G Model
BCP-12033; No. of Pages 12
Biochemical Pharmacology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Biochemical Pharmacology
journal homepage: www.elsevier.com/locate/biochempharm
Review
Targeting antioxidants for cancer therapy
Andrea Glasauer a,b,*, Navdeep S. Chandel b
a
b
Bayer Pharma AG, Global Drug Discovery, Therapeutic Research Group Oncology/Gynecological Therapies, 13353 Berlin, Germany
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 29 May 2014
Received in revised form 16 July 2014
Accepted 17 July 2014
Available online xxx
Cancer cells are characterized by an increase in the rate of reactive oxygen species (ROS) production and
an altered redox environment compared to normal cells. Furthermore, redox regulation and redox
signaling play a key role in tumorigenesis and in the response to cancer therapeutics. ROS have
contradictory roles in tumorigenesis, which has important implications for the development of potential
anticancer therapies that aim to modulate cellular redox levels. ROS play a causal role in tumor
development and progression by inducing DNA mutations, genomic instability, and aberrant protumorigenic signaling. On the other hand, high levels of ROS can also be toxic to cancer cells and can
potentially induce cell death. To balance the state of oxidative stress, cancer cells increase their
antioxidant capacity, which strongly suggests that high ROS levels have the potential to actually block
tumorigenesis. This fact makes pro-oxidant cancer therapy an interesting area of study. In this review,
we discuss the controversial role of ROS in tumorigenesis and especially elaborate on the advantages of
targeting ROS scavengers, hence the antioxidant capacity of cancer cells, and how this can be utilized for
cancer therapeutics.
ß 2014 Elsevier Inc. All rights reserved.
Chemical compounds studied in this article:
L-Buthionine-sulfoximine(PubChem CID:
119565
Phenethyl isothiocyanate(PubChem CID:
160602)
Lanperisone(PubChem CID: 198707)
Elesclomol(PubChem CID: 300471)
Imexon(PubChem CID: 68791)
Piperlongumine(PubChem CID: 637858)
Sulphasalazine(PubChem CID: 5359476)
Motexafin(PubChem CID: 12047567)
ATN-224(PubChem CID: 18442052)
Keywords:
Antioxidants
ROS
Cancer
Pro-oxidants
Therapy
Metabolism
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ROS – the Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Spatially localized sources of ROS . . . . . . . . . . . .
2.1.
Intracellular regulation of ROS . . . . . . . . . . . . . . .
2.2.
ROS and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ROS regulate cell signaling . . . . . . . . . . . . . . . . . .
3.1.
ROS stress and adaptation in cancer cells . . . . . .
3.2.
3.2.1.
ROS stress in cancer cells . . . . . . . . . . .
ROS adaptation of cancer cells (Fig. 2) .
3.2.2.
ROS promote pro-tumorigenic cell signaling . . . .
3.3.
ROS promote tumor cell proliferation .
3.3.1.
ROS promote tumor cell survival . . . . .
3.3.2.
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* Corresponding author at: Muellerstrasse 178 S107, 7th Floor, Room: 7. 302 13353 Berlin, Germany Tel.: +49 30 468 194467; fax: +49 30 468 94535.
E-mail address: andrea.glasauer@bayer.com (A. Glasauer).
http://dx.doi.org/10.1016/j.bcp.2014.07.017
0006-2952/ß 2014 Elsevier Inc. All rights reserved.
Please cite this article in press as: Glasauer A, Chandel NS. Targeting antioxidants for cancer therapy. Biochem Pharmacol (2014),
http://dx.doi.org/10.1016/j.bcp.2014.07.017
G Model
BCP-12033; No. of Pages 12
A. Glasauer, N.S. Chandel / Biochemical Pharmacology xxx (2014) xxx–xxx
2
3.3.3.
ROS promote angiogenesis and metastasis. . . . . . . . . . . . . . . . . . . . .
ROS promote anti-tumorigenic cell signaling . . . . . . . . . . . . . . . . . . . . . . . . . .
ROS promote cell death through the ASK1/JNK/P38 MAPK signaling
3.4.1.
ROS regulate cell cycle arrest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.2.
Modulating ROS levels to treat cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Decrease ROS levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Increase ROS levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Target antioxidants to decrease ROS scavenging capacity . . . . . . . . . . . . . . . .
4.3.
4.4.
Metabolic and redox modulation: combination therapy option . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
4.
5.
1. Introduction
ROS act as secondary messengers in cell signaling and are
required for various biological processes in normal cells. Under
physiological conditions, ROS are continuously generated by ROS
producers and eliminated through ROS scavenging systems in
order to maintain redox homeostasis. Cells aim to maintain a redox
balance that is ideal to support cellular processes like differentiation and proliferation and allow for the adaptation to metabolic
and immune stress. Changes in redox balance, which can have
endogenous or exogenous causes, can either lead to an increase in
ROS levels or rate of production, resulting in cell damaging
oxidative stress and aberrant cell signaling, or a decrease in ROS,
leading to a disruption of cell signaling and therefore disruption of
cellular homeostasis. Redox imbalance, oxidative stress, which are
often a result of changes in cancer cell metabolism, and aberrant
antioxidant levels to balance this stress, are hallmarks of many
cancers [1]. The role of ROS in cancer is two-sided. One the one
hand, ROS can contribute to cancer initiation, progression and
spreading through the activation and maintenance of signaling
pathways that regulate cellular proliferation, survival, angiogenesis and metastasis [2–4]. Through this role in promoting
tumorigenic cell signaling events, ROS are considered oncogenic.
However, on the other hand, the excessive levels of ROS in cancer
cells can also induce cell death signaling, senescence and cell cycle
arrest [5,6]. In the context of this imbalanced redox status,
oncogene-induced cancer cells adapt and increase antioxidant
pathways and regulators [7–12] leading to increased ROS
scavenging [13,14], in order to maintain ROS levels that allow
pro-tumorigenic signaling pathways to be activated without
inducing cell death. Various studies have shown that further
ROS elevation, either through ROS producers or antioxidant
inhibitors, can selectively kill cancer cells and suppress tumor
growth and progression in various cancer cell lines [15–22].
The contradictory, ‘‘doubled-edged-sword’’ property of ROS
allows for the induction of cancer cell survival or death depending
on intracellular ROS levels. Hence, ROS-manipulation strategies,
meaning ways to eliminate or produce ROS in cancer cells, can
potentially be effective in cancer therapies. Non-transformed,
normal cells have a different redox environment compared to
cancer cells and are therefore less sensitive to redox manipulation.
