review article the tumorigenic roles of the...

Review ArticleThe Tumorigenic Roles of the Cellular REDOXRegulatory Systems

Steacutephanie Anaiacutes Castaldo Joana Raquel FreitasNadine Vasconcelos Conchinha and Patriacutecia Alexandra Madureira

Centre for Biomedical Research (CBMR) University of Algarve Campus of Gambelas Building 8 Room 222 8055-139 Faro Portugal

Correspondence should be addressed to Patrıcia Alexandra Madureira pamadureiraualgpt

Received 7 June 2015 Accepted 10 August 2015

Academic Editor Thomas Kietzmann

Copyright copy 2016 Stephanie Anaıs Castaldo et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

The cellular REDOX regulatory systems play a central role in maintaining REDOX homeostasis that is crucial for cell integritysurvival and proliferation To date a substantial amount of data has demonstrated that cancer cells typically undergo increasingoxidative stress as the tumor develops upregulating these important antioxidant systems in order to survive proliferate andmetastasize under these extreme oxidative stress conditions Since a large number of chemotherapeutic agents currently used in theclinic rely on the induction of ROS overload or change of ROS quality to kill the tumor the cancer cell REDOXadaptation representsa significant obstacle to conventional chemotherapy In this review we will first examine the different factors that contribute to theenhanced oxidative stress generally observed within the tumormicroenvironmentWe will thenmake a comprehensive assessmentof the current literature regarding the main antioxidant proteins and systems that have been shown to be positively associated withtumor progression and chemoresistance Finally we will make an analysis of commonly used chemotherapeutic drugs that induceROSThe current knowledge of cancer cell REDOX adaptation raises the issue of developing novel and more effective therapies forthese tumors that are usually resistant to conventional ROS inducing chemotherapy

1 Introduction

Reactive oxygen species (ROS) are radical and nonradicaloxygen-containing chemical molecules that show differentdegrees of reactivity ROS include biologically importantmolecules such as superoxide anion (O

2

∙minus) hydroxyl radical(∙OH) and hydrogen peroxide (H

2O2) For a long time ROS

have been tagged as harmful oxidants however it is currentlywell established that the ROS molecule H

2O2constitutes an

important second messenger in cell signaling transductionThis is due to its high diffusion rate across membranes partic-ularly through the use of aquaporins and its ability to targetreactiveREDOX sensitive cysteine residues in proteins [1ndash6]Activation of NADPH oxidases (NOX) through the bindingof growth factors cytokines neurotransmitters and hor-mones to their receptors leads to the inducible production ofO2

∙minus that is subsequently converted intoH2O2 by the enzyme

superoxide dismutase (SOD) To date H2O2-dependent sig-

naling has been shown to play a key role in the regulation ofmany cellular processes including differentiation prolifera-tion migration and apoptosis [3 7ndash9] Due to their reactiveproperties these species contribute on different levels toprotein oxidation lipid peroxidation andor DNA damagethat can ultimately result in cell death or tumorigenesis (incase of DNA mutagenesis) [10 11] Consequently cells haveseveral antioxidant systems to inactivate ROS and to recycleoxidized molecules these include catalase SOD glutathioneperoxidases and thioredoxin peroxidases The main cellu-lar antioxidant systems responsible for recycling REDOXsensitive proteins are the thioredoxin (Trx) and glutathione(GSH) systems that reduce active cysteine residues presentin ROS scavenging proteins (reestablishing their antioxidantfunction) and other proteins whose functions are regulatedby the oxidative status of key reactive cysteine residues

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 8413032 17 pageshttpdxdoiorg10115520168413032

2 Oxidative Medicine and Cellular Longevity

Tumorigenesis

Catalase

SOD ROS

Trx

Proteinoxidation

GSHGR

Lipidperoxidation

Cancer cell death

DNAdamage

Trx peroxidases

GSH peroxidases

Figure 1 The cellular antioxidant systems Tumor progressioninduces increasing oxidative stress Cells have several antioxidantsystems to directly inactivate ROS (eg Trx peroxidases GSHperoxidases catalase and SOD) as well as REDOX regulatory sys-tems that recyclereactivate the ROS scavenging proteins and otherREDOX sensitive proteins (eg PTPs PTEN and transcriptionfactors)

(eg protein tyrosine phosphatases (PTPs) transcriptionfactors and the phosphatase and tensin homolog PTEN)(Figure 1)

Several studies have shown an important role for ROSin tumor development [12 13] Cancer cells generally dis-play elevated ROS compared to normal counterparts thatgive them a proliferative advantage and promote malignantprogression [14] In the tumor site the hypoxic cancer cells(in a low oxygen environment) typically show even higherlevels of ROS compared to nonhypoxic cancer cells [15]To deal with the increasing oxidative stress experienced asthe tumor progresses cancer cells upregulate the cellularantioxidant systems This allows the cancer cells to maintainlow to moderate levels of ROS (important for the activationof proliferative signaling pathways) while avoiding high levelsof ROS that have damaging effects and can induce cell death[16ndash18]

A large number of currently used chemotherapeuticagents kill cancer cells in part through the generation of ROSThese drugs are less toxic to normal cells that have lowerendogenous levels of ROS Consequently the upregulation ofantioxidant proteins within the cancer cells will render themmore resistant to chemotherapy [17ndash20]

In this reviewwewill make a comprehensive examinationof the current literature regarding the redox regulatory sys-tems that become upregulated in cancer and their role in pro-moting tumor progression and resistance to chemotherapy Abetter understanding of the molecular mechanisms used bycancer cells to adapt and survive to oxidative stress may also

allow the development of more efficient chemotherapeutictreatments

2 Sources of ROS in Cancer

The existing high levels of ROS typically observed in cancercells are the result of accumulation of intrinsic andorenvironmental factors

