancer-relevant regulation
of MOMP and discuss the molecular mode of action of
MOMP inducers and of agents that enhance the
proapoptotic activity of mitochondrial death effectors.
Mitochondrial membrane permeabilization: the central
event of apoptosis
The most commonly used cancer therapeutics eliminate
tumors by inducing apoptosis (Green and Kroemer,
2004, 2005). Chemotherapy and radiation therapy, for
instance, cause DNA damage, leading to activation of
the proapoptotic members of the B-cell lymphoma
protein 2 (Bcl-2) superfamily – a process known as the
cell-intrinsic pathway. Other cancer drugs are designed
to engage cell surface death receptors and activate
apoptosis through a p53-independent signaling mechanism known as the cell-extrinsic pathway. Most chemotherapy agents and irradiation trigger tumor cell
apoptosis through the intrinsic pathway, as an indirect
consequence of cellular damage. Both apoptotic signaling pathways involve mitochondrial membrane permeabilization, a process also referred to as the ‘central
executioner’ of apoptosis (Green and Kroemer, 1998;
Ferri and Kroemer, 2001b) (Figure 1). During this
process, the mitochondrial outer membrane (OM) and
inner membrane (IM) are both permeabilized, resulting
in the release of soluble proteins from the intermembrane space. As a consequence, a number of proteases
and nucleases are activated to begin the process of
breaking down the cell (Patterson et al., 2000). MOMP
culminates in the complete loss of the barrier function of
the OM and the consequent release of potentially toxic
proteins, which normally are secured in the intermembrane space. Such cytotoxic proteins include caspaseindependent death effectors (nucleases and proteases) as
Figure 1 Schematic overviews of the interactions involved in mitochondrial apoptosis converging on the PTPC (upper panel) and p53
(lower panel). Please refer to the text for additional details. Abbreviations: ANT, adenine nucleotide translocator; Bak, Bcl-2
antagonist/killer; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2 protein; BH3, Bcl-2 homology domain 3; CK, creatine
kinase; CypD, cyclophilin D; GSK3b, glycogen synthase kinase 3b; HK, hexokinase; Mn-SOD, manganese-dependent superoxide
dismutase; mtCLIC/CLIC4, mitochondrial chloride intracellular channel/chloride intracellular channel 4; p53AIP1, p53-regulated
apoptosis-inducing protein 1; PBR, peripheral-type benzodiazepine receptor; PTPC, permeability transition pore complex.
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well as caspase activators, namely cytochrome c (cyt c,
which activates the so-called apoptosome, a caspase
activation complex including dATP, apoptosis-protease
activating factor 1, that is Apaf-1, and procaspase-9),
second mitochondria-derived activator of caspases/
direct inhibitor of apoptosis-binding protein with a
low isoelectric point (Smac/DIABLO) and the high
temperature requirement protein A2 (Omi/HtrA2)
(which both function as inhibitors of caspase-inhibitory
IAPs) (Danial and Korsmeyer, 2004). The consequence
of a partial IM permeabilization, which does not result
in the release of matrix proteins but contribute to cell
death, is that mitochondria lose their vital metabolic and
redox functions (Zamzami et al., 1995; Metivier et al.,
1998; Poncet et al., 2003). Mitochondrial permeabilization is therefore recognized as a crucial checkpoint
in programmed cell death of both normal and cancer
cells.
Dozens or perhaps hundreds of signal transducing
molecules act on mitochondria to induce or to inhibit
MOMP (Tables 1 and 2). Although many of the factors
that regulate mitochondrial permeabilization are
known, the exact molecular mechanisms are controversial (Green and Kroemer, 2004; Perfettini et al., 2005;
Zamzami et al., 2005). During recent years, some
insights into how MOMP is regulated have been gained.
Bax and Bak. Mouse embryonic fibroblasts (MEF)
lacking both Bcl-2-associated X protein (Bax) and Bcl-2
antagonist/killer (Bak), two tumor-suppressor gene
products from the proapoptotic arm of the Bcl-2 family,
are resistant to different types of apoptotic stimuli (Wei
et al., 2001; Boya et al., 2005) and are more susceptible
to rat sarcoma viral oncogene homolog (Ras)-mediated
transformation than control cells (Zong et al., 2001).
Bak is normally associated with OM, where it interacts
with the voltage-dependent anion channel isoform 2
(VDAC2), which prevents its activation (Cheng et al.,
2003). Upon apoptosis induction Bak fully inserts into
OM, as a result of a conformational change. Bax
translocates from the cytosol to OM where it inserts and
oligomerizes. Recombinant Bax can permeabilize liposomal membranes and form channels in planar lipid
bilayers. Such studies suggested that Bax alone (Saito
et al., 2000) (or associated with VDAC) (Shimizu et al.,
1999) would form a conduit selective for small proteins
such as cyt c (14.5 kDa). Bax combined with another
proapoptotic protein of the Bcl-2 family, t-Bid, can
permeabilize cardiolipin-containing liposomes in vitro to
fluorescent dextran of size up to 2000 kDa (Kuwana
et al., 2002), correlating with the fact that apoptotic
MOMP occurring in true cells is nonselective and affects
all soluble intermembrane proteins, irrespective of their
size (Patterson et al., 2000). The mechanisms of
membrane permeabilization induced in isolated mitochondria exposed to recombinant Bax depends on its
oligomerization status, although oligomerization by
itself may be insufficient for the induction of MOMP
(Poncet et al., 2004). Bax oligomers trigger cyclosporin
A (CsA)-resistant cyt c release, while Bax monomers
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cause permeabilization through a pathway that can be
inhibited by CsA (Gogvadze et al., 2001). This suggests
a functional interaction between Bax and the CsAsensitive permeability transition pore complex (PTPC)
(Marzo et al., 1998b; Belzacq et al., 2003). Another
protein outside of the PTPC that may be required for
Bax-mediated MOMP is the so-called modulator of
apoptosis 1 (MAP-1) (Baksh et al., 2005; Tan et al.,
2005).
Other proapoptotic Bcl-2 family members. Truncated
Bid (t-Bid) is thought to induce apoptosis through the
induction of a conformational change in Bax (or Bak),
thereby triggering its full membrane insertion and
oligomerization (Wei et al., 2000). Accordingly, Bax/
Bak/ MEF are relatively resistant to t-Bid-induced
cyt c release (Cheng et al., 2001). Nevertheless, it has
also been suggested that t-Bid forms membrane-inserted
homotrimers that do not interact with other mitochondrial proteins (Grinberg et al., 2002). Moreover, t-Bid
can form channels in planar lipid bilayers (Schendel
et al., 1999) and destabilize them (Kudla et al., 2000).
The question of whether t-Bid’s effects on mitochondria
depend on interactions with sessile mitochondrial
proteins, including a CsA target, has been controversial
(Zamzami et al., 2000). One study indicates that t-Bidmediated permeabilization occurs in a two-step process,
the first step (CsA-independent) leading to a partial
(B15%) cyt c release, and the second step (CsAsensitive) causing the total cyt c release and remodeling
of the mitochondrial ultrastructure (Scorrano et al.,
2002). t-Bid-mediated MOMP has also been reported to
involve obligatory interactions with carnitine palmitoyl
transferase 1 (Giordano et al., 2005) or mitochondrial
carrier homolog 2 (Grinberg et al., 2005). Other
proapoptotic proteins from the Bcl-2 family such as
Bcl-2 antagonist of cell death (Bad), Bcl-2-interacting
mediator of cell death (Bim), and Noxa are believed to
induce apoptosis via an interaction with either Bax or
Bak and/or by generating stable complexes with
antiapoptotic Bcl-2/Bcl-XL (Adams, 2003).
p53. This transcription factor can induce MOMP
through two pathways (Perfettini et al., 2004b). First,
p53 can trans-activate a large panel of genes whose
products locate to mitochondria. Such proteins include
proapoptotic members of the Bcl-2 family (such
as Bax, Noxa, p53-upregulated modulator of apoptosis/Bcl-2-binding component 3 (Puma/Bbc3)), the mitochondrial chloride intracellular channel/chloride
intracellular channel 4 (mtCLIC/CLIC4), redox-active
enzymes (such as proline oxidase and ferredoxin
reductase) and proteins that operate through a yet
unknown mode of action (such as maspin). Second,
p53 can translocate to mitochondria, where it presumably interacts with members of the Bcl-2 family, namely
Bcl-2, Bcl-XL (Mihara et al., 2003), Bax (Chipuk
et al., 2004) and Bak (Leu et al., 2004) as well as with
other proteins, such as glycogen synthase kinase-3b
(Watcharasit et al., 2003) or the manganese-dependent
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superoxide dismutase (Zhao et al., 2005). Which
among these interactions are relevant for MOMP
induction by p53 is subject of an ongoing controversy.