The varying redox status of normal cells compared to cancer cells is
mainly characterized by the lower rate of ROS production and
therefore the decreased requirement for ROS-scavenging mechanisms. Redox modulation cancer therapy is a young and
unexplored field and little research shows efficient results with
respect to treatment mechanisms or utility in pre-clinical animal
models. This review will focus on exploring the two-sided role of
ROS in tumorigenesis, and how understanding ROS signaling and
the aberrant redox status of cancer cells can be used for the
development of novel anticancer therapeutics. To that end, special
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consideration will be paid to the idea of increasing ROS and
targeting cancer cells’ antioxidant systems for therapy.
2. ROS – the Basics
2.1. Spatially localized sources of ROS
ROS are intracellular chemical species that contain oxygen and
are reactive towards lipids, proteins and DNA. ROS include the
superoxide anion (O2 ), hydrogen peroxide (H2O2), as well as
hydroxyl radicals (OH). Different types of ROS have different
intrinsic chemical properties, which dictate their reactivity and
preferred biological targets. The two main sources of ROS are
mitochondria and the family of NADPH oxidases (NOXs) [23]
(Fig. 1). The three best-characterized sites in the mitochondria are
complex I, II and III within the mitochondrial electron transport
chain, which is located in the inner mitochondrial membrane [24].
These complexes generate superoxide by the one-electron reduction of molecular oxygen. Complex I, II, and III release superoxide
into the mitochondrial matrix where superoxide dismutase 2
(SOD2) rapidly converts it into H2O2. Complex III can also release
Fig. 1. Sources, regulation and biological outcomes of ROS.
Mitochondria can release either superoxide (O2 ) or H2O2. In the cytosol O2 is
converted to H2O2 by SOD1. NADPH oxidases can also generate O2 in the cytosol.
Catalase, GPXs and PRXs can convert H2O2 to water. Upon reaction with ferrous or
cuprous ions, H2O2 forms OH radicals that can be damaging to DNA, proteins and
lipids. H2O2 controls cell signaling through the oxidation of thiols on proteins.
Different levels of H2O2 lead to different cellular outcomes. Intracellular H2O2
concentrations in the low nanomolar range provide a permissive oxidative
environment for cellular signaling which is ideal to maintain homeostasis (e.g.
differentiation and proliferation) and to adapt to stress (e.g. metabolic). H2O2 levels
below this optimal range lead to a disruption of cell signaling resulting in loss of
homeostasis. H2O2 levels above the optimal range cause oxidative damage and
aberrant cell signaling resulting in pathologies including cancer. Very high levels of
H2O2 can promote cell death.
Please cite this article in press as: Glasauer A, Chandel NS. Targeting antioxidants for cancer therapy. Biochem Pharmacol (2014),
http://dx.doi.org/10.1016/j.bcp.2014.07.017
G Model
BCP-12033; No. of Pages 12
A. Glasauer, N.S. Chandel / Biochemical Pharmacology xxx (2014) xxx–xxx
superoxide into the mitochondrial intermembrane space. Superoxide traverses through voltage dependent anion channels (VDAC)
into the cytosol and is converted into H2O2 spontaneously or by
superoxide dismutase 1 (SOD1) [25]. Additionally, NOX2 triggers
the transfer of electrons from intracellular NADPH across the cell
membrane to oxygen, producing superoxide in the extracellular
space. Here, superoxide can either enter the cell through chloride
channels or SOD3 dismutates superoxide into H2O2, which freely
diffuses across membranes [26]. It is worth mentioning that SOD
proteins have the largest kcat/KM (catalytic efficiency) of any known
enzyme (7 109 M 1 s 1), making the dismutation of superoxide
to H2O2 diffusion-limited [27]. In the presence of ferrous or
cuprous ions, mitochondrial and NOX-produced H2O2 can become
OH in a process called the Fenton Reaction. OH are very reactive
and cause oxidation of lipids, proteins and DNA resulting in
damage to the cell. Due to its extremely high reactivity, OH have a
short half-life and their diffusion is limited to their site of
production. Another cell damaging form of ROS is peroxynitrite,
which is generated from the reaction of superoxide with excess
nitric oxide [28]. In contrast, H2O2 is the most stable form of ROS
and, in the low nanomolar range can impinge on cellular signaling
by interacting with select cysteine residues on target proteins [29]
(Figure 1). Unlike superoxide and OH, H2O2 readily diffuses
through membranes making it an ideal intracellular signaling
molecule. Here, it is important to note that mitochondria and NOX
proteins can spatially localize to the signaling proteins that are
responsive to the produced ROS.
2.2. Intracellular regulation of ROS
Given the reactivity and toxicity of high levels of ROS, and given
that specific, locally produced quantities of ROS determine various
cellular signaling events (Fig. 1), spatial and temporal regulatory
strategies must exist to regulate intracellular ROS levels. Superoxide produced by NOX proteins and the mitochondria can oxidize
and damage iron-sulfur clusters of proteins. However, specific SOD
enzymes can localize to the mitochondria (SOD2), the cytosol
(SOD1) and the extracellular matrix (SOD3) and convert superoxide to H2O2 at a rate that is diffusion-limited (catalytic efficiency:
Kcat/Km 7 109 M 1 s 1) [30]. Therefore intracellular superoxide
concentrations are very low. H2O2, the more stable and diffusible
form of ROS, is selectively reactive towards cysteine residues on
proteins and therefore can control cell signaling. There are ample
mechanisms in place that convert intracellular H2O2 to water and
therefore control cysteine modifications, protein and signaling
pathway activity. Peroxiredoxins (PRXs) have emerged as critical
regulatory systems that quench H2O2 [27]. Six mammalian PRXs
have been identified and are located in the cytosol and
mitochondria. PRXs function by undergoing H2O2-mediated
oxidation of their active site cysteines. This process removes
H2O2 from the cell and inactivates PRXs. The inactivation can be
reversed by thioredoxin (TRX), thioredoxin reductase and the
reducing equivalent NADPH [31]. Glutathione peroxidases (GPXs)
can also convert H2O2 to water in the cytosol and mitochondria.
The eight known GRXs function similar to PRXs and eliminate H2O2
through the H2O2-mediated oxidization of glutathione (GSH), the
most abundant antioxidant in the cell [32]. GSH can get reduced
and therefore re-activated by glutathione reductase and NADPH.