21 Intrinsic Sources of ROS Several factors within thetumor site contribute to the generation of high levels ofROS in the cancer cells The more relevant factors includehypoxia (low levels of oxygen) enhanced cellular metabolicactivity mitochondrial dysfunction increased growth factorreceptor mediated signaling transduction oncogene activ-ity increased activity of oxidases lipoxygenases cyclooxy-genases and thymidine phosphorylase and the crosstalkbetween cancer cells and immune cells recruited to the tumorsite (Figure 2) [21 22]

Within the tumor mass it has been well established thathypoxic cancer cells generally have higher levels of ROScompared to nonhypoxic counterparts Hypoxia contributesto the production of ROS through different mechanismsThemajor regulator of the hypoxic response is the transcriptionfactor Hypoxia Inducible Factor (HIF) The regulation ofthe alpha subunit of this transcription factor (HIF-120572) isdependent on intracellular levels of oxygen HIF-120572 regulationis mediated by the action of prolyl hydroxylases (PHDs)enzymes that in the presence of normal concentrations ofoxygen (normoxia) are able to hydroxylate HIF-120572 at twoprolyl residues allowing the binding of the protein vonHippel-Lindau (pVHL) VHL in its turn recruits E3 ubiquitinligases which target HIF-1120572 for proteasomal degradation [23ndash25] Low levels of oxygen lead to the inhibition of PHDsand subsequent stabilization and accumulation of the HIF-120572 subunit HIF-120572 translocates to the nucleus and bindsto the HIF-1120573 subunit and cofactors such as CBPp300inducing the transcription of more than one hundred genesinvolved in promoting angiogenesis (formation of new bloodvessels from preexisting blood vessels) glycolysis epithelial-mesenchymal transition (EMT) proliferation invasion andrecruitment of inflammatory cells to the tumor site [26 27]

Hypoxia induced glycolysis and subsequent inhibitionof oxidative phosphorylation at the mitochondrial mem-brane leads to an increase in ROS levels mediated by themitochondrial complex III [28ndash30] The hypoxic responsealso promotes the elevation of intracellular ROS via HIFdependent transcriptional activation of genes that encode forgrowth factors and their receptors Binding of these growthfactors to their receptors at the surface of cancer cells triggerssignaling pathways that induce the activation of NADPHoxidases (NOX) NOX are responsible for the production ofO2

∙minus which is then converted into H2O2

HIF-1120572 and HIF-2120572 stabilization are also dependent onROS Gao et al showed for the first time a decrease in tumorgrowth inmice treated with the antioxidant N-acetyl cysteine(NAC) that was traced to a redox mediated reduction in thelevels of HIF [31] In this way ROS is not only a by-product

Oxidative Medicine and Cellular Longevity 3

HIF

Protein oxidation

120573-oxidation of fatty acids Flavin oxidase activity

Oncogene activity

Reducing extracellular

oxygen

Secretion of growth factors

Mitochondria

Nucleus

Peroxisomes

Endoplasmicreticulum

Noncancerous cells

Ionizing radiation

Tobacco componentsxenobiotics andmetal ions (eg)

Radiolysis of water molecules

Activating endogenoussources

ROS

ROS

ROS

ROS

Mitochondrial dysfunction

Hypoxia

NOX


Glycolysis

Oxidative phosphorylation

Figure 2 Sources of ROS in cancer A number of intrinsic and extrinsic factors contribute to oxidative stress within the tumor as illustratedin the figure

of hypoxia but it also contributes to the hypoxic responseby stabilizing its main regulator and thus creating a positivefeedback loop A number of studies have shown that theROS produced in the mitochondria during hypoxia promotethe oxidationinactivation of prolyl hydroxylases (PHDs)thus stabilizing HIF-1120572 and HIF-2120572 [30 32] Furthermorethe enhanced activation of NOX observed during hypoxiapromotes NF-k120573 dependent HIF-1120572 transcription [33]

In cancer cells (as in normal cells) the mitochondria isthought to be the largest contributor to intracellular ROS thatare generated as by-products of oxidative phosphorylationThe mitochondrial electron transport chain is composed ofcomplexes IndashIV and ATP synthase in the inner mitochon-drial membrane Complexes I and II oxidize NADH andFADH2 respectively and transfer the resulting electrons toubiquinol which carries it to complex III Within complexIII the electrons are shuttled across the inner mitochondrialmembrane to cytochrome c which carries them to complexIV The flow of electrons throughout the respiratory chainculminates at complex IV with the reduction of molecularoxygen to water The incremental release of energy resultingfrom electron transfer is used to pump protons (hydrogenions) into the intermembrane space generating a protongradient the dissipation of which is used by ATP synthaseto power the phosphorylation of ADP to ATP Throughoutthis process a small percentage of molecular oxygen can alsoundergo a one-electron reduction generating O

2

∙minus [27 34]O2

∙minus is produced in complexes I and III of the electrontransport chain and released to the intermembrane space

(approximately 80) or to themitochondrialmatrix (approx-imately 20) [35 36] O

2

∙minus can be converted into H2O2

that is able to cross the membranes and translocate to thecytoplasm and subsequently into the nucleus [1 2] In thesedifferent cellular compartments H

2O2can oxidize several

cellular components including proteins lipids and DNA (inthe nucleus and mitochondria) Although peroxisomes arecellular organelles that are involved in ROS scavenging (viacatalase mediated conversion of H

2O2into O

2and H

2O)

they also contribute to intracellular ROS production throughthe 120573-oxidation of fatty acids and by flavin oxidase activity[37] The endoplasmic reticulum (ER) also contributes to theelevation of intracellular ROS levels via protein oxidation(disulphide bond formation) that occurs during the processof protein folding [38]