Irrespective of this, p53 can induce MOMP both in a
transcription-dependent and in a transcription-independent fashion.
Voltage-dependent anion channel. VDAC the most
abundant OM protein, has been reported to be required
for apoptosis induction. VDAC is normally responsible
for the exchange of metabolites between the cytosol and
the mitochondrial intermembrane space. Microinjection
of VDAC-specific antibodies or of a VDAC-specific
inhibitor (König’s polyanion) can reduce apoptosis
induced by microinjected Bax (Ferri et al., 2000),
etoposide, paclitaxel, and staurosporine (Shimizu
et al., 2001). VDAC might by sufficient to permeabilize
membranes, since VDAC proteoliposomes release cyt c
in the presence of reactive oxygen species (ROS)
(Madesh and Hajnoczky, 2001). BCL-2 and Bcl-XL
have been reported to close VDAC, both in liposomes
and in plain lipid bilayers. This effect can be mimicked
by peptides corresponding to the BH4 domains, which
are present in Bcl-2 and Bcl-XL yet absent from the
proapoptotic proteins Bax, Bak, Bid, Bim and Noxa
(Shimizu et al., 2000b). In proteoliposomes, Bax or Bak
(but not Bid) might interact with VDAC to create
composite channels sufficiently large to release cyt c
(Shimizu and Tsujimoto, 2000). VDAC therefore
appears to be the prime cyt c release channel in the
OM, and its activity might be suppressed by Bcl-2 or
Bcl-XL, or increased by Bax or Bak. However, there is
perhaps another completely different mechanism
through which VDAC might participate in apoptosis
induction. Upon growth factor withdrawal, indeed, the
exchange of metabolites (ATP, ADP, NADH, creatine
and creatine phosphate) across OM might be reduced,
due to the closure of VDAC (Vander Heiden et al.,
2001). Although the exact reasons for VDAC closure
have not been elucidated, it has been suggested that an
increased IM transmembrane potential (DCm) would
directly affect OM, creating a local voltage gradient and
closure of VDAC. This OM DCm causing the closure of
VDAC would be dissipated by Bcl-2 by virtue of its
capacity to create ion-permeable channels (Vander
Heiden et al., 2001). Of note, there are several VDAC
isoforms (VDAC1, VDAC2, VDAC3). Although there
is no systematic study that has addressed the contribution of VDAC isoforms to apoptosis, it appears that
VDAC1 is proapoptotic (Zaid et al., 2005), while
VDAC2 might be antiapoptotic, acting as an endogenous inhibitor of Bak (Cheng et al., 2003).
Adenine nucleotide translocator. ANT is a protein that
interacts with VDAC and other proteins, such as
cyclophilin D (CypD), to form the PTPC at the contact
sites between IM and OM (Beutner et al., 1998; Marzo
et al., 1998b). ANT, the most abundant IM protein, is
an antiporter responsible for the exchange of ATP and
ADP. ANT can form nonspecific pores that have been
proposed to mediate IM permeabilization and osmotic
matrix swelling, to which OM rupture follows when the
surface area of the IM (with its folded cristae) exceeds
that of the OM. Alternatively, the conformation of
ANT, which is modulated by ANT ligands (Brustovetsky
et al., 2002) and CsA-sensitive interactions with CypD,
might indirectly impinge on VDAC activity (Vieira
et al., 2000). When reconstituted into liposomes or
into planar lipid bilayers, ANT can form nonspecific
channels in response to proapoptotic agents such as
atractyloside, Ca2 þ (Brustovetsky et al., 2002), lonidamine (Ravagnan et al., 1999) and the HIV-1 viral
protein R (Vpr) (Jacotot et al., 2001). Moreover, ANT
channel formation is enhanced by Bax (Marzo et al.,
1998a), and inhibited by Bcl-2 (Brenner et al., 2000).
However, mouse knockout studies led to the conclusion
that ANT would not (always) be required for apoptotic
MOMP (Kokoszka et al., 2004). Recent evidence
suggests that some ANT isoforms (ANT1, ANT3) are
apoptogenic while others are not (ANT2) (Schubert and
Grimm, 2004; Zamora et al., 2004). In 2005, a fourth
ANT isoform (ANT4) has been identified in man (Dolce
et al., 2005) and mouse (Rodic et al., 2005) by means of
two independent experimental approaches. The role of
this isoform in apoptosis has not been elucidated yet.
Cyclophilin D. CypD (gene name: Ppif, for peptidylprolyl cis-trans isomerase F) is the pharmacological
target of CsA in mitochondria. Hepatocyte mitochondria from control and Ppif/ mice exhibited identical
cyt c release patterns when treated with recombinant
Bax or t-Bid (truncated Bid) proteins, whereas Ppif/
mitochondria were protected from Ca2 þ -induced cyt c
release (Baines et al., 2005; Nakagawa et al., 2005). This
indicates that the MOMP induced by proapoptotic Bcl-2
family members can occur independently from CypDregulated events. In contrast, cells from Ppif/ mice
were protected against cell death induced by H2O2, Ca2 þ
ionophores and ischemia/reperfusion (Baines et al.,
2005; Nakagawa et al., 2005), indicating the existence
of CypD-dependent death modalities.
MOMP-inhibitory proteins in mitochondria. It is well
established that the antiapoptotic tumor-suppressors
Bcl-2 and Bcl-XL are OM proteins that act as barriers
against membrane permeabilization (Kroemer, 1997). It
is controversial, however, how they stabilize the
membrane – it could be by neutralizing the function of
proapoptotic Bcl-2 family members, by inhibiting
VDAC, by neutralizing ANT channel activity, by
physicochemical effects on the lipid bilayer or by a
combination of all of these (Green and Kroemer, 2004).
Hexokinase II, a mitochondrial protein that catalyses
the first step of glycolysis, has also been shown to inhibit
apoptosis. Hexokinase II transcription and mitochondrial translocation are both induced by the
Akt-mediated antiapoptotic signaling pathway (Gottlob
et al., 2001). As a possibility, hexokinase II might inhibit
the VDAC-mediated membrane insertion of Bax (Pastorino et al., 2002).
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Table 1 Protein factors and second messengers that permeabilize mitochondria
Class of molecules
Examples
Putative target
References
Sessile membrane proteins
VDAC
Bax, Bcl-2
(Shimizu and Tsujimoto, 2000)
(Rapizzi et al., 2002)
ANT
Bak
BNIP3
Siva-1
PLS-3
CypD
Ca2+ flux
Bax, Bcl-2
VDAC2, ANT
Bcl-2/Bcl-XL
Bcl-XL
Cardiolipin transported to OM?