Lastly catalase is found in peroxisomes and removes intracellular
H2O2 without cofactors (Fig. 1).
In addition to antioxidants, transcription factors nuclear factor
erythriod 2-related factor 2 (NRF2) and forkhead box O (FOXO) are
master regulators of antioxidant expression. Under normal
conditions NRF2 localizes in the cytoplasm, where it interacts
with the actin-binding protein, Kelch-like ECH-associated protein
1 (KEAP1) [33,34]. KEAP1 functions as an adaptor of Cul3-based E3
3
ubiquitin ligase and targets NRF2 for proteasomal degradation
[35]. Upon pathway activation, NRF2 dissociates from KEAP1 and
translocates to the nucleus, heterodimerizes with small proteins
(MAFs) and then binds to antioxidant-responsive elements (AREs)
within regulatory region of many genes. NRF2 modulates
transcription of around 200 genes whose protein products function
as antioxidants, detoxification enzymes, heat-shock proteins and
GSH-synthesis enzymes. These proteins all play a role in cellular
defense against oxidative stress [36]. NRF2 also activates antioxidant enzymes such as heme oxygenase-1, PRXs, catalase, GPXs,
SOD2 and TRX (Fig. 1). Furthermore, NRF2 regulates the de novo
synthesis of GSH by (1) activating the gene expression of
glutamylcysteine synthetase components [33] [12] and by (2)
controlling the abundance of cysteine within the cells, which is a
required substrate for GSH synthesis. This is regulated through
NFR2-mediated expression of the cysteine/glutamate antiporter
(xCT) [37]. In exchange for glutamate, xCT imports cysteine. FOXOs
also control ROS levels by promoting the expression of genes
associated with cell cycle arrest, apoptosis, tumor suppression and
antioxidant defense [38,39].
Regulating intracellular ROS levels through ROS production and
ROS elimination is essential to control various cell signaling events
and is utilized by normal cells and cancer cells to support the
signaling required for cell proliferation, angiogenesis, invasion and
survival. Interestingly, cancer cells also utilize ROS scavenging
systems, including NRF2 and the related antioxidant systems, to
control their oxidative stress phenotype to prevent cell death
[1,40]. This following section will focus on how ROS promote cell
signaling which lays the foundation to investigate the contradictory role of ROS in cancer.
3. ROS and cancer
3.1. ROS regulate cell signaling
Traditionally ROS have been thought of as toxic metabolic
byproducts, which cause cellular damage. However, various
studies over the last decade have shown that low levels of ROS,
which are spatially localized produced, permit for a large range of
effects that allow for the maintenance of homeostasis [41,42].
Upon stress stimuli these baseline levels of ROS can fluctuate to
control biological outcomes and regulate cell signaling by directly
reacting with, and modifying the structure of proteins, transcription factors and genes, to modulate their functions. The following
sections will discuss how ROS control cell signaling, describe the
ROS status of cancer cells and the pro- as well as anti-tumorigenic
roles of ROS, which can be potentially exploited therapeutically.
ROS are produced at specific cellular locations by mitochondria
and NOX proteins. The ROS entity H2O2 can reversibly oxidize
cysteine residues on proteins. The best-characterized classes of
redox-regulated targets are phosphatases, which can negatively
regulate cell signaling through the de-phosphorylation and
inactivation of kinases [43,44]. However, kinases, transcription
factors and antioxidant proteins like GSH and PRX are also direct
physiological targets of H2O2 [27,45,46]. The redox-regulatory
properties of cysteine depend on protein context. Protein tyrosine
phosphatase active sites are susceptible to redox regulation
because they possess a common motif (Cys-X5-Arg), which
renders their active site cysteine (SH) in a thiolate state (S ).
Thiolated cysteines are nucleophiles (pKa = 4.7–5.4), making them
highly susceptible to H2O2-oxidation, which results in the
generation of different, reversible redox forms. Reversible modifications include sulfenic acid (SO ), disulfide bonds (S–S) and
sulfenic–amide bonds (S–N), which can inactivate protein activity.
Prolonged oxidative stress can also lead to hyper-oxidation of
protein targets resulting in irreversible modifications, which
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include sulfinic (SO2 ) or sulfonic acids (SO3 ) [47]. H2O2regulated signaling pathways include pro-survival and proproliferative pathways like phosphatidylinositol 3-kinase
(PI3K)/AKT, hypoxia-inducible factor (HIF) and mitogen-activated
kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling cascades [4], but also death-inducing pathways like c-Jun Nterminal kinase (JNK) and P38 MAPK [5,22,48]. Additionally to
H2O2, superoxide can react and inactivate iron-sulfur proteins like
aconitase, which can be toxic to the cell [26]. However, the reaction
of superoxide with protein thiols is not fast enough to compete
with the powerful SOD enzymes which rapidly dismuate
superoxide, making H2O2 the dominant signaling ROS [27].
3.2. ROS stress and adaptation in cancer cells
ROS homeostasis is required for proper cell signaling and
cellular fitness in normal cells. ROS levels in the nanomolar range
can be potent mitogens and initiate cellular adaptations that lead
to cell survival, growth, proliferation and angiogenesis in a
controlled manner. However, higher ROS levels can be toxic to
the cell and therefore can trigger signaling pathways initiating cell
proliferation arrest or even cell death.
3.2.1. ROS stress in cancer cells
Fig. 2 Cancer cells are characterized by an increased rate of
spatially localized ROS production, compared to normal cells due
to a loss in proper redox control [1,49]. This occurs in order to
hyper-activate signaling pathways that promote cell proliferation,
survival and metabolic adaptation to the tumor microenvironment. For example leukemia cell samples from patients showed
increased ROS production compared to normal lymphocytes [50]
and solid tumor patient samples had increased levels of oxidative
DNA damage [51]. Reasons for the increased rate of ROS production
in cancer cells are alterations in signaling pathways that affect
cellular metabolism. The tumor suppressor P53 has a crucial role in
initiating antioxidant genes in response to oxidative stress to
prevent DNA, protein or lipid damage and to restore redox balance
[52]. P53 mutations or the loss of P53 are seen in over 50% of human
cancers and are associated with increased ROS stress and
aggressive tumor growth [53]. Furthermore, oncogenes that lead
to increased ROS production include RAS, MYC and AKT [54].