NOX constitute another important source of ROS incancer cells The NOX family consists of seven membersnamely NOX 1ndash5 and the dual oxidases DUOX 1-2 NOX arecomposed of transmembrane and cytoplasmic subunits thatexert distinct functions (regulatorycatalytic) The catalyticsubunit of all NOX isoforms contains six transmembranedomains in the N-terminal half four conserved histidineresidues located in the third and fifth transmembrane heliceswhich coordinate two hemes and a flavoprotein and anNADPH-binding domain in the cytosolic C-terminal region[39] The NOX catalytic subunit transfers an electron fromintracellular NADPH across the cytoplasmic membrane tooxygen via FAD and the two heme groups with the secondheme group being responsible for reducing extracellular


molecular oxygen to produce O2

∙minus The O2

∙minus can be rapidlyconverted into H

2O2either spontaneously or through the

action of SOD which crosses the plasma membrane intothe cytoplasm [39] NOX are activated by various signalingproteins including growth factors cytokines hormones andneurotransmitters that are typically overexpressed within thetumor microenvironment leading to exacerbated activationof NOX and consequently increased levels of ROS within thecancer cells [3 8]

Nowadays it is well established that in addition tothe cancer cells the tumor mass is constituted by innateimmune cells (including macrophages neutrophils mastcells myeloid-derived suppressor cells dendritic cells andnatural killer cells) adaptive immune cells (T and B lym-phocytes) and cells from the surrounding stroma thatare recruited to the tumor site (consisting of fibroblastsendothelial cells and pericytes) [40] These noncancerouscells constitute the tumor microenvironment and play a keyrole in tumorigenesis Tumor associated cells are capableof inducing the generation of ROS in cancer cells throughthe secretion of various growth factors and other signalingproteins leading to the activation of NOX in the cancercell Neutrophils and macrophages can produce a rapidburst of O

2

∙minus (primarily mediated via NOX) leading to thesubsequent generation of H

2O2that can diffuse through

the cytoplasmic membrane and into the neighboring cancercells [35 41] Tumor associated macrophages (TAMs) canalso produce nitric oxide within the tumor site through theactivation of nitric oxide synthase 2 (NOX2) Nitric oxidereacts with superoxide to produce peroxynitrite (ONOO-)that can either be protonated to peroxynitrous acid and thenspontaneously decompose into nitrogen dioxide (NO

2) and

∙OH (highly reactiveoxidizing) or react with carbon diox-ide (CO

2) yielding nitrosoperoxy carboxylate (ONOOCO

2)

which decomposes into carbonate radicals (CO3

∙minus) and NO2

[42 43]

22 Environmental Sources of ROS Environmental sourcesof ROS can also significantly contribute to tumorigenesisIonizing radiation is the most studied source of environmen-tal ROS and has been shown to play a role in all stages ofcarcinogenesis from cancer initiation to tumor progressionIonizing radiation generates ROS through the radiolysis ofwater molecules and also by secondary reactions that canpersist and diffuse within the cells [44]

Other environmental factors such as tobacco compo-nents xenobiotics chlorinated compounds metal ions bar-biturates and phorbol esters can generate ROS in the cells bymetabolism to primary radical intermediates or by activatingendogenous sources of ROS (Figure 2) [45]

3 Cancer REDOX Adaptation

To balance the beneficial effects of low to moderate levelsof ROS which induce proliferative signaling pathways andavoid the harmful oxidant effects of high levels of ROS thatcan damage proteins lipids and DNA cancer cells undergoREDOX adaptation Increasing evidence has demonstrated a

crucial role for the cellular antioxidant systems in supportingtumor initiation progression and chemoresistance Bellowwe summarize what is currently known regarding the mainantioxidant proteinssystems involved in cancer (Figure 3)

31 GSH System The GSH and Trx systems are the mainantioxidant systems responsible for the reduction of redoxsensitive proteins in the cells

The tripeptide GSH is the most abundant nonenzymaticantioxidant in the cell GSH is a multifunctional antioxidantbeing able to (i) function as a cofactor of several oxida-tive stress detoxifying enzymes for example glutathioneperoxidase (GPx) glutathione transferase and others (ii)directly scavenge ROS such as hydroxyl radical and singletoxygen (iii) detoxify hydrogen peroxide and lipid peroxidesthrough the catalytic activity of glutathione peroxidase (iv)regeneratereduce vitamins C and E and (v) react withoxidized sulphenic acid and thiyl radical groups in proteins toform S-glutathionylated proteins (protein-SSG) protectingthese proteins from further oxidation S-Glutathionylatedproteins can then be further reduced by the glutathionecycle through the action of glutathione reductase and smallproteins such as glutaredoxin and thioredoxin [46ndash48]

It is well known that GSH metabolism is modified ina vast number of cancers High levels of GSH have beenreported inmany types of cancer including breastmelanomaand liver Furthermore a direct correlation between GSHconcentration and cellular proliferation and metastasis hasalso been established [18 47 49] It is important to keepin mind that the GSH system has many components andthat a slight alteration in one of them may have an instantresult disrupting the balance of cellular antioxidant responseand REDOX homeostasis Various modifications within theGSH system have been observed in cancer higher levelsof GSH-related enzymes such as 120574-glutamylcysteine ligase(GCL) 120574-glutamyl-transpeptidase (GGT) and glutathione-S-transferases (GST) have been reported as well as higherexpression of GSH-transporting pumps [50ndash52] DecreasedGSHGSSG ratio has also been found in advanced cancerpatients this can be explained by an increased generation ofH2O2that readily oxidizes GSH turning it into GSSG [48]

The GSH system is a major contributor to chemother-apy resistance This system participates not only in thecellular antioxidant defense but also in drug-resistancemetabolic processes including the detoxification and effluxof xenobiotics The GSH system also participates in DNArepair processes as well as in the inactivation of the cancercell proapoptotic pathway [18 51 53 54] GSH is able todirectly interactwith cisplatin and trisenox inactivating thesechemotherapeutics [55 56] For all these reasons significanteffort has been engaged at depleting cellular GSH levels tosensitize tumors to the cytotoxic effects of chemotherapeuticdrugs

Recently a study showed that GSH plays a crucial role intumor initiation [57] Using the oncogene-induced murinemodel of mammary cancer (MMTV-PyMT) it was shownthat a 75 depletion in the levels of GSH in these mice led tothe formation of fewer tumors that progressed more slowlythan those in mice with normal GSH levels [57]