ANT
(Marzo et al., 1998a; Belzacq et al., 2003)
(Shimizu and Tsujimoto, 2000; Cheng et al., 2003)
(Vande Velde et al., 2000)
(Xue et al., 2002)
(He et al., 2005)
(Baines et al., 2005; Nakagawa et al., 2005)
Bax
ANT, VDAC opening
(Marzo et al., 1998a; Shimizu et al., 2000a)
t-Bid
Cardiolipin
Bax, Bak, cardiolipin
(Kuwana et al., 2002)
(Cheng et al., 2001;
Wei et al., 2001)
(Rostovtseva et al., 2004)
(Giordano et al., 2005)
(Garofalo et al., 2005)
(Grinberg et al., 2005)
(Cheng et al., 2001)
(Sugiyama et al., 2002)
(Letai et al., 2002)
(Danial et al., 2003)
(Cartron et al., 2004; Perfettini et al., 2004a)
(Baksh et al., 2005;
Tan et al., 2005)
Proteins translocating to
mitochondria
Proapoptotic Bcl-2-like
proteins
Bim
Bad
Puma/Bbc3
MAP-1
p53-induced proteins
VDAC closure
Carnitine palmitoyl transferase 1
Lipid microdomains
Mitochondrial carrier homolog 2
Bcl-2
VDAC opening
Bcl-2, Bcl-XL
Glucokinase
Bax, Bak
Bax
Bax
BH3-only proteins:
Noxa, Puma/Bbc3
Proline oxidase
Ferredoxin reductase
p53AIP1
mtCLIC/CLIC4
Maspin
p66Shc
VDAC, ANT
(Vogelstein et al., 2000)
Bax, Bak
Locally generates ROS
Locally generates ROS
Bcl-2
Is a chloride channel
?
Mitochondrial HSP70
(Han et al., 2001)
(Donald et al., 2001)
(Hwang et al., 2001)
(Oda et al., 2000; Matsuda et al., 2002)
(Fernandez-Salas et al., 2002)
(Latha et al., 2005)
(Orsini et al., 2004)
p53-regulated proteins
LKB1
Histone H1.2
Serine/threonine kinase
Bak?
(Karuman et al., 2001)
(Konishi et al., 2003)
Transcription factors
p53
Bcl-XL, Bcl-2,
Bax
Bak
GSK3b
Mn-SOD
Bcl-2
(Mihara et al., 2003)
(Chipuk et al., 2004)
(Leu et al., 2004)
(Watcharasit et al., 2003)
(Zhao et al., 2005)
(Lin et al., 2004)
Dynamin-related
protein 1
Endophilin B1/Bif-1
?
(Frank et al., 2001)
Bax
(Takahashi et al., 2005)
Cytoskeleton regulators
Cofilin
?
(Chua et al., 2003)
Kinases
JNK
SEK1
PKCd
c-Abl
Bcl-2
JNK?
PLS-3
?
(Aoki et al., 2002)
(Aoki et al., 2002)
(He et al., 2005)
(Kumar et al., 2003)
Caspases
Caspase-2
Caspase-3
Bid?
Bcl-XL
Mcl-1
Complex I and II
(Guo et al., 2002)
(Kirsch et al., 1999)
(Han et al., 2004)
(Ricci et al., 2003)
Cytotoxic granule
components
Granzyme A
?
(Martinvalet et al., 2005)
Granzyme B
Granzyme C
Mcl-1, Bid
?
(Han et al., 2004; Waterhouse et al., 2005)
(Johnson et al., 2003)
Nur77/TR3/NGFIB
Fission-regulatory proteins
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Table 1 (continued )
Class of molecules
Examples
Putative target
References
Granulysin
Negatively charged lipids
(Pardo et al., 2001)
(Sphingo)lipid messengers
Palmitate
Arachidonic acid
Ganglioside GD3
ANT
?
Lipid microdomains ?
(de Pablo et al., 1999)
(Scorrano et al., 2001)
(Rippo et al., 2000; Garofalo et al., 2005)
Divalent cations
Ca2+
ANT, VDAC
(Gincel et al., 2001)
Pro-oxidants
Superoxide
ANT, VDAC, CK
Metabolites
4-Hydroxyhexenal
Nitric oxide
Glucose-6-phosphate
ANT
ANT, Bcl-2
HKI
(Marzo et al., 1998a; Madesh and Hajnoczky, 2001;
Schlattner et al., 2006)
(Vieira et al., 2001)
(Vieira et al., 2001; Cahuana et al., 2004)
(Azoulay-Zohar et al., 2004)
Nonproteaceous factors
Abbreviations: ANT, adenine nucleotide translocator; Bad, Bcl-2 antagonist of cell death; Bak, Bcl-2 antagonist/killer; Bax, Bcl-2-associated X
protein; Bcl-2, B-cell lymphoma protein 2; Bcl-XL, B-cell lymphoma X protein, long splicing isoform; Bid, BH3 interacting domain death agonist;
Bif-1, Bax interacting factor 1; BH3, Bcl-2 homology domain 3; Bim, Bcl-2-interacting mediator of cell death; BNIP3, Bcl-2/E1B 19 kDa interacting
protein; c-Abl, v-abl Abelson murine leukemia viral oncogene homolog; CK, creatine kinase; CypD, cyclophilin D; GSK3b, glycogen synthase
kinase 3b; HKI, hexokinase I; HSP70, heat shock 70 kDa protein; JNK, c-Jun N-terminal kinase; LKB1, synonym of STK11 (serine/threonine
kinase 11); MAP-1, modulator of apoptosis 1; Mcl-1, myeloid cell leukemia sequence 1 (Bcl-2-related); Mn-SOD, manganese-dependent superoxide
dismutase; mtCLIC/CLIC4, mitochondrial chloride intracellular channel/chloride intracellular channel 4; Noxa, synonym of PMAIP1 (phorbol12-myristate-13-acetate-induced protein 1); Nur77/TR3/NGFIB, nuclear orphan receptor 77/thyroid hormone receptor 3/nerve growth factor
induced protein IB; OM, mitochondrial outer membrane; p53AIP1, p53-regulated apoptosis-inducing protein 1; p66Shc, Src homology 2 domain
containing 66 kDa protein; PKCd, protein kinase Cd; PLS-3, phospholipid scramblase 3; Puma/Bbc3, p53-upregulated modulator of apoptosis/Bcl2-binding component 3; ROS, reactive oxygen species; SAPK, stress-activated protein kinase; SEK1, SAPK/ERK kinase 1; Siva-1, synonym of
CD27BP-1 (CD27-binding protein 1); t-Bid, truncated Bid; VDAC, voltage-dependent anion channel.
Mitochondrial lipids. The lipid composition of the IM
is significantly different from that of other intracellular
membranes. The IM is essentially cholesterol-free, and it
is the only eukaryotic membrane containing the
phosphoglyceride cardiolipin. The IM also contains a
relatively high portion of negatively charged phospholipids such as phosphatidylserine. These specific features
might determine the preferential insertion of certain
proteins into mitochondrial membranes. For instance,
t-Bid preferentially associates with cardiolipin-containing membranes (Lutter et al., 2000), which might explain
why t-Bid is enriched at the contact sites between IM
and OM. Cationic ampholytes – molecules whose
structure includes both a hydrophobic and a hydrophilic
cationic moiety – might also be expected to preferentially redistribute to IM, not only driven by the DCm,
but also because of the acidic phospholipids present in
the membrane. It is important to note that the
composition of mitochondrial lipids changes during
apoptosis, with cardiolipin oxidation as a prominent
feature (Sandra et al., 2005). This might facilitate the
desorption of cyt c from IM (Ott et al., 2002). Of note, it
appears that a growing number of MOMP-regulatory
proteins are involved in lipid metabolism. This applies
to phospholipid scramblase 3, carnitine palmitoyl
transferase 1 (Table 1), and perhaps also t-Bid, which
has been suggested to have a lipid transferase activity
(Sandra et al., 2005).
Mitochondria isolated from tumor cells are intrinsically resistant to the induction of MOMP, when
compared to mitochondria from normal cells (Chandra
et al., 2002). This may be due to the upregulation of
MOMP-inhibitory proteins or to the downregulation of
MOMP promoters. Indeed, antiapoptotic proteins from
the Bcl-2 family are widely overexpressed in cancer while
proapoptotic Bcl-2 antagonists and p53 often undergo
loss-of-function mutations (Green and Kroemer, 2004).
Outside of the Bcl-2 family, prominent examples of
MOMP inhibitors that are overexpressed in cancer are
hexokinase II (Mathupala et al., 1997), as well as the
peripheral-type benzodiazepine receptor (PBR) (Casellas et al., 2002), a mitochondrial protein interacting
with ANT and VDAC (Castedo et al., 2002). Cancer
cells also undergo a shift in the expression pattern of the
ANT isoenzymes, reducing expression of the proapoptotic ANT1 isoform and increasing expression of the
antiapoptotic protein ANT2 (Giraud et al., 1998).