Downstream of RAS, the PI3K/AKT/mTOR survival pathway is
activated in a majority of cancers [55]. AKT activation is associated
with ROS accumulation partially through the AKT/mTOR-dependent increase in mitochondrial metabolism [56] and the AKTdriven phosphorylation and inhibition of FOXO transcription
factors [57], which promote antioxidant defense. Oncogenic
activation of AKT can therefore result in increased ROS production
from the mitochondria through metabolic pathways, and by
impairing ROS scavenging though the inhibition of FOXOs [38].
Another tumor-associated condition with respect to ROS is
hypoxia. Hypoxia is a feature of most tumors and arises because
of oxygen diffusion limitations in avascular primary tumors or
their metastases [58]. Research showed that hypoxia leads to an
increase in mitochondrial ROS produced from complex III of the
electron transport chain. ROS can subsequently stabilize HIF-1a
[59]. The exact mechanism by which hypoxia leads to complex III
ROS production is currently unknown. Mutations in nuclear
encoded mitochondrial enzymes have also been found in certain
cancers but exceed the scope of this review [3].
3.2.2. ROS adaptation of cancer cells (Fig. 2)
In order to survive the oxidative stress environment just
described, cancer cells adapt and acquire mechanisms to
counteract the potential toxic effects of ROS stress in order to
promote proximal pro-tumorigenic signaling. More specifically, to
avoid the detrimental effects of ROS, cancer cells actively upregulate various antioxidant proteins at the sites of ROS production
[7] [60]. For example, RAS transformed cells, which are characterized by oxidative stress, were shown to have higher levels of PRXs
and TRXs compared to normal cells [61]. The antioxidant master
regulator NRF2 is also activated and stabilized by various
oncogenes including KRAS, MYC and PI3K [11], which promote
cancer cell growth and survival. Furthermore primary tissue
samples from cancer patients showed increased levels of ROSscavenging enzymes such as GPXs, SODs and PRXs, and also
mutations in the NRF2 inhibitor KEAP1, suggesting a control of
redox balance in cancer cells, which aids tumorigenesis [8,62–65].
In the past, antioxidants were solely seen as tumor suppressors.
However, recent research uncovered the ‘‘dark side of antioxidants’’ [66,67], which are used by cancer cells to promote survival
and growth.
Cancer cells function with higher rates of ROS production and
higher levels of antioxidant proteins compared to normal cells in
order to maintain redox homeostasis. This permits high ROS levels
to activate proximal pro-tumorigenic signaling pathways without
building up excessively high ROS, which could induce cell death or
senescence. It is important to note that this balance leads to the
fact that steady state levels of ROS in cancer cells might actually be
similar to those in normal cells. While ROS contribute to cancer
development and progression [51,68], oxidative stress can also
potentially have anti-tumorigenic effects. The following sections
will discuss how ROS can either promote or limit cancer, which sets
the stage for redox modulation anti-cancer therapies.
3.3. ROS promote pro-tumorigenic cell signaling
Fig. 2. Cancer cells adapt to oxidative stress by up-regulating antioxidant proteins.
Low levels of ROS can be mitogens and initiate cellular adaptations that lead to cell
survival, growth, proliferation and differentiation in a controlled manner. Cancer
cell characteristics like oncogene activation, enhanced metabolism, hypoxia or the
loss of the tumor suppressor p53 can lead to an accumulation of ROS, which allows
for hyper-active cell signaling and pro-tumorigenic signaling events. In order to
counteract the oxidative stress and to prevent oxidative damage and cell death,
cancer cells up-regulate ROS scavenging systems to keep ROS levels under the
cytotoxic limit. Cancer cells function at ROS levels that are high enough to support
pro-tumorigenic cell signaling without inducing cell death. Thus, cancer cells are
ROS- as well as antioxidant-addicted.
ROS promote adaptation to hypoxia, cell proliferation, cell
growth and survival in normal cells in response to various
growth and survival stimuli [69]. This suggests that the hyperactive mitogenic and pro-survival signaling effects of ROS in
cancer cells may be a universal occurrence. Indeed, research
indicates that the increased rate of ROS production in cancer
cells plays a causal role in the acquisition of various hallmarks of
cancer: sustained cell proliferation and mitogenic signaling [4],
increased cell survival and disruption of cell death signaling
[70,71], epithelial to mesenchymal transition (EMT), metastasis
[72] and angiogenesis [73].
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3.3.1. ROS promote tumor cell proliferation
In various cancer cells, exogenous addition of H2O2 or endogenous oncogene-induced production of ROS have been shown to
enhance proliferation by increasing pro-proliferative signaling
pathways like PI3K/AKT/mTOR and MAPK/ERK cascades. ROS
promote oxidation and inactivation of the phosphatases; protein
tyrosine phosphatase 1B (PTP1B) [74,75] and phosphatase and
tensin homolog deleted on chromosome 10 (PTEN) [43,76], which
both inhibit PI3K/AKT signaling. Furthermore ROS inactivate
pathway-inhibiting MAPK phosphatases to activate mitogenic
signaling [77]. As described before (see Section 3.1), phosphatase
inhibition is medicated through the oxidation of active site
cysteines. ROS-mediated cancer cell proliferation was observed in
breast [78], lung [2], liver [79] and various other cancer cells and was
prevented by the addition of ROS-scavenging antioxidants [80,81].
Our lab has shown that mitochondrial-derived ROS are required for
anchorage-independent growth in KRAS-driven lung cancer cells
through the regulation of MAPK/ERK signaling. Furthermore,
disruption of mitochondrial function, which increases ROS, reduced
tumorigenesis in an oncogenic mouse model of lung cancer [2].
3.3.2. ROS promote tumor cell survival
As mentioned, aberrant ROS levels hyper-activate PI3K/AKT
survival signaling through the inhibition of PTEN. ROS-induced
PI3K/AKT signaling and survival was shown in a mouse model of
prostate cancer [82] and various other cancers [15,83]. As
previously stated, oncogenes including KRAS and AKT can also
activate and stabilize the antioxidant master regulator NRF2 [20],
which has been shown to play a critical role in the protection
against oxidative stress to promote cell survival [33,84]. ROS can
activate NRF2 through the oxidation and inactivation of KEAP1 at
redox-sensitive cysteine sites. This oxidative modification inhibits
KEAP1-mediated proteasomal degradation of NRF2, allowing for its
stabilization, nuclear accumulation [85] and pro-survival signaling
in cancer cells. Lastly, ROS also promote cell survival in colon
cancer and melanoma cells through the activation of redoxsensitive nuclear factor kappa B (NFkB) signaling [86,87]. In
response to ROS, active NFkB controls cell survival through the upregulation of various pro-survival genes including B-cell lymphoma 2 (BCL2), caspase inhibitors and antioxidant proteins [88,89].