ROS-induced apoptosis

Intercellular ROS

ROS

DNA damage and

cell proliferation

CytoplasmNucleus

Peroxisomes

CAT

Membrane associated CAT

TRX

DJ-1GSH

ANXA2 PRDX

Transcriptionfactors

Ref-1 HIFP53

NF-120581B

Mitochondria

MnSOD

DNA damage

MnSOD

H2O2

H2O2

O2∙minus

O2∙minus

Figure 3 Antioxidant systems in cancer Cancer cells undergo REDOX adaptation to survive and proliferate in an environment withincreasing oxidative stress Regulation of ROS levels by the cellular antioxidant systems is crucial to maintain a proliferative and mutagenicphenotype (associated with lowmoderate levels of ROS) and avoid apoptosis or senescence (associated with high levels of ROS)

32 TRX System Thioredoxins (Trx) are small proteins (witha molecular weight of approximately 12 KDa) that repairoxidized proteins Trx possess a conserved Cys-Gly-Pro-Cysredox catalytic site that is able to reduce oxidized thiols(reactive cysteine residues) in target proteins Trx reductases(TrxR) recycle the oxidized Trx through the transfer ofreducing equivalents from NADPH to the oxidized catalyticsite of Trx (Trx-S

2) reducing it to a dithiol (Trx-(SH)

2) [9

58] Amongst all members of the thioredoxin system Trx1and TrxR1 have emerged as critical redox regulators and aspotential therapeutic targets formany types of human cancers[59]

Trx are major protein disulphide reductases in the cellbeing able to catalyze the reduction of disulphide bondsin proteins orders of magnitude faster than GSH [60] Trxare involved in multiple redox-dependent signaling path-ways in cancer by regulating redox-sensitive transcriptionfactors (eg activator protein 1 (AP-1) NF-120581B and p53)signaling proteins (eg protein tyrosine phosphatases PTPsand PTEN) and other antioxidant proteins involved in theregulation of these signaling cascades (eg peroxiredoxins)Reduced Trx has been shown to bind to and inhibit apoptosissignal-regulated kinase 1 (ASK1) [61] ASK1 activates thec-Jun N-terminal kinase (JNK) and p38 mitogen-activatedprotein kinase pathways leading to apoptosis [62 63] Fur-thermore Trx also play an important role controlling cancercell growth through the supply of reducing equivalents forDNA synthesis [64]

Elevated levels of Trx have been reported in multipletypes of cancers including cervical liver gastric lung andcolorectal cancers [48 64] Many studies have also revealed apositive correlation between elevated levels of Trx in humantumors and resistance to chemotherapy [65ndash67] Although a

large number of reports have established a key role for the Trxsystem in cancer a recent study seems to indicate that the Trxsystem is essential for tumor progression but not initiationwhere the GSH system plays a more prominent role [57]

33 SOD Superoxide dismutase (SOD) is responsible for thedismutation of O

2

∙minus into oxygen (O2) and H

2O2(that is less

reactive than O2

∙minus) thus providing an antioxidant defense[47] In humans there are three isoforms of SOD cytosolicCu Zn-SODmitochondrialMn-SOD and extracellular SOD(EC-SOD) [68] Of these isoforms the mitochondrial Mn-SOD has been more associated with cancer by functioning asa mitochondrial ROS switch

A large number of reports demonstrated the elevationof Mn-SOD in tumors (eg lung esophageal gastric headand neck prostate and colon) compared to matched normaltissues and elucidated that the enhanced expression of Mn-SOD resulted in increased cancer cell invasiveness growthsurvival and metastatic behavior [69ndash75] Overexpression ofMn-SOD is likely a compensatory mechanism to intrinsicROS stress especially in cancer cells with mitochondrialdysfunction and consequently increased levels of O

2

∙minus Inthis situation enhanced expression of Mn-SOD might helpthe cancer cell to counteract superoxide stress and thuspromote tumor progression A potential mechanism for Mn-SOD induced metastasis is the H

2O2-dependent increase in

matrix metalloproteases expression [76 77] Interestinglyother reports demonstrated low activity ofMn-SOD in awiderange of cancers including cervical breast prostate lung andliver [78ndash82] These studies also showed that overexpressionof Mn-SOD in cancer cells led to decreased proliferationanchorage-dependent growth and invasiveness Howeverthese tumor suppressive properties of Mn-SOD were mainly


observed in vitro in experimental systems where cancer cellswere artificial transfected with Mn-SOD-expressing vectorsto induce high expression of this enzyme [78 83] Underthese conditions the cancer cell redox homeostasis canbe significantly disturbed leading to inhibition of cancercell proliferation However the physiological relevance ofsuch tumor-suppression function of Mn-SOD is still unclearin cancer cells in vivo Also Mn-SOD cancer cell growthsuppression can be modulated by diminishing the levelsof carcinogen-inducing O

2

∙minus [84ndash86] and sensitization ofcancer cells to cell death induced by different ROS-generatingagents [87] This dual effect of SOD acting as either a tumorpromoter or a tumor suppressor should be addressed takinginto account the nature of the ROS molecules generated inlow or high SOD expressing cancer cells O

2

∙minus (which iselevated in tumors with low SOD activity) is a reductantof iron which subsequently generates ∙OH by transferringthe electron to H

2O2[88] The highly reactive ∙OH can lead

to enhanced mutagenesis via DNA oxidation On the otherhand increased SOD activity will lead to enhanced levels ofH2O2that oxidizes reactive cysteine residues in proteins with

high specificity constituting an important second messengerin a wide variety of signaling pathways that activate prolifer-ation invasiveness and metastasis Furthermore increasedlevels of O

2

∙minus (associated with low levels of SOD) might bemore beneficial to cancer cells in the early stages of tumordevelopment where oxidative stress within the tumor massis still low increased levels of H

2O2(associated with high

levels of SOD) might have a more prominent role at laterstages of tumor progression lowering unspecific damageof cellular components while increasing H