Another example is given by the oncoprotein mucin 1
(DF3/MUC1), that translocates to mitochondria in
response to heregulin (ligand for ErbB-2, a growth
factor receptor) and inhibits MOMP in tumor cells (Ren
et al., 2006). From these observations, it appears why
advances in the understanding of cancer-specific deregulation of MOMP are not only desirable, but crucial.
Indeed, the identification of relevant MOMP regulators
might yield novel therapeutic approaches for cancer
therapy.
Direct inducers of mitochondrial membrane
permeabilization
Reportedly, a number of conventional chemotherapeutics can induce cell death by permeabilizing mitochondrial membranes. These include 2-chloro-20 -deoxyadenosine (Genini et al., 2000), etoposide (Robertson
Oncogene
Chemotherapy and mitochondria
L Galluzzi et al
4818
Table 2 Protein factors and second messengers acting on mitochondria to prevent membrane permeabilization
Class of molecules
Examples
Putative target
References
Sessile membrane proteins
Bcl-2, Bcl-XL
Mcl-1
Bcl-w
PBR
VDAC2
VDAC, ANT, BH3 proteins
Bak
?
ANT, VDAC
Bak
(Kroemer and Reed, 2000)
(Leu et al., 2004)
(Wilson-Annan et al., 2003)
(Stoebner et al., 2001)
(Cheng et al., 2003)
Cytosolic proteins that can
translocate to mitochondria in
response to growth factors
DF3/MUC1
?
(Ren et al., 2006)
Cytosolic protein associated
y.with PTPC
HKII
HKI
VDAC, competing for Bax binding
VDAC1 closure
(Pastorino et al., 2002)
(Azoulay-Zohar et al., 2004; Zaid et al., 2005)
Intermembrane protein
y.of the PTPC
CK
ANT, VDAC
(Schlattner et al., 2001)
Antioxidant enzymes
Mn-SOD2
PHGPx
Thioredoxin 2,
peroxiredoxin 3
Signal transducers
PKG
PKA
PKCe
?
Bad
ERKs, JNKs, and p38 MAPK
ANT1, VDAC2, HKII
Bax
(Takuma et al., 2001)
(Harada et al., 1999)
(Baines et al., 2002)
(Baines et al., 2003)
(McJilton et al., 2003)
Metabolites
Glucose
ATP, ADP
HK
ANT
NAD+
Glutathione
Creatine
Glutamate
VDAC
?
CK
VDAC
(Beutner et al., 1998; Majewski et al., 2004)
(Haworth and Hunter, 2000; Vieira et al.,
2000)
(Zoratti and Szabò, 1995)
(Zoratti and Szabò, 1995)
(Dolder et al., 2003)
(Gincel and Shoshan-Barmatz, 2004)
(Motoori et al., 2001)
(Nomura et al., 1999)
(Tanaka et al., 2002; Nonn et al., 2003)
Abbreviations: ANT, adenine nucleotide translocator; Bad, Bcl-2 antagonist of cell death; Bak, Bcl-2 antagonist/killer; Bax, Bcl-2-associated X
protein; Bcl-2, B-cell lymphoma protein 2; Bcl-w, synonym of Bcl-2L2 (Bcl-2 like protein 2); Bcl-XL, B-cell lymphoma X protein, long splicing
isoform; BH3, Bcl-2 homology domain 3; CK, creatine kinase; DF3/MUC1, mucin 1; ERK, extracellular signal-regulated kinase; HK, hexokinase;
JNK, c-Jun N-terminal kinase; Mcl-1, myeloid cell leukemia sequence 1 (Bcl-2-related); Mn-SOD2, manganese-dependent superoxide dismutase 2;
p38 MAPK, mitogen-activated protein kinase of 38 kDa; PBR, peripheral-type benzodiazepine receptor; PHGPx, phospholipid hydroperoxide
glutathione peroxidase; PKA, protein kinase A; PKCe, protein kinase Ce; PKG, cGMP-dependent protein kinase; PTPC, permeability transition
pore complex; VDAC, voltage-dependent anion channel.
et al., 2000), and paclitaxel (Kidd et al., 2002). High
doses of these drugs, however, are often required to
obtain such effects, casting doubts on the possibility
that they truly induce cell death via direct MOMP
induction. A number of other mitochondrion-permeabilizing molecules exist and several drugs are being
developed (Table 3). The physicochemical and pharmacological profiles of such mitochondrion-targeted agents
allows for their classification in several subgroups.
Bcl-2 targeted drugs. Multiple approaches have been
developed to target Bcl-2 family members in cancer cells.
For example, a recombinant chimeric protein that
contains interleukin-2 fused to Bax kills interleukin-2
receptor-bearing cells in vitro (Aqeilan et al., 1999).
Similarly, Bak can be targeted to the Fce receptor by
fusing it to the constant region of the immunoglobulin E
molecule. This fusion protein has been shown to
selectively induce apoptosis in vitro in IgE producing
cells, such as mast cells and basophils (Belostotsky and
Oncogene
Lorberboum-Galski, 2001). An antisense oligonucleotide designed to downregulate the expression of Bcl-2
(Genasense, G3139, Oblimersen) is being evaluated in
phase I/II trials against solid and hematopoietic
neoplasia (Tolcher, 2005). Such antisense oligonucleotides, which are relatively nontoxic to normal cells,
might be particularly useful for treating tumors that
express high levels of Bcl-2. However, it has not yet been
formally proven that Bcl-2-targeted antisense oligonucleotides exert their antitumor effects solely by downregulating Bcl-2 and it remains possible that they
provoke more unspecific effects, for instance by
stimulating the innate immune response.
BH3 mimetics. Several small molecules that disrupt the
interaction between Bcl-XL and Bak have been identified
and shown to occupy the BH3-binding pocket of BclXL. These molecules induce apoptosis by blocking the
BH3-mediated heterodimerization between Bcl-2 family
members, thus acting as BH3 mimetics (Degterev et al.,
Chemotherapy and mitochondria
L Galluzzi et al
4819
2001). The small molecule ethyl 2-amino-6-bromo-4(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1), which binds to the surface pocket of
Bcl-2, may induce apoptosis in a similar manner (Wang
et al., 2000). Antimycin A, a compound that inhibits
complex III of the respiratory chain, and its methoxy
derivative (which does not block complex III) also bind
to the BH3-binding hydrophobic groove of Bcl-2 and
Bcl-XL, thereby permeabilizing purified mitochondria
expressing Bcl-XL (Tzung et al., 2001). Peptides that
correspond to the BH3 domains of Bax (BaxBH3) or
Bcl-2 (Bcl2BH3) permeabilize mitochondria in a CsAsensitive fashion. When fused to the Antennapedia
plasma membrane translocation domain (Ant), which
facilitates
cellular
uptake,
BaxBH3Ant
and
Bcl2BH3Ant induce mitochondrial permeabilization
via a mechanism that is not inhibited by overexpression
of Bcl-2 or Bcl-XL (Vieira et al., 2002). Peptides with an
improved stability that can induce apoptosis of Bcl-2
expressing cells in vitro and in vivo have been developed
(Walensky et al., 2004) and a small inhibitory BH3
mimetic has yielded promising preclinical results (Oltersdorf et al., 2005). Similar agents might be used alone
or in combination with other molecules to overcome
multidrug resistance in cancer cells that overexpress Bcl2-like antiapoptotic proteins.
Peripheral-type benzodiazepine receptor ligands. Synthetic ligands of the PBR (such as 1-(2-chlorophenyl)-Nmethyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide
– known as PK11195 – or the benzodiazepine 40 chlorodiazepam – Ro5-4864) can induce apoptosis or
sensitize cells to apoptosis induction, thereby overcoming the cytoprotective effects of Bcl-2 or Bcl-XL.