3.3.3. ROS promote angiogenesis and metastasis
Tumor angiogenesis, invasion and metastasis are interrelated
processes and induce the final, most devastating, stage of
malignancy. Angiogenesis vascularizes solid tumors in order to
provide nutrients and oxygen for continuous tumor growth. The
main angiogenic growth factor triggering formation of new blood
vessels is vascular endothelial growth factor (VEGF), which gets
activated downstream of HIFs [90]. As mentioned previously,
hypoxia is a hallmark characteristic of many cancers [58] and has
been shown to increase ROS production [59]. ROS leads to HIFa
stabilization through the inhibition of prolyl hydroxylases (PHDs)
[91,92], which under normoxic conditions mark HIFa for proteasomal degradation [93,94], and subsequent VEGF activation. ROS
have been shown to stabilize HIFa [95], leading to VEGF activation
and subsequent angiogenesis and tumor progression; this effect
could be prevented by the antioxidant N-acetyl-cysteine (NAC)
[96,97]. NAC treatment also prevented HIF stabilization and
diminished MYC-mediated tumorigenesis in vivo [80]. Angiogenesis allows for cancer cell migration and metastasis. Metastasis
requires extracellular remodeling and intracellular adaptations
including EMT, reduced cell adhesion, increased migration and
degradation of tissue barriers and extracellular matrix [98]. ROS
have been shown to mediate metastasis in various cancer cell
types through the regulation of transcription factors and signaling
components including MAPK and PI3K/AKT pathways, HIFs and
5
the EMT regulator Snail [99–102]. ROS can also modulate
structural changes in tumor cells like the formation of invasive
microdomains called invadopodia [103], which promote cell
invasion and metastasis. Furthermore ROS promote the activation
of matrix metalloproteinases (MMPs) [104,105] that participate in
the degradation of membranes and help detach primary tumor
cells from extracellular matrix [106]. Taken together, these
ROS-mediated events promote tumor progression.
3.4. ROS promote anti-tumorigenic cell signaling
While ROS are associated with the activation of pro-tumorigenic survival and growth pathways, oxidative stress can also lead
to the induction of cell death and cell cycle arrest.
3.4.1. ROS promote cell death through the ASK1/JNK/P38 MAPK
signaling pathway
Apoptosis signal-regulating kinase 1 (ASK1) has been shown to
act as a redox sensor by mediating the sustained activation of JNK
and P38 MAPK, resulting in apoptosis upon excessive oxidative
stress [5]. In its inactive state, ASK1 is coupled to the reduced form
of TRX1, which prevents ASK1 activation. TRX1 can be oxidized
upon ROS at two cysteine residues, resulting in its dissociation
from ASK1 [107]. Activated ASK1 can then trigger apoptosis
through MAP kinase-kinase (MKK)4- and 7-mediated JNK activation or MKK3- and 6-mediated P38 activation [108]. JNK and P38
MAPKs trigger the expression of pro-apoptotic factors [109] and
the down-regulation of anti-apoptotic factors [110–112]. P38
MAPK has been established as a tumor suppressor and ROS sensor
in tumorigenesis [111]. Supporting this fact, various aggressive
human cancer cell lines with high levels of ROS have impaired P38a
activation and thus can avoid cell death signaling [113].
3.4.2. ROS regulate cell cycle arrest
High levels of ROS have been shown to inhibit cellular
proliferation in order to prevent cell division through the oxidation
and negative regulation of pro-proliferative kinases, which contain
redox-sensitive cysteines. For example, ROS-induced P38/JNK
MAPK signaling can lead to the down-regulation of cyclins and
the induction of cyclin-dependent kinase (CDK) inhibitors
[114,115] resulting in cell cycle arrest. ROS can also induce cell
cycle arrest directly through the oxidation of various cell cycle
regulators. One example is the H2O2-mediated oxidation
and inactivation of the cell cycle phosphatase cdc25, which
is required for cell cycle progression from G2 to M phase [116].
ROS-mediated cell cycle arrest has been demonstrated in many
systems in vitro and recently also in a number of cases in vivo
[117,118]. Furthermore ROS can induce reduction of tumor
angiogenesis and metastasis [19,21].
In summary, ROS have a causal role in tumorigenesis but can
also be toxic to the cell and can potentially induce cancer cell
death, cell cycle arrest and inhibit cancer progression. Therefore
cancer cells are dependent on maintaining high enough ROS levels
that allow for pro-tumorigenic cell signaling without inducing cell
death. The reliance of cancer cells on ROS homeostasis can be
potentially exploited to target them therapeutically. The next
section will focus on strategies to exploit the unique redox status of
cancer cells for therapeutic purposes; a novel treatment strategy
that potentially allows for the selective targeting of cancer cells.
4. Modulating ROS levels to treat cancer
4.1. Decrease ROS levels
Due to the causal role of ROS in promoting cancer (see Section
3.3) and the fact that various antioxidant promoters like NRF2
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are considered tumor suppressors, so far, research focused on
antioxidant treatments to dampen ROS levels as therapeutic
strategies against tumorigenesis [119,120]. Antioxidant treatments include supplementation of natural ROS scavengers
[121,122], treatment with exogenous antioxidants [123–125]
and also other strategies that decrease oxidative stress like the
disruption of the ROS-producing mitochondrial electron transport
chain [2]. One of the most published on transcriptional effects of
antioxidant treatments is the regulation of HIF1 levels. As
mentioned, ROS regulate hypoxic activation of HIF [95] (see
Section 3.3). Supporting this data, antioxidants like NAC and
vitamin C have been shown to prevent HIF stabilization and
diminish MYC-mediated tumorigenesis in vivo [80]. Other studies
also reported anti-tumorigenic results of antioxidant treatments in
vitro [126–128], including overexpression of SOD3, which
inhibited breast cancer metastasis in a mouse xenograft indicating
the potential anti-tumorigenic effect of restoring extracellular
superoxide scavenging capacity [129].