2O2dependent

signaling pathways However there is still a lot of work to bedone to investigate these hypotheses

34 Catalase Catalase (CAT) was originally regarded asa monofunctional peroxisomal enzyme that efficiently cat-alyzes the conversion of H

2O2into water and O

2 This notion

has evolved over the years and catalase is now considered amultifunctional enzyme that exhibits not only classic catalaseactivity but also peroxidase [89 90] and oxidase functions[91] Moreover catalase activity is not limited to the degrada-tion ofH

2O2 as this enzyme also degrades peroxynitrite in an

enzymatic reaction that similarly to its classical reactionwithH2O2 involves the formation of compound I (CATFeIV=O∙+)

[92 93] In addition compound I of catalase can oxidizeNO (CATFeIV=O∙+ + 2∙NO + H

2O rarr CATFeIII + 2H+

+ 2NO2

minus) [94 95] whereas native ferricatalase (CATFeIII)is reversibly inhibited by NO [96] Thus catalase has thepotential to execute a central modulatory function at thecross point between H

2O2and NOperoxynitrite-mediated

signaling pathwaysDecreased CAT activity has been reported in cancer [69]

This low CAT activity leads to high levels of H2O2and

creates an intracellular environment favorable to DNAmuta-genesis and to the activation of H

2O2-dependent signaling

pathways that typically trigger cell proliferation invasionand metastatic phenotypes consequently promoting tumorprogression [35 97 98]

However malignant cells may acquire membrane-associated catalase Cancer cells exhibit enhanced NOX1-dependent superoxide anion generation [93 99ndash102] Variousstudies have shown that the overexpression of membrane-associated catalase on the outer surface of tumor cells hasa protective role against apoptosis induced intercellularROS signaling [93 101ndash103] Catalase-mediated protectionfrom intercellular ROS signaling was found in all humancancer cell lines studied so far (more than 70 cell lines)[104] indicating that this might be an important mechanismfor tumor survival Efficient protection of tumor cells bymembrane-associated catalase is not in contradiction to thefinding that in general tumor cells have less catalase thannormal tissue as the surface of the tumor cell with its highlocal concentration of catalase represents a small proportionof the total cellular mass [105]

35 Peroxiredoxins Peroxiredoxins (Prdx) are thioredoxinperoxidases that are divided into three classes typical 2-cysteine peroxiredoxins (PrxIndashIV) atypical 2-cysteine perox-iredoxins (PrxV) and 1-cysteine peroxiredoxins (PrxVI) [50]Although their individual roles in cellular redox regulationand antioxidant protection are distinct they all catalyzethe reduction of H

2O2 organic hydroperoxides and per-

oxynitrite to balance intracellular ROS levels [106 107]Due to their widespread distribution within the cell Prdxare thought to constitute broad-range cellular antioxidantdefenders However recent studies have demonstrated thattypical 2-cysteine peroxiredoxins (Prdx IndashIV) play key cellsignaling regulatory roles by either interacting directly withspecific REDOX-sensitive signaling protein(s) or by beinglocated in the vicinity of REDOX-dependent signaling cas-cades (lipid rafts) and buffering ROS generated byNOX [108]The 2-Cys Prx have been implicated in the regulation ofdiverse cellular processes including proliferation migrationapoptosis and metabolism [108]

Overexpression of all known Prdx has been reportedin many types of cancers including prostate breast lungthyroid and mesothelioma and is associated with cancer cellsurvival and tumor progression [109ndash112]The ROS bufferingand signaling regulatory (prosurvival) functions of Prdx havebeen suggested to play a role in tumor chemoresistance [106107 112ndash114]

36 APE1Ref-1 The Apurinicapyrimidinic endonucleaseredox factor-1 (APE1Ref-1) is a key enzyme that in additionto its DNA base excision repair function it also exertsimportant cellular functions in the REDOX control of mul-tiple transcription factors involved in cancer progressionincluding NF-120581B STAT3 AP-1 HIF-1 and p53 [115ndash118]All of these transcription factors possess reactive cysteineresidue(s) within their DNA binding domain that can bereadily oxidizedinactivated by cellular ROS APE1Ref-1is able to reduce these cysteine residue(s) through theexchange of a proton from one or two of its redox cysteineresidues (Cys65 Cys93 Cys99 or Cys138) This restores theDNA binding capability of the transcription factors andsubsequently promotes transcription of their target genes


Oxidized APE1Ref-1 is then recycledreduced by the Trxsystem [119]

APE1Ref-1 is highly expressed in many cancers (egbreast lung liver and gliomas) [120ndash122] APE1Ref-1 rolein cancer progression is likely due to its ability to increaseDNA repair and to activate antiapoptotic inflammatory andgrowth-promoting transcription factors [121] APE1Ref-1 hasalso been shown to be associated with tumor resistance toboth ionizing radiation and chemotherapy [123ndash125] Conse-quently APERef-1 has emerged as a promising therapeutictarget for cancer treatment [115 120 126]

37 Transcription Factors Transcription factors canindirectly counteract ROS in cancer The transcriptionfactor nuclear factor erythroid 2-related factor 2 (NRF2)binds to antioxidant response elements (ARE) in theregulatory regions of target genes and induces thetranscriptionexpression of antioxidant enzymes [egNAD(P)Hquinone oxidoreductase 1 (NQO1) SOD catalaseheme oxygenase-1 (HO-1) TrxR GST GSH-synthetizingenzymes and UDP-glucuronosyltransferases (UGTs)][127ndash129] NRF2 is considered to be the master regulator ofintracellular antioxidant responses NRF2 is regulated by itsbinding partner KEAP1 that targets NRF2 to proteasomaldegradation [130] It has been shown that hyperactiveand oncogenic phosphoinositide 3-kinase- (PI3K-)AKTsignaling which is commonly observed in a large numberof cancer cells activate NRF2 [46] NRF2 mutations havealso been found in several types of tumors such as skinesophageal lung ovarian and breast cancers [131] Generallythese mutations are observed in the KEAP1-binding domainof NRF2 preventing KEAP1-mediated degradation of thistranscription factor [131 132] Inactivating mutations inKEAP1 have also been identified [133] All of these mutationslead to the constitutive stabilization of the NRF2 proteinin the nucleus providing strong evidence for a role forNRF2 in tumorigenesis High expression of antioxidantNRF2 target genes has been linked to chemoresistanceFor instance HO-1 seems to be an important effector ofNRF-2 induced chemoresistance in myeloid leukemias andinhibition of either NRF2 or HO-1 sensitizes the tumor totherapy [127] It was also described that NRF2 enhances thecellular antioxidant capacity to counteract ROS mediatedstress in cancer cells overexpressing oncogenic KRas [20]