This chemosensitizing effect has been demonstrated in
several tumor cell lines, in vitro, as well as in SCID mice
transplanted with human cancer cells (Decaudin et al.,
2002). In these models, treatment with PBR ligands was
not able to induce cell death on its own. However, when
used in combination with etoposide, cisplatin, arsenite,
lonidamine, anti-CD95 antibody, dexamethasone or
ceramide, these agents were cytotoxic and neutralized
the antiapoptotic potential of Bcl-2 (Debatin et al.,
2002). Nonetheless, there is strong evidence against
the possibility that the apoptogenic or chemosensitizing effects of PBR ligands would be truly due to a
direct interaction with the PBR. The doses of PBR
ligands required to obtain such cytotoxic effects,
indeed, are several orders of magnitude higher than
the Kd of the high affinity PBR-binding site. Moreover,
the knockdown of PBR with specific small interfering
RNAs does not reduce the chemosensitizing effects
of PBR ligands in vitro (Gonzalez-Polo et al., 2005).
Hence, PBR ligands either act on a low affinity binding
site present on mitochondria yet distinct from PBR, or
via a completely different mechanism. In fact, the
proapoptotic action of PK11195 might involve the
induction of ROS generation (Walter et al., 2004) or
the inhibition of the multidrug resistance pumps (Walter
et al., 2005).
Adenine nucleotide translocator ligands. A number of
different agents are able to permeabilize ANT-containing proteoliposomes, but not plain liposomes, suggesting that they might be used to specifically permeabilize
mitochondrial membranes. These include cytotoxic
drugs such as lonidamine, arsenite and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid
(CD437) (Belzacq et al., 2001a) as well as the
aforementioned BaxBH3 peptide. (Vieira et al., 2002).
All these compounds induce channel formation when
ANT is reconstituted into lipid bilayers, but it is not
known whether they act directly on ANT or at the
ANT/lipid interface. They are likely, however, to
promote a conformational change in ANT, since
ANT-containing proteoliposomes permeabilization can
be suppressed by the natural ANT ligands ATP and
ADP (Belzacq et al., 2001a). Lonidamine showed
remarkable effects on benign prostate hypertrophy and
is undergoing clinical trials for the treatment of
malignant tumors. In addition to CD437, other retinoids
were shown to induce apoptosis through mitochondrial
pathways, independently from the binding to nuclear
receptors. Among these, all-trans-retinoic acid (atRA)
(Notario et al., 2003), but not N-(4-hydroxyphenyl)retinamide (4-HPR) (Boya et al., 2003) nor [(4-nitrophenyl)amino][2,2,4,4-tetramethyl thiochroman-6-yl)amino]
methane-1-thione (SHetA2) (Chun et al., 2003), induces
CsA-sensitive mitochondrial permeability transition
(MPT) in isolated organelles and selectively binds to
ANT. On theoretical grounds it is possible that ANT
inhibitors might exhibit a selective toxicity on particular
cell populations, depending on the expression of the
ANT isoforms (Giraud et al., 1998). Thus, it might be
conceivable to create ANT-specific agents that would
selectively kill ANT2-overexpressing cancer cells or
tumor cells having accumulated mutations in the
mitochondrial genome.
Steroid analogs. A number of agents that act on
mitochondria possess a steroid-like core structure. For
instance, this applies to avicins, betulinic acid, CD437,
resveratrol, and the bile acid glycochenodeoxycholic
acid. These agents might perturb the lipid composition
of mitochondrial membranes and induce lipid rafts,
which in turn may favor MOMP (Garofalo et al., 2005).
Avicins can form channels in synthetic membranes (Li
et al., 2005). Betulinic acid has the interesting ability to
selectively kill tumor cells, including neuroblastoma,
medulloblastoma, glioblastoma and Ewing sarcoma
cells, yet to spare many normal cell types (Fulda and
Debatin, 2005). Isolated mitochondria from different
cell types, including normal murine hepatocytes, are
permeabilized by betulinic acid, and this effect is
prevented by CsA, the ANT ligand bongkrekate, as
well as by Bcl-2 overexpression (Fulda et al., 1998a). It is
unclear, however, through which receptor (if any)
betulinic acid acts on mitochondria.
Cationic ampholytes. Reportedly, an increased intrinsic DCm correlates with increased malignancy (apoptosis
Oncogene
Chemotherapy and mitochondria
L Galluzzi et al
4820
resistance and tumor progression) (Heerdt et al., 2003,
2005), suggesting that cytotoxic agents whose accumulation into the cells is driven by a high DCm may have
selective effects on cancer cells. The specific physicochemical properties of the IM and the net deficit of
positive charges on the inner side of the IM results in the
DCm-driven accumulation of cationic lipophils in the
mitochondrial matrix. Recently, cationic ceramide
derivatives, but not their neutral counterparts, have
been reported to buildup in isolated and in situ
mitochondria in an energy-dependent manner (Novgorodov et al., 2005). Following the Nernst equation,
positively charged agents sufficiently lipophilic to insert
in or to cross cellular membranes enrich in IM and/or in
the mitochondrial matrix. Any compound with mild
detergent-like properties could permeabilize mitochondria if it reached high enough concentrations in and
around the IM. Representatives of such compounds
are F16 and FTY720. The peptide DKLAKLAKK
LAKLAK or (KLAKLAK)2 (K ¼ lysine, L ¼ leucine,
A ¼ alanine) is a cationic ampholyte, being an a-helical
peptide that possess positive charges clustered on one
side of the helix. (KLAKLAK)2 directly permeabilizes
mitochondria when added to isolated organelles. Moreover, it can be fused to targeting peptides that interact
with surface receptors expressed on angiogenic endothelial cells in tumors (Ellerby et al., 1999) or on prostate
vasculature (Arap et al., 2002). These fusion peptides are
translocated into the cytoplasm, and induce apoptosis
via MOMP (Ellerby et al., 1999) specifically in the
targeted cell population. Thus, a prostate-targeted
(KLAKLAK)2 peptide has been used to target prostate
tumors in mice (Arap et al., 2002). Treatment of mice
with this peptide postponed the development of cancer
in model of spontaneously developing prostate
adenocarcinoma (Arap et al., 2002). Similarly, (KLAKLAK)2 has been fused to a peptide that inhibits the
ErbB-2 receptor kinase (Fantin et al., 2005). The
resulting fusion protein specifically affects mitochondria
of cells that express ErbB-2, but not those of cells
lacking ErbB-2 expression, causing MOMP and DCm
dissipation. In addition, this peptide has been used to
induce massive apoptosis in vivo, in mice carrying
established human breast cancer xenografts (Fantin
et al., 2005). These experiments provide a proof-ofconcept for the strategy of targeting toxic hybrid
molecules to cancer cells, first to surface receptors and
then to mitochondria.
Redox-active compounds. Agents that promote oxidative reactions can also be used to permeabilize the
mitochondrial membrane. These compounds include
arsenite (which depletes glutathione), 2-methyl1,4-naphthoquinone (menadione, which undergoes
futile redox cycles on the respiratory chain), and
thiol-crosslinking agents such as diazenedicarboxylic
acid bis5N,N-dimethylamide (diamide), bismaleimidohexane (BMH) and dithiodipyridine (DTDP), which are
able to overcome cytoprotection by Bcl-2 and to cause
ANT thiols oxidation (Costantini et al., 2000). Arsenite,
Oncogene
which permeabilizes purified mitochondria in vitro
(Belzacq et al., 2001a; Larochette et al., 1999) has also
pro-oxidant effects and is used nowadays for the routine
treatment of acute promyelomonocytic leukemia (Kroemer and de Thé, 1999). The organic arsenic chemical
4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide
(GSAO) directly affects mitochondria, where it crosslinks the matrix-facing thiols of Cys-160 and Cys-257 of
ANT, thus causing MOMP (Don et al., 2003). Surprisingly, this agent is particularly toxic for proliferating
endothelial cells of tumors yet it spares the other cell
types. This may be linked to the particular characteristics of endothelial cells which lack the multidrug
resistance-associated proteins capable of extruding
GSAO from the cytoplasm (Dilda et al., 2005).