However, most clinical trials have failed to show beneficial
effects of antioxidants on a variety of pathologies including cancer
[130,131]. Long-term studies showed that taking vitamin E
supplements significantly increased the risk of prostate cancer
in healthy men [132] and supplementation with b-carotene,
vitamin A or E increased the incidence of lung cancer [133,134]. A
recent study agrees with these findings showing that antioxidants,
NAC and vitamin E, accelerated lung cancer progression in mice by
reducing ROS [67]. NAC also did not affect tumorigenesis in
multiple breast cancer models in vivo [135]. Here, NAC treatment
diminished HIF levels but actually increased metastatic burden.
Overall, nine long-term, randomized controlled trials of antioxidant supplements for cancer prevention did not provide evidence
that dietary antioxidant supplements are beneficial in primary
cancer prevention [127,132–134,136–140]. The reason that
antioxidants display poor efficacy as anticancer agents might be
due to the fact that many of the therapeutic antioxidants are not
effective in targeting the locally produced pools of ROS, which are
required for tumorigenic signaling. Mitochondrial targeted antioxidants for example would be a way to address this issue. These
targeted antioxidants have shown efficacy in diminishing tumorigenic potential when dietary ones failed to do so [2,141]. However,
major caveats of antioxidant-based therapy remain that (1) ROS
and ROS-dependent cell signaling are essential for normal cell
function and can promote tumor cell survival in cases when ROS
are required for cell death of transformed cells and (2) that
antioxidants can interfere with chemotherapy, which are dependent on ROS-induced cytotoxicity [142]. Due to the negative
results of dietary antioxidant cancer therapies, recent studies have
focused on alternative ways to exploit the aberrant redox status of
cancer cells for therapeutics. Since exceedingly high levels of ROS
can induce cell death and cell cycle arrest (see Section 3.4), cancer
cells, with an increased rate of ROS production, are potentially
more vulnerable to damage by further ROS insult [60,143,144].
Therefore, elevating ROS levels, either by increasing ROS generation or decreasing ROS scavenging potential, could be a way to
selectively kill or arrest cancer cells without causing significant
toxicity to normal cells with a lower rate of ROS production and
lower levels of antioxidant proteins.
4.2. Increase ROS levels
Many chemotherapeutic agents as well as ionizing radiation
function by promoting ROS production and therefore causing
irreversible oxidative damage [145,146]. Chemotherapeutic drugs
such as taxanes (e.g. paclitaxel), vinca alkaloids and anti-folates
promote mitochondrial cell death through the release of cytochrome c and also disrupt the mitochondrial electron transport
chain which leads to increased superoxide production [147]. Other
chemotherapeutics like cisplatin, carboplatin and doxorubicin also
significantly increase ROS, which is the basis of their antitumorigenic effect [148,149]. One of the first ROS-producing
anticancer drugs was procarbazine [150], which is readily oxidized
to its ROS-producing azo derivative and is approved for the
treatment of lymphoma and primary brain tumors. Targeted ROSproducing drugs also include monoclonal antibodies like rituximab, an anti-CD20 antibody that is used for the treatment of nonHodgkin’s lymphoma [151]. Arsenic trioxide (ATO) impairs the
function of the mitochondrial electron transport chain and
therefore increases superoxide production [144]. ATO agents can
effectively treat acute promyelocytic leukemia (APL) and some
other ROS-dependent leukemia [152]. Elesclomol (STA-4783) is
another ROS-generating compound in clinical trials for malignant
melanoma. It was shown to increase progression-free survival in
phase II clinical trials given as a single agent, and efficacy was even
increased in combination with the chemotherapy agent paclitaxel.
The mechanism by which Elesclomol increases ROS is unknown
but neutralization of ROS by antioxidants suppressed the drug’s
effectiveness [153].
A well-known problem with many chemotherapeutic cancer
drugs, which produce extreme levels of ROS, is the toxic effect on
normal, healthy cells. Other, more targeted ROS producing cancer
drugs have also shown promise by inducing cancer cell apoptosis.
A recent study identified a genotype-selective drug that induces
oxidative stress. The piperidine derivative lanperisone was
identified out of a small molecule, synthetic lethal screen using
oncogenic KRAS-driven mouse embryonic fibroblasts (MEFs). The
compound selectively killed KRAS-mutant cells through the
induction of ROS, which is mediated through RAS-MEK-MAPK
signaling. Normal, KRAS-wildtype MEFs were unaffected by
lanperisone. The drug also showed efficacy against tumor growth
in a KRAS-driven mouse model of lung cancer [16].
4.3. Target antioxidants to decrease ROS scavenging capacity
A downside of ROS-production therapy is that cancers can
become resistant to the sole exogenous increase of ROS. For
example multi-drug resistant HL-60 leukemia is resistant to the
raising of ROS due to endogenous elevation of antioxidants like
catalase that detoxify and scavenge ROS [13]. As already
mentioned, various oncogene-induced cancer cells increase
antioxidant proteins, such as activation of NRF2 [8,11,20,154] to
maintain ROS levels that allow pro-tumorigenic signaling pathways to be activated without inducing cell death. Furthermore,
GSH metabolism, specifically an increase in GSH, seems to play an
active role in protecting cancer cells from cell death and also from
ROS-inducing therapy strategies like chemotherapy and radiation
[14].
The reliance on antioxidants may represent the cancer cell’s
‘‘Achilles Heel’’, as non-transformed have a lower rate of ROS
production and therefore are less dependent on their detoxification by antioxidants. In fact, studies have shown that disabling
antioxidant mechanisms trigger ROS-mediated cell death in a
variety of cancer cell types [15,17,18,22] (Fig. 3). Phenethyl
isothiocyanate (PEITC) conjugates with GSH through electrophile–
nucleophile interactions, depleting the GSH pool and leading to
oxidative stress and cancer cell death. Additionally, the drug
inhibits GPX activity. PEITC led to cell death in HRAS (V12)
transformed ovarian cancer cells and BCR-ABL transformed
hematopoietic cells. The compound also prolonged survival in
an ovarian cancer cell xenograft model [15]. L-Buthioninesulfoximine (BSO) targets de novo GSH synthesis as an inhibitor
of glutamylcysteine synthetase (g-GCS) [155]. BSO depletes GSH
[156] and exhibits anticancer activity through apoptosis as a single
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Fig. 3. The Achilles Heel of cancer cells.