Forkhead box O (FOXO) transcription factors belong tothe large group of forkhead transcription factors that are allcharacterized by a conserved DNA binding domain termedthe forkhead box [134] FOXO activate the transcriptionof genes that encode for antioxidant proteins includingMn-SOD catalase and sestrin 3 [135] Although FOXO isgenerally considered to be a tumor suppressor and FOXOinactivation has been reported in a number of cancers [136137] recent studies have indicated that these transcriptionfactors might also have protumorigenic functions It has beenshown that activated FOXO transcription factors supportthe survival of Acute Myeloid Leukemia (AML) cells [138]FOXO transcription factors are inactivated by the PI3K-AKT pathway Phosphorylation of FOXO by AKT leads toFOXO translocation from the nucleus into the cytoplasm

where they cannot exert their transcriptional function [134]Interestingly it has been observed that the FOXO genes areinvolved in chromosomal translocations that lead to alve-olar rhabdomyosarcoma and acute lymphoblastic leukemia(ALL) [139] Specifically the paired box 3- (PAX3-) FOXO1translocation is found in approximately 60 of all alveolarrhabdomyosarcoma tumors [140 141] The PAX3-FOXO1fusion protein is insensitive to AKT inactivation meaningthat AKT cannot inhibit PAX-FOXO1 translocation to thenucleus or regulate its transcriptional activity [142] Howeverthe contribution of FOXO transcriptional activity within thefusion protein is still fairly unknown and increased activity ofPAX3 has been reported [141]

38 Dietary Antioxidant Compounds Dietary antioxidantsare nonenzymatic compounds that although less specificcompared to enzymatic antioxidants appear to be importantin cellular responses to oxidative stress including duringtumorigenesis For instance vitamin C (ascorbic acid) is awater-soluble antioxidant which is mostly present in the cellin its reduced form ascorbate which acts as a reductant andenzyme cofactor and directly reacts with O

2

∙minus ∙OH andvarious lipid hydroperoxides Vitamin E (120572-tocopherol) is afat-soluble antioxidant which acts as a free radical scavengerby converting free radicals into tocopheryl radicals thus low-ering their radical damaging abilities Selenium is a nonmetalelement that forms part of antioxidant selenoproteins such asglutathione peroxidase and thioredoxin reductase VitaminA (120573-carotene) is a known fat-soluble antioxidant and itsantioxidant property derives from its ability to quench singletoxygen and trap peroxyl radicals Deficiency of vitamin Acauses oxidative stress inhibiting cell repair function andcausing cell damage [46 47]

Much debate has focused on the consumption of antioxi-dant supplements by cancer patients undergoing chemother-apy due to concerns that the antioxidants may interferewith the mechanism of action of ROS generating therapeuticagents and subsequently decrease their efficacy [143 144]In this way antioxidant supplementation might help thecancer cells to achieve redox homeostasis during tumorprogression (generally accompanied by increasing oxidativestress) A recently published research using B-Raf and K-Rasinduced lung cancer mouse models has demonstrated thatthe dietary antioxidant compound vitamin E can actuallypromote tumor progression [145] This study further showedthat vitamin E increased cell proliferation by decreasing ROSDNA damage and p53 expression in both mouse and humanlung cancer cells [145]

Interestingly vitamin C has also been shown to have aprooxidant function Vitamin C can reduce catalytic metalswithin the cells that in turn react with oxygen producingO2

∙minus that subsequently dismutates intoH2O2Theprooxidant

function of vitamin C is observed at pharmacological doses(millimolar concentrations) It is currently accepted thatthe anticancer effect of pharmacological doses of ascorbateis mediated by the generation of high concentrations ofextracellular H

2O2that diffuses through the plasma mem-

brane causing DNA damage and triggering proapoptoticsignaling pathways which will ultimately lead to cell death


[146 147] A recent study investigated the synergistic actionof pharmacological doses of vitamin C in combination withchemotherapeutic drugs used in the clinic for the treatmentof ovarian cancer These results showed that vitamin Csignificantly increased the efficacy of carboplatin andorpaclitaxel using a tumorigenic mouse model where ovariancancer cells were intraperitoneally injected in the mice [147]A small pilot phase 12a clinical trial was also conducted inpatients newly diagnosed with stage IIIIV ovarian cancer[147] Reduction of chemotherapy-associated toxicity wasobserved in patients receiving intravenous vitamin C inaddition to carboplatin and paclitaxel treatment A tendencyfor enhanced overall survival and longer time to relapse inpatients receiving vitamin C in combination with carboplatinand paclitaxel compared to patients receiving only carbo-platin andpaclitaxelwas observed however these resultswerenot statistically significant A larger clinical trial might beuseful to further clarify these results The use of ascorbate incancer therapy is still a matter of debate as preclinical studieshave shown a large variation in ascorbate sensitivity evenwithin cancers of the same type This may be the result ofintrinsic differences between cancer cells fromdiverse origins(eg antioxidant defenses) or the tumor microenvironmentin the case of organ-specific cancers which are presentlypoorly understood The fact that vitamin C can functionas an antioxidant (at low doses) or a prooxidant (at highdoses) is most likely at the basis of these contradictoryresults and dosage as well as other factors (eg intrin-sic antioxidant defenses expression of sodium-dependentvitamin C transporters activation of signaling pathway(s)etc) should be taken into account when considering theuse of this compound in combination with ROS producingchemotherapeutics