Photosensitizing agents. Photosensitizing agents that
act on mitochondria – some of which by interacting with
PBR – generate ROS when exposed to light. Locally
generated ROS might then act on mitochondrial PTPC
components, including VDAC and ANT, and cause the
formation of protein-permeable conduits or nonspecific
ion channels (Belzacq et al., 2001b). The photosensitizer
hypericin reportedly detaches hexokinase from mitochondria (Miccoli et al., 1998), whereas the phthalocyanine photosensitizer Pc 4 causes the photochemical
destruction of Bcl-2 (Xue et al., 2001). Altogether,
available data suggest that photosensitizing agents can
target mitochondria, where they induce apoptosis
independently from the p53 status, even in Bax-negative
cells (Chiu et al., 2005).
Mitochondrial proapoptotic factors as chemotherapeutic
agents
As outlined above, apoptotic MOMP results in the
release of a plethora of proapoptotic factors from the
intermembrane space. Such factors include Smac/
DIABLO, a protein that exerts much of its proapoptotic
function by neutralizing IAPs, which function as caspase
inhibitors. The binding of Smac/DIABLO to IAPs is
mediated by a relatively short stretch of aminoacids
located in the N-terminus of the protein (Wu et al.,
2000). Several investigators have developed peptidomimetics in which the N-terminus of Smac/DIABLO is
fused to plasma membrane translocation domains, thus
allowing for its intracellular delivery. Such Smac/
DIABLO peptidomimetics have been successfully used
to induce apoptosis in vivo, in orthotopically implanted
glioblastoma xenografts (Fulda et al., 2002). Moreover,
small molecule Smac/DIABLO analogs have been
developed and have been shown to sensitize to apoptosis
induction several tumor cell lines (Li et al., 2004;
Bockbrader et al., 2005), including MDA-MB-231
breast cancer cells characterized by high levels of IAPs
(Bockbrader et al., 2005).
An alternative strategy can exploit the properties of
apoptosis-inducing factor (AIF), a mitochondrial flavoprotein that normally resides in the intermembrane
space where it participates in redox reactions (Miramar
et al., 2001; Mate et al., 2002), maintains normal
Table 3 Cytotoxic drugs capable of inducing MOMP in isolated mitochondria
Agent
Mode of action
Reference
2-Chloro-2 deoxy-adenosine
Hairy cell leukemia
Chronic lymphocytic leukemia
Induces Bcl-2-sensitive MOMP in isolated mitochondria.
(Genini et al., 2000)
5-Aminolevulinic acid
In vitro
Induces catalase-, DTT-, Mg2+-, RR-, ADP- and SODsensitive, o-phenanthroline-prevented MPT in isolated mitochondria.
(Hermes-Lima, 1995)
ABT-737
In vitro and in vivo, in mouse
models
Small molecule inhibitor of Bcl-2, Bcl-XL and Bcl-w.
(Oltersdorf et al., 2005)
all-trans-retinoic acid
In vitro
Induces CsA-sensitive, Ca2+-dependent MPT in isolated
mitochondria, by binding to ANT. Activity independent from
the binding to nuclear receptors.
(Notario et al., 2003)
Alloxan
Cytotoxic for pancreatic b cells
(diabetogenic)
Induces PT in isolated mitochondria.
(Sakurai et al., 2001)
Amyloid-b peptide
In vitro
Induces UCD- and TUDC-sensitive, CsA-insensitive MPT and
cyt c release in isolated mitochondria.
(Rodrigues et al., 2000)
Antimycin and its methoxy
derivative
Particularly toxic for Bcl-XL
overexpressing cells, in vitro
Acts on Bcl-XL, by binding to the hydrophobic groove.
(Tzung et al., 2001; Manion et al., 2004)
AQ8, AQ9 and AQ10
Toxic for wild-type and multidrug
resistant HL-60 cells, in vitro
Induce rapid and irreversible MPT in cell cultures. Induce
CsA-, BA- and RR-sensitive MPT in isolated mitochondria.
May sensitize mitochondria to Ca2+.
(Wang et al., 2005)
Arsenite
Treatment of promyelocytic
leukemia and multiple myeloma
Induces PT in isolated mitochondria and ANT
proteoliposomes.
(Larochette et al., 1999)
Avicins
In vitro
Induces MOMP in isolated mitochondria.
Steroid-related structure. Form channels in membranes.
(Haridas et al., 2001)
(Li et al., 2005)
BaxBH3
Kills Bcl-2 overexpressing
cells in vitro
Induces PT and PT-independent
MOMP in isolated mitochondria
and ANT proteoliposomes.
(Vieira et al., 2002)
Betulinic acid
Kills neuroectodermal tumors in
vitro and in mice
Induces PT in isolated mitochondria.
(Fulda et al., 1998a; Fulda et al., 1998b)
Chemotherapy and mitochondria
L Galluzzi et al
Antitumor activity
0
Steroid-related structure (triterpenoid).
Benzyl isothiocyanate
Chemoprevention
Induces MOMP in isolated mitochondria.
(Nakamura et al., 2002)
Bismaleimido-hexane
In vitro
Induces ADP- and ATP-sensitive
PT in ANT proteoliposomes and
CsA-sensitive PT in isolated mitochondria. Oxidize ANT on
Cys 56, irrespective of Bcl-2 levels.
(Costantini et al., 2000)
BMAP-28
In vitro
Induces CsA-sensitive, Ca2+-potentiated
MOMP in isolated mitochondria.
(Risso et al., 2002)
4821
Oncogene
4822
Oncogene
Table 3 (continued )
Agent
Antitumor activity
Mode of action
Reference
2+
In vitro
Induces CsA-insensitive, Ca - and Pi-potentiated, potentialdependent swelling in isolated mitochondria.
(Lemeshko et al., 2005)
Butylated hydroxylanisole
Chemoprevention
Induces PT in isolated mitochondria.
(Yu et al., 2000)
Butyrate
Chemoprevention
Induces PT in isolated mitochondria and ANT
proteoliposomes.
(Jan et al., 2002; Heerdt et al., 2003)
Carbenoxolone
In vitro
Induces CsA- and BA-sensitive MOMP in isolated Ca2+-loaded
mitochondria.
(Salvi et al., 2005)
CD437
In vitro
Induces PT in isolated mitochondria and ANT
proteoliposomes. Steroid-related structure.
(Marchetti et al., 1999; Belzacq et al.,
2001a)
CDDO
In vitro
Induced cyt c release in isolated mitochondria. Steroid-related
structure (triterpenoid).
(Konopleva et al., 2004)
Citrinin
In vitro
Induces dose- and Ca2+-dependent,
CsA-, RR- and ATP-Mg2+-sensitive,
DTT-potentiated, BHT- and catalase-insensitive MPT in
isolated mitochondria.
(Da Lozzo et al., 1998)
Clodronate
Osteoclasts (bone metastases)
Adenosine metabolite. Inhibits ANT.
(Lehenkari et al., 2002)
Daphnetoxin
In vitro
Induces CsA-, catalase- and DTT-sensitive MPT in isolated
mitochondria.
Steroid-related structure (diterpenoid).
(Peixoto et al., 2004)
Diamide
In vitro
Induces ADP- and ATP-sensitive PT in
(Petronilli et al., 1994; Costantini et al.,
2000)
ANT proteoliposomes and CsA-, DTT- and NEM-sensitive PT
in isolated mitochondria. Oxidize ANT on Cys 56, irrespective
of Bcl-2 levels.
Dithiodipyridine
In vitro
Induces ADP- and ATP-sensitive
PT in ANT proteoliposomes and
CsA-sensitive PT in isolated mitochondria. Oxidize ANT on
Cys 56, irrespective of Bcl-2 levels.
(Costantini et al., 2000)
DNOC and DNP
In vitro
Induce Ca2+-dependent, CsA- catalase-sensitive MTP in
isolated mitochondria. Uncouplers.
(Castilho et al., 1997)
DTNB
In vitro
Induces CsA-, Mg2+- and PPi-sensitive,
Ca2+- and CATR-potentiated MPT in energized isolated
mitochondria. Redox- cycling agent.