(a) In non-transformed cells and cancer cells, ROS levels are kept in balance through ROS production and ROS elimination. ROS homeostasis is required to provide a favorable
signaling environment. In cancer cells both processes occur at an increased rate compared to normal cells, making cancer cells more dependent on their ROS scavenging
capacity. (b) The reliance of cancer cells on antioxidants can potentially be used to selectively target them therapeutically. Various studies (see Section 4.3) have shown that
antioxidant inhibitors have anti-tumorigenic effects without affecting normal, non-transformed cells. (c) Antioxidant inhibitors diminish the ability of cells to scavenge ROS.
This event leaves cancer cells, which are characterized by an increased rate of ROS production, with a large overload of ROS. (d) Normal cells are somewhat affected by the
small overload of ROS after antioxidant inhibition, but do not lose cellular homeostasis completely. Cancer cells on the other hand, which are left with a large overload of ROS,
lose homeostasis and die due to oxidative stress.
agent and in combination with ATO in solid tumors and APL cells
[157,158]. BSO also increased efficacy of cisplatin in preclinical
studies [159]. Similar to BSO, Imexon also has GSH-depleting, ROSaccumulating, and death-inducing potential as shown in a phase I
study of non-Hodgkin’s lymphoma [160] and melanoma patients
[161]. Recently, a cell-based molecular screen for pro-apoptotic
effects in cancer but not normal cells, identified the natural, plantderived compound piperlongumine (PL). PL leads to an increase in
ROS by binding and modulating the antioxidant enzyme glutathione transferase and therefore changes the ROS-stress response. PL
induces apoptosis in osteosarcoma, breast, bladder and lung cancer
cells but has little effect even on rapidly dividing, primary normal
cells. The compound also showed efficacy in mouse models of
breast, bladder and lung cancer [17]. As mentioned before, cysteine
is required for GSH synthesis. Inhibition of the solute carrier family
7 member 11 (SLC7A11), which encodes the cysteine/glutamate
antiporter (xCT), with sulphasalazine (SASP) decreases cysteine
and GSH levels and increases ROS. SASP has shown to
reduce pancreatic cancer cell growth and viability in vivo and in
vitro [162] and has shown efficacy in a small-cell lung cancer
xenograft model [163]. A recent study also identified xCT as a
therapeutic target in a xenograft model of triple-negative breast
cancer [164].
Another thiol-based antioxidant is thioredoxin (TRX). TRXs are
up-regulated in various cancer cells [61] and the TRX inhibitor PX12 showed anti-tumor activity in vivo [165]. ATO, additionally to
inducing superoxide production, has been shown to inhibit
thioredoxin reductase (TRXR) and to increase ROS levels [166].
Furthermore, motexafin gadolinium is a TRXR inhibitor that
selectively localizes in tumors [167]. The drug showed anti-tumor
activity in a phase II trial in patients with chronic lymphocytic
leukemia [168] and in phase III clinical trials of patients with
metastatic non-small cell lung cancer (NSCLC) [169]. Finally the
gold compound auranofin is a TRX inhibitor and has been shown to
cause sensitivity of head and neck squamous cell carcinoma cells to
EGFR inhibitors [170], and also cause cell death of ovarian cancer
cells [171]. Cell death was shown to be ROS-mediated.
Furthermore the antioxidant SOD1, which converts superoxide
into H2O2, has emerged as a target to selectively kill cancer cells.
Malignant cells are highly dependent on SODs to keep ROS levels
under the cytotoxic limit. Varmus and colleagues utilized an
unbiased small molecule screen and identified SOD1 as a target for
inhibitors of the growth of both KRAS- and EGFR-mutant lung
adenocarcinoma cells in vitro. SOD1 was also shown to be
expressed at higher levels in lung adenocarcinomas compared
to normal lungs [172]. The SOD1 inhibitor methoxyestradiol
(2-ME) increases superoxide [173] and is currently in phase I and II
clinical trials for prostate and metastatic breast cancer [174,175]. It
also induces ROS-mediated apoptosis selectively in leukemia cells
but not normal lymphocytes [173] and in neuroblastoma cells
[176]. Furthermore, recent studies identified the copper chelator
and SOD1 inhibitor ATN-224 to cause selective cancer cell death
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and growth impairment in various cancer cells through ROSmediated mechanisms [177–179]. The compound showed efficacy
in an oncogenic KRAS/P53-deficient mouse model of NSCLC. ATN224-induced cancer cell death was mediated through ROSdependent activation of P38 MAPK, leading to a decrease in the
anti-apoptotic factor MCL1 [22]. Interestingly, extracellular SOD3
is differentially expressed in cancers. SOD3 mRNA was shown to be
decreased in some clinical mammary adenocarcinoma samples
compared to normal mammary tissues and research found that
overexpression of SOD3 inhibited breast cancer metastasis in a
mouse xenograft model [129]. On the other hand, SOD3 is shown to
be amplified in various other cancers for example sarcomas
(cBioPortal for Cancer Genomics Database) making it a potential
target for silencing in these cancers.
Finally, the antioxidant master regulator NRF2 presents a
possible anti-cancer therapeutic target. As previously mentioned,
oncogenes like KRAS, MYC and PI3K have been shown to stabilize
NRF2 and therefore antioxidant proteins [8,11,20,154]. Additionally, mutations in NRF2 and inactivating mutations in its negative
regulator KEAP1 have been identified in various cancers leading to
the constitutive stabilization and transcription activity of NRF2
[64,65,180]. This data suggests a promoting role for NRF2 activity
in tumorigenesis. Hence, NRF2 inhibition has the potential to
dampen various antioxidant systems and induce ROS-mediated
cancer cell death. Effective NRF2 inhibitors have yet to be
developed and tested for anti-cancer effects.
4.4. Metabolic and redox modulation: combination therapy option
Pro-oxidant therapy can exploit the difference between normal
cells and cancer cells based on their difference in the rate of ROS
production and resulting redox regulation. However, off-target
cytotoxicity from high doses of ROS-generators is still a major
concern, as is the compensatory up-regulation of various antioxidants, which counteracts the ROS-generating compounds.
Combination therapy, meaning the simultaneous treatment with
various anti-cancer agents is one possibility to (1) lower drug
treatment doses, (2) augment drug efficacy and (3) also impair
central parts of the antioxidant machinery. To that end, metabolic
modulation is a suitable candidate for combination therapy with
ROS-generators or ROS-scavenging inhibitors. Metabolic reprogramming, similar to aberrant redox adaptation, is cancer cell
specific, which further opens the therapeutic window. Metabolism
pathways, which will be elaborated on here, play a central role in
regulating redox balance particularly through the production of
reducing equivalents like NADH and NADPH, which are required
for the function of various antioxidant proteins. Based on this
knowledge, targeting the unique metabolic and redox balance
pathways of cancer cells, will potentially allow to biosynthetically
starve cancer cells and also induce cancer-killing redox stress.