39 Others

391 Annexin A2 Annexin A2 belongs to the familyof annexins which are commonly described as calcium-dependent phospholipid-binding proteins [9] Annexin A2is a multifunctional protein that has been shown to beoverexpressed in a large number of cancers (eg breast livergastric pancreatic lung gliomas colorectal and ovarian)and to be positively associated with metastasis and resistanceto chemotherapy [9 148ndash151] It was demonstrated thatannexin A2 is unique among the vertebrate annexins in thatit possesses an N-terminal reactive cysteine residue Cys-8which is reversibly oxidized by H

2O2inactivating this ROS

molecule and generating H2O and O

2 Oxidized annexin

A2 is then recycledreduced by the Trx system Thus onemolecule of annexin A2 has the ability to degrade severalmolecules of H

2O2[9 58] The role of the antioxidant

function of annexin A2 in tumorigenesis was investigatedusing a mouse animal model This study showed that thegrowth of tumors derived from annexin A2 depleted cancercells was significantly impaired compared to tumors derivedfromcontrol cancer cells (expressing normal levels of annexinA2) However the growth impairment of the annexin A2-depleted tumors was rescued by the administration of theantioxidant compound N-acetyl cysteine (NAC) in the mice

during tumor formation [9 58] These results indicate thatannexin A2 REDOX regulatory function plays a significantrole in promoting tumor growth It was also demonstratedthat annexin A2 depleted cancer cells were significantly moresensitive to death induced by the ROS generating chemother-apeutic agents etoposide doxorubicin and tamoxifen [58]elucidating for the first time a molecular mechanism bywhich annexin A2 provides resistance to chemotherapy byfunctioning as an antioxidant protein More recently it hasbeen shown that a fraction of cellular annexinA2 translocatesinto the nucleus in response to different oxidative stressstimuli including X-ray radiation Gamma-radiation UVradiation etoposide chromium VI and H

2O2[9 152 153]

Nuclear annexin A2 was shown to protect cellular DNA fromoxidative damage [153]

392 DJ-1 DJ-1 is a multifunctional protein that has beenshown to also have antioxidant functions DJ-1 containsthree reactive cysteine residues namely Cys46 Cys53 andCys106 being Cys 106 the most susceptible to oxidationIn fact Cys 106 is essential for DJ-1 cytoprotective functionagainst oxidative stress and mutation of this cysteine residueabolishes all functions of DJ-1 [154ndash158] The antioxidantfunctions attributed to DJ-1 include the upregulation ofintracellular glutathione synthesis via increasing glutamatecysteine ligase enzyme [159] inhibition of oxidative stressinduced apoptosis via direct binding of its Cys 106 residueto ASK1 [156 160] stabilization of NRF2 transcription factorthat regulates the expression of many antioxidant genes (asdescribed above) by preventing the binding of NRF2 to itsinhibitor KEAP1 [161] A recent study using cardiac cellsshowed that DJ-1 was able to inhibit ischemiareperfusion-induced ROS generation via upregulation of antioxidantenzymes [162] These results suggest that DJ-1 might alsotrigger a similar antioxidant response in hypoxic cancer cellsHowever this has not yet been investigated

DJ-1 has been shown to be upregulated in many humancancer types (eg lung prostate endometrial and bladder)which correlated with cancer cell proliferation tumor sur-vival and chemoresistance [59 163ndash165]

4 ROS Inducing Chemotherapy

Typically cancer cells exhibit higher levels of endogenousROS compared to normal cells For this reason a commonlyused strategy for killing cancer cells consists of using ionizingradiation andor chemotherapeutic drugs that induce thegeneration of these oxidants to levels that are capable oftriggering apoptosis once ROS levels reach or exceed a certainthresholdwithin the cellThe rationale for this approach relieson the fact that since cancer cells already have high levels ofendogenous ROS prior to treatment they should reach thisapoptotic threshold fastereasier compared to normal cells[166 167]

Accordingly oxidative stress has been recognized as atumor specific target for the design of chemotherapeuticagents A large number of chemotherapeutic drugs capableof inducing oxidative stress by interfering with various


Table 1 Chemotherapeutic drugs commonly used in the clinic capable of inducing ROS

Drug name Tumor type Mechanism of action for ROS induction References

Actinomycin DSarcomas Wilmsrsquo tumor testicularmelanoma neuroblastoma germ cellretinoblastoma choriocarcinoma

Inhibition of Bcl-2 [179]

BleomycinMelanoma Hodgkinrsquos and non-Hodgkinrsquoslymphomas testicular head and neckcervical malignant pleural effusions

Formation of Fe(II)-bleomycin-DNAcomplex that is oxidized by O

2

[185 187]

Busulfan Chronic myeloid leukemia GSH depletion and NOX activation [182 183]

Carmustine Brain Hodgkinrsquos and non-Hodgkinrsquoslymphoma melanoma myeloma GSH depletion via inhibition of GR [169]

Cisplatin Ovarian colon testicular germ cellbladder lung head and neck

Increased expression of p47phox subunitof NOX [17 188]

DMAT Prostate Inhibition of CK2 activity [173]

DoxorubicinHodgkinrsquos and non-Hodgkinrsquos lymphomaleukemia breast gastric neuroblastomaovarian lung soft tissue and bonesarcomas thyroid bladder

p53-dependent transcription ofcytochrome oxidase 2FOXO3-dependent transcription of Noxaand BIM quinone metabolism

[190]

Etoposide Lymphomas leukemias neuroblastomabreast lung testicular gastric

FOXO3 dependent transcription of Noxaand BIM [188 190]

5-Fluorouracil Gastric colon gynecological breasthead and neck lung skin p53-dependent transcription of ROMO 1 [188 189]

Gemcitabine Pancreatic lung in combination withother drugs breast bladder and ovarian