(Wudarczyk et al., 1996)
Etoposide
Multiple neoplasias
Can induce CsA- and Bcl-2- sensitive MOMP in isolated
mitochondria, at high concentration.
(Robertson et al., 2000)
F16
In vitro
Cationic lipophilic agent that induces MOMP in isolated
mitochondria.
(Fantin et al., 2002)
Chemotherapy and mitochondria
L Galluzzi et al
BTM-P1
Table 3 (continued )
Antitumor activity
Mode of action
Reference
FCCP
In vitro
Induces CsA-, catalase- and DTT-sensitive, BHT-insensitive,
Ca2+- dependent MPT in isolated mitochondria.
Uncoupler, classical MPT inducer.
(Bernardi, 1992; Kowaltowski et al., 1996)
FTY720
Immunosuppressive
Cationic lipophilic agent that induces PT in isolated
mitochondria.
(Nagahara et al., 2000)
Glycyrrhetinic acid
In vitro
Induces CsA- and BA-sensitive, Ca2+-dependent MOMP in
isolated mitochondria.
(Salvi et al., 2003)
GSAO
Angiogenesis inhibitor in vitro and
in vivo
Induces PT in isolated mitochondria and oxidizes thiols of
ANT.
(Don et al., 2003)
HA14-1
In vitro
Bcl-2 ligand that induces MOMP via an oxidative mechanism.
(Wang et al., 2002; An et al., 2004)
Hyperforin
In vitro
Induces MOMP in isolated mitochondria.
(Schempp et al., 2002)
HOFQ
In vitro
Its oxidation products induce PT in isolated mitochondria.
Photosensitizer compound toxic also in the dark.
(Chilin et al., 2005)
Jasmonate
In vitro
Induces CsA- and BA-sensitive
MOMP in isolated mitochondria.
(Rotem et al., 2005)
(KLAKKLAK)2 peptide
In vivo (mice)
Cationic lipophilic peptide with a helices acting on inner
membranelipids.
(Ellerby et al., 1999)
Lonidamine
Glioblastoma (phase II)
Induces PT in isolated mitochondria and ANT
proteoliposomes.
(Ravagnan et al., 1999; Oudard et al.,
2003)
Mastoparan
In vitro
At low doses, it induces oligomycin and
CsA-sensitive, Ca2+- and Pi-facilitated
MPT in isolated mitochondria. The
MPT at higher concentrations is Ca2+- independent and
CsA-insensitive.
(Pfeiffer et al., 1995)
Menadione
In vitro
Induces CsA-, NEM-, and BQ-sensitive, Ca2+-dependent MPT
in isolated mitochondria. Redox-cycling agent.
(Petronilli et al., 1994; Palmeira and
Wallace, 1997)
MT21
In vitro
ANT ligand that induces MOMP in isolated mitochondria.
(Watabe et al., 2000; Machida et al., 2002)
Paclitaxel
Multiple neoplasias
Can induce CsA- and Bcl-2-sensitive MOMP in isolated
mitochondria, at high concentration.
(Kidd et al., 2002)
Phenylarsine oxide
In vitro
Induces CsA- and BHT-sensitive,
Ca2+-potentiated MPT in isolated mitochondria.
Thiol-crosslinking agent, classical MPT inducer.
(Lenartowicz et al., 1991)
Photoactivated merocyanine 540 CL
In vitro
Induces PT in isolated mitochondria.
(Pervaiz et al., 1999)
Chemotherapy and mitochondria
L Galluzzi et al
Agent
4823
Oncogene
4824
Oncogene
Table 3
(continued )
Agent
Antitumor activity
Mode of action
Reference
PK11195
In vitro and in animals
Induces PT in isolated mitochondria.
(Hirsch et al., 1998; Banker et al., 2002;
Decaudin et al., 2002; Muscarella et al.,
2003; Gonzalez-Polo et al., 2005)
PBR ligand but may act on different locations.
Pristimerin
In vitro
Induces CsA-insensitive cyt c release from isolated
mitochondria, not associated with MPT.
(Wu et al., 2005)
Resveratrol
Chemoprevention
Induces PT in isolated mitochondria.
(Hirsch et al., 1998; Banker et al., 2002;
Decaudin et al., 2002; Muscarella et al.,
2003)
SAHB peptide
In vitro and in animals
Mimics the BH3 domain of Bid and binds to Bcl-XL in
mitochondria.
(Walensky et al., 2004)
Taurine chloramine
In vitro
Induces PT in isolated mitochondria, in a CsA- and Bcl-2sensitive fashion.
(Klamt and Shacter, 2005)
tert-butylhydroperoxide
In vitro
Induces CsA-, NEM- and DTT-sensitive,
Ca2+-dependent MPT in isolated mitochondria. Induces
oxidative stress, followed by thiol crosslinking. Classical MPT
inducer.
(Petronilli et al., 1994)
Thyroid hormones (T3, T4
and to a less extent T2 and
reverse T3)
In vitro
Induce dose- and Ca2+-dependent, CsA-, RR-, DTT- and
catalase-sensitive MPT in isolated mitochondria.
(Castilho et al., 1998)
TT2 and TT13
In vitro
Induce Ca2+-dependent, RR-, CsA-, BA- and decylubiquinonesensitive
MPT in isolated mitochondria.
(Wang et al., 2006)
Unconjugated bilirubin
In vitro
Induces CsA-, UCD- and TUDC- sensitive MPT and cyt c
release in isolated mitochondria.
(Rodrigues et al., 2000)
Verteporfin plus light
Photodynamic therapy
Induces PT in isolated mitochondria, and ANT
proteoliposomes. Can bind to PBR.
(Belzacq et al., 2001b)
Note that only drugs that have been shown to have direct membrane-permeabilizing effects on mitochondria are listed in this table. Abbreviations: ANT, adenine nucleotide translocator; AQ, 1,4anthraquinone analog; BA, bongkrekic acid; Bax, Bcl-2-associated X protein; BaxBH3, peptide corresponding to the BH3 domain of Bax; Bcl-2, B-cell lymphoma protein 2; Bcl-w, synonym of Bcl2L2 (Bcl-2 like protein 2); Bcl-XL, B-cell lymphoma X protein, long splicing isoform; BH3, Bcl-2 homology domain 3; BHT, butylhydroxytoluene; Bid, BH3 interacting domain death agonist;
BMAP-28, bovine myeloid antimicrobial peptide of 28 residues; BQ, 1,4-benzoquinone; BTM-P1, Bacillus thuringiensis subsp. medellin peptide 1 (sequence VAPIAKYLATALAKWALKQGFAKLKS); CATR, carboxyatractyloside; CD437, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid; CDDO, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid; citrinin, (3R,4S)-4,6dihydro-8-hydroxy-3,4,5-trimethyl-6-oxo-3H-2-benzopyran-7-carboxylic acid; CsA, cyclosporin A; cyt c, cytochrome c; diamide, diazenedicarboxylic acid bis 5N,N-dimethylamide; DNOC, 4,6dinitro-o-cresol; DNP, 2,4-dinitrophenol; DTNB, 5,50 -dithiobis(2-nitrobenzoic acid); DTT, dithiothreitol; FCCP, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone; FTY720, 2-amino-2-(2-(4octylphenyl)ethyl)propane-1,3-diol; GSAO, 4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide; HA14-1, ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate;
HOFQ, 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1 H)-one; menadione, 2-methyl-1,4-naphthoquinone; mastoparan, the peptide INLKALAALAKKIL-NH2; MOMP, mitochondrial
outer membrane permeabilization; MPT, mitochondrial permeability transition; NEM, N-ethylmaleimide; PBR, peripheral-type benzodiazepine receptor; PK11195, 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline-carboxamide; Pi, inorganic phosphate; PPi, inorganic pyrophosphate; PT permeability transition; reverse T3, 3,50 ,30 -triiodo-L-thyronine; RR, ruthenium red; SAHB,
stabilized alpha-helix of Bcl-2 domains; SOD, superoxide dismutase; T2, 30 ,50 -diiodo-L-thyronine; T3, 3,5,30 -triiodo-L-thyronine; T4, L-thyroxine; TT, triptycene synthetic analog; TUDC,
tauroursodeoxycholate; UCD, ursodeoxycholate.