The metabolic pathway predominantly involved in redox
modulation is glutamine metabolism. It plays a central role in
redox regulation and antioxidant response through the generation
of GSH and the reducing equivalent NADPH. Glutamine is the
precursor of glutamate, which, as previously mentioned, is
required for GSH synthesis and therefore antioxidant response.
Glutamine metabolism has been shown to be required for cancer
cell survival leading to the notion that some cancers are glutamineaddicted [181–183]. Inhibition of glutaminase 1 (GLS1), the
enzyme that converts glutamine to glutamate for entry into the
TCA cycle, inhibits oncogenic transformation [2,184]. Furthermore,
an approved agent for the treatment of leukemia has been shown
to deplete glutamine levels and therefore GSH synthesis. The drug
L-asparaginase was thought to function through its role in limiting
asparagine levels, however recent data has shown that the anticancer effect of the drug can be attributed to its effect on glutamine
levels [185]. Finally, the alternative glutamine pathway, mediated
by the aspartate transaminase GOT1 has been shown to be
required for KRAS-driven pancreatic ductal adenocarcinoma
(PDAC) growth in vitro and in vivo [186]. GOT1 is a key enzyme
in the aspartate-malate shuttle, producing pyruvate and increasing
the NADPH/NADP+ ratio, which in turn maintains reduced GSH
levels and therefore redox homeostasis. Indeed, GOT1 inhibition
led to a decrease in the ratio of reduced-to-oxidized GSH, an
increase in ROS levels and suppression of PDAC growth. The role of
glutamine metabolism in NADPH production and GSH synthesis
makes glutamine pathway inhibitors potentially suitable partners
for pro-oxidants in anti-cancer therapy.
5. Conclusion
Studies over the past several years have established a causal
role of ROS in maintaining cellular homeostasis and also in
triggering cell signaling events and stress adaptation [69]. Cancer
cells, compared to normal cells, have an increased rate of ROS
production as byproducts of their increased metabolism [1] and
furthermore have aberrant ROS regulation mechanisms to cope
with their unique redox status. The fact that ROS have a welldefined role in promoting and maintaining tumorigenicity [2–4],
led to the assumption that antioxidants could prevent or reduce
tumorigenesis [187]. However, most clinical trials have failed to
show beneficial effects of dietary antioxidants in a variety of cancer
types [132]. In fact, there has been evidence indicating that dietary
antioxidants contribute to tumorigenesis by reducing the potentially death-inducing oxidative stress in cancer cells [188]. This
failure of therapeutic antioxidants might be due to the fact that
they are unlikely to diminish the local pools of ROS required for
pro-tumorigenic signaling. Thus, recent studies have focused on
alternative ways to exploit the aberrant redox status of cancer cells
for therapeutics. Since exceedingly high levels of ROS can induce
cell death, research has focused on pro-oxidant approaches to
cancer therapy [60]. Chemotherapy, radiation and also small
molecule compounds induce cancer cell death by increasing
intracellular ROS [16,188]. However, cancer cells are masters of
adaptation and even though oncogene mutations, reprogrammed
metabolism, extreme microenvironments and nutrient starvation
induce highly stressful conditions, tumor cells manage to regulate
and adapt to these stressors and advantageously survive and
proliferate. Hence, cancer cells have the ability to develop
resistance to therapeutics that exogenously raise ROS by increasing their antioxidant mechanisms, such as activation and
stabilization of the antioxidant master regulator NRF2 [8,11,154]
or other ROS scavengers [13,14]. With that, tumor cells can
Fig. 4. Pro-oxidants as cancer therapeutics.
Redox modulation therapeutics used to focus on antioxidant cancer treatments
(left) because of the role of ROS in promoting tumorigenesis. However these
therapies did not show success in the clinic (see Section 4.1). Recent studies suggest
pro-oxidant cancer therapy (right), especially the inhibition of ROS scavengers and
antioxidants, to selectively target cancer cells by inducing ROS-dependent cancer
cell death.
Please cite this article in press as: Glasauer A, Chandel NS. Targeting antioxidants for cancer therapy. Biochem Pharmacol (2014),
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A. Glasauer, N.S. Chandel / Biochemical Pharmacology xxx (2014) xxx–xxx
maintain ROS levels that allow proximal pro-tumorigenic signaling
without inducing cell death, but at the same time they also rely
more heavily on ROS detoxification compared to normal cells with
lower metabolic demands and rates of ROS production. This
reliance on high levels of antioxidants may represent the cancer
cell’s ‘‘Achilles Heel’’ [189].
The impairment of redox scavenging, or antioxidant systems
opens a novel therapeutic window and has potential to selectively
induce cancer cell death via oxidative stress, while sparing normal
cells (Fig. 4). In fact, studies have shown that disabling antioxidant
mechanisms trigger ROS-mediated cell death in a variety of cancer
cell types in vitro and in vivo [15,17,18,20,22]. Hence, the design of
dual pro-oxidant therapies has the potential to be efficacious in
selectively killing cancer cells. Combining ROS-generating agents
with ROS-scavenging inhibitors like GSH, TRX or SOD inhibitors
can diminish the ability of cancer cells to adapt to either agent.
Even though various antioxidant proteins and regulators are upregulated in cancers and can be efficiently targeted to cause antitumor effects, it will be necessary to do careful antioxidant
profiling of tumor cells and their normal counterparts to decipher
the mechanisms and redox regulation properties that are enriched
in tumor cells and consequently use them as clinically relevant
therapeutic targets.
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
Conflict of Interest
[23]
Andrea Glasauer is a full-time employee of Bayer Pharma AG.
The remaining author declares no conflict of interest.
[24]
[25]
Acknowledgements
[26]
This work was supported by the LUNGevity Foundation and a
Consortium of Independent Lung Health Organizations convened
by Respiratory Health Association of Metropolitan Chicago (N.S.C.),
National Institutes of Health Grant R01CA123067 (N.S.C), Dixon
Translational Grant (N.S.C.) and Northwestern University Malkin
Scholar Award (A.G).
[27]
[28]
[29]
[30]
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