Activation of AKT and ERK 12 whichleads to upregulation of CXCR4 [198]

Mitomycin C Colon breast head and neck bladdercervical gastric pancreatic liver Inhibition of Bcl-2 [180 202]

Paclitaxel Ovarian breast non-small cell lungcarcinoma Kaposirsquos sarcoma

Activation of Rac1 subunit of NOXdisruption of the mitochondrialmembrane

[177 178]

Tamoxifen Breast Inhibition of CK2 activity [175]

antioxidantredox regulatory proteins andor ROS inducingpathways are currently being used in the clinic (Table 1)[168]

The chemotherapeutic agent carmustine interferes withthe GSH antioxidant system by inhibiting glutathione reduc-tase activity GSH is an abundant cellular antioxidant thatplays a key role in cellular REDOX homeostasis as alreadydescribed in this review Inhibition of glutathione reductaseleads to the build-up of oxidized glutathione (GSSG) that canno longer exert its antioxidant function as a consequence asignificant accumulation of ROS within the cell is observeddriving caspase-3 activation and apoptosis [166 169 170]

Other chemotherapeutic drugs function through ROS-independent as well as ROS-inducing mechanisms This isthe case for the estrogen receptor inhibitor tamoxifen andfor 2-dimethylamino-4567-tetrabromo-1H-benzimidazole(DMAT) that inhibit the catalytic activity of protein cyclinkinase 2 (CK2) Under normal conditions CK2 phospho-rylates the apoptosis repressor with caspase recruitmentdomain (ARC) and Bid (proapoptotic member of the Bcl-2 family) proteins Phosphorylated ARC localizes to themitochondria inhibiting caspase 8 while Bid phosphory-lation by CK2 protects it from being cleaved by caspase8 In conjunction phosphorylation of ARC and Bid byCK2 contributes to cell survival via inhibition of apoptosis

However when CK2 is inhibited by tamoxifen or DMAT itis not able to phosphorylate neither ARC nor Bid proteinsThis will lead to caspase 8 activation which will cleave Bidpromoting its translocation to the mitochondrial membranewith the subsequent release of cytochrome C and activationof additional caspases ultimately triggering apoptosis [171ndash173] Disruption of the mitochondrial membrane by Bid willalso lead to the release of ROS into the cytosol CK2 inhibitionalso mediates NOX activation and the subsequent generationof ROS (O

2

∙minus andH2O2)This occurs because CK2 can phos-

phorylate the cytosolic subunit of NOX p47phox negativelyregulating NOX activity Inhibition of CK2 by tamoxifenor DMAT will thus enhance NOX activity and induce theelevation of intracellular ROS which will also contribute tocell death induced by these chemotherapeutic agents [174ndash176]

Paclitaxel (also known as taxol) is another drug that isable to enhance NOX activity This chemotherapeutic is amicrotubule stabilizing agent that interferes with the normalbreakdown of spindle microtubules during cell divisioninhibitingmitosis and inducing apoptosis [177] Paclitaxel hasbeen shown to induce the translocation of Rac1 (regulatorysubunit of NOX) from the cytosol to the plasma membraneThe increase of Rac 1 in the plasma membrane promoted theactivation of NOX and led to the production of O

2

∙minus which


was subsequently converted to H2O2either spontaneously or

by SOD [178] This study showed that paclitaxel displayed asignificant cytotoxic bystander effect in neighboring cancercells [178] suggesting that this effect might play a substantialrole in the antitumor activity of this drug It is noteworthythat paclitaxel has limited ability to reach cancer cells thatare distant from the vasculature The fact that H

2O2can

diffuse reasonably far from its site of production and canuse aquaporins to enter the cells suggest that this mechanismmight contribute significantly to paclitaxel induced cancercytotoxicity

The chemotherapeutic drugs actinomycin D and mito-mycin C also activate the mitochondria-dependent apoptoticpathway This occurs via inactivation of the antiapoptoticprotein Bcl-2 Bcl-2 forms heterodimers with the proapop-totic Bcl-2 family members Bax Bak Bid BIM PUMA andBAD sequestering these proteins and inhibiting apoptosisInactivation of Bcl-2 by actinomycin D or mitomycin Cwill elicit the release of the proapoptotic Bcl-2 family mem-bers causing mitochondrial membrane potential collapseand cytochrome C release from the mitochondria into thecytosol subsequently increasing intracellular ROS levels Inthe cytosol cytochrome C induces apoptosis through theactivation (via cleavage) of caspase-3 and caspase-9 ExcessiveROS generation also contributes to cell death induced bythese chemotherapeutic drugs [179ndash181]

Awide variety ofDNAdamaging (genotoxic) chemother-apeutic agents have been shown to induce cancer cell death inpart through the increase of intracellular ROS levels This isthe case of busulfan an alkylating agent that causes significantDNA damage by promoting the crosslinking between DNAmolecules and also between DNA and proteins Since thesecrosslinks can potentially originate DNA strand breaks itwas hypothesized that busulfan most likely activates theDNA-damage response p53 signaling pathway to inducesenescence or apoptosis Interestingly a p53 independentpathway has been reported for busulfan induced senescenceIt was demonstrated that busulfan is metabolized throughconjugationwithGSHThis reaction is catalyzed byGSTThisleads to depletion of intracellular levels of GSH followed by acontinuous increase in ROS production via NOX activationwhich in turn activate the ERK and p38 MAPK signalingpathways inducing cell senescence [182ndash184]

Bleomycin (BLM) is a chelator and a DNA damagingagent that is known to produce single- and double-strandbreaks in the DNA as well as the release of free bases BLMbinds to DNA via its bithiazole and N-terminal moietiesand interacts with Fe(II) via its ferrous binding site formingan Fe(II)-BLM-DNA complex BLM induces an increase inintracellular levels of ROS due to oxidation of the Fe(II)-BLM-DNAcomplex byO

2that leads to the generation ofO

2

∙minus

and ∙OH [185ndash