Chemotherapy and mitochondria
L Galluzzi et al
Steroid-related structure.
Chemotherapy and mitochondria
L Galluzzi et al
4825
glutathione levels (Cande et al., 2004b) and allows for
optimal assembly or maintenance of respiratory chain
complexes I and III (Vahsen et al., 2004). Upon
apoptosis induction, AIF translocates to the nucleus
where it contributes to chromatin condensation via a
direct interaction with DNA (Ye et al., 2002; Vahsen
et al., 2006) and recruits other proteins into the
‘degradosome’, which mediates chromatinolysis (Cande
et al., 2002; Cande et al., 2004a). Microinjection of
recombinant AIF is sufficient to induce hallmarks of
apoptosis (chromatin condensation, rounding up of
cells, phosphatidyl serine exposure) (Susin et al., 2000).
Similarly, transfection of cells with an AIF mutant
lacking the mitochondrial localization sequence in the
N-terminus, misdirects AIF to the cytosol and to the
nucleus, and results in cell killing (Loeffler et al., 2001).
Recently, a chimeric protein containing an ErbB-2specific antibody in the C-terminus and the cytotoxic
moiety of AIF in the N-terminus has been shown to
direct AIF to ErbB-2-expressing cancer cells, causing
their demise (Yu et al., 2006). This strategy of tumor
killing could be used for anticancer therapy in vivo, as
demonstrated in mice xenotransplanted with human
ErbB-2-overexpressing cancer cells when the chimeric
protein was produced by Jurkat T-lymphoma cells that
were coinoculated (Yu et al., 2006).
Another AIF derivative is ADD70 (for AIF-derived
decoy of heat shock 70 kDa protein (HSP70)). As a
matter of fact, the peptide-binding domain of HSP70
can interact with AIF (Ravagnan et al., 2001) and
HSP70 can inhibit the translocation of AIF to the
nucleus, retaining it within the cytosol (Gurbuxani et al.,
2003). The HSP70-binding domain within AIF has been
determined (Gurbuxani et al., 2003), and this domain
has been transfected into a variety of cell types,
conferring a marked chemosensitizing effect in response
to DNA damaging agents and tyrosine kinase inhibitors
(Schmitt et al., 2003). The same effect was not found in
cells that lack HSP70 expression, suggesting that it is
truly due to the neutralization of the antiapoptotic
effects of HSP70. ADD70 mediated chemosensitization
relied upon both an enhanced translocation of AIF to
the nucleus and an increased activation of caspases
(Schmitt et al., 2003). These results illustrate the
possibility of designing a new class of HSP70 inhibitors
that may facilitate the induction of cell death (Figure 2).
Concluding remarks
Most of the currently used cytotoxic anticancer therapeutics have no clear-cut cell specificity, yet tend to kill
tumor cells more efficiently than normal cells. Based on
this empiric observation, it may be hoped that a novel
class of mitochondrion-targeted agents could also kill
tumor cells with an acceptable therapeutic index. Future
will tell which, if any, among the compounds capable of
inducing MOMP (or their look-alikes) will withstand
clinical evaluation and for which precise tumors
they will be useful, alone or in combination with other
drugs. Nonetheless, it appears tempting to generate very
specific drugs (for instance agents that selectively act on
only one of the Bcl-2 family members), to target
cytotoxic agents (first) to a tumor-specific surface
receptor (and then to mitochondria) or to imagine
protocols that will cause tumor cells to undergo
immunogenic cell death (Casares et al., 2005). In the
latter scenario, a ‘bystander effect’ would be elicited, in
which the immune system would contribute to the
eradication of residual tumor cells, allowing for a
complete and permanent therapy response. As it stands,
these are theoretical considerations that await urgent
experimental and clinical verification, for the sake of
medical progress.
Abbreviations
ADD70, AIF-derived decoy of heat shock protein 70; AIF,
apoptosis-inducing factor; Akt, v-akt murine thymoma viral
oncogene homolog; ANT, adenine nucleotide translocator;
Bad, Bcl-2 antagonist of cell death; Bak, Bcl-2 antagonist/
killer; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma
protein 2; Bcl-XL, B-cell lymphoma X protein, long splicing
isoform; BH, Bcl-2 homology domain; Bid, BH3 interacting
domain death agonist; Bim, Bcl-2-interacting mediator of cell
death; CD437, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid; CsA, cyclosporin A; CypD, cyclophilin
D; cyt c, cytochrome c; DCm, mitochondrial transmembrane
potential; ErbB-2, v-erb-b2 avian erythroblastic leukemia viral
oncogene homolog 2; GSAO, 4-(N-(S-lutathionylacetyl)amino)phenylarsenoxide; HSP70, heat shock 70 kDa protein; IAP,
inhibitor of apoptosis protein; IM, mitochondrial inner
membrane; MEF, mouse embryonic fibroblasts; MOMP,
mitochondrial outer membrane permeabilization; Noxa,
synonym of PMAIP1 (phorbol-12-myristate-13-acetateinduced protein 1); OM, mitochondrial outer membrane;
PBR, peripheral-type benzodiazepine receptor; PK11195, 1(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; Ppif, peptidyl-prolyl cis-trans isomerase F;
PTPC, permeability transition pore complex; Puma/Bbc3,
p53-upregulated modulator of apoptosis/Bcl-2-binding component 3; Ras, rat sarcoma viral oncogene homolog; ROS,
reactive oxygen species; Smac/DIABLO, second mitochondria-derived activator of caspases/direct inhibitor of apoptosisbinding protein with a low isoelectric point; VDAC,
voltage-dependent anion channel.
Acknowledgements
This work was supported by a Special Grant from the Ligue
Nationale contre le Cancer, European Union (projects
RIGHT and Trans-Death) and Ministère pour la Recherche.
LG receives a fellowship from Region 92.
Oncogene
Chemotherapy and mitochondria
L Galluzzi et al
4826
Figure 2 IAPs and HSP70 exert their antiapoptotic activity by binding to and inactivating apoptosis executioners such as caspases
and AIF, respectively. Chemosensitization of cancer cells may be achieved via a treatment with MPT inducers, promoting the
mitochondrial release of apoptogenic factors (i.e. Smac/DIABLO), in association with peptidomimetics (for instance, ADD70), able to
inhibit specific protein-to-protein interactions. Published crystallographic data (Chen et al., 2003) allowed the use of the following
structures for the construction of this figure: AIF, residues 128–608D540–559 (Schmitt et al., 2003); Rattus norvegicus HSC70 substratebinding domain, residues 383–540 (Morshauser et al., 1999); caspase-3 heterodimeric catalytic domain with a nicotinic acid aldehyde
inhibitor, residues 150–295/320–401 (Becker et al., 2004); two caspase-3 heterodimeric catalytic domains, residues 148–296D(157–
160,223,248–253)/310–401 and 148–297D(157–160,223,248–253)/310–401, complexed with XIAP Bir2 domains, residues 127–237 and
135–236D(170–178) (Riedl et al., 2001); Smac/DIABLO monomer, residues from 12 to 184 (Chai et al., 2000); Smac/DIABLO
homodimer, residues 1–157, complexed with two XIAP Bir3 domains, residues 256–344 and 256–357 (Wu et al., 2000). Owing to the
lack of available crystallographic data, ADD70 is represented with the same structure of AIF, but only residues highlighted in orange
are actually part of the peptide (Schmitt et al., 2003). Abbreviations: ADD70, AIF-derived decoy of heat shock protein 70; AIF,
apoptosis-inducing factor; Bir, baculovirus inhibitor of apoptosis repeat; HSC70, heat shock cognate 70 kDa protein; HSP70, heat
shock 70 kDa protein; IAP, inhibitor of apoptosis protein; Smac/DIABLO, second mitochondria-derived activator of caspases/direct
inhibitor of apoptosis-binding protein with a low isoelectric point; XIAP, X-linked inhibitor of apoptosis protein.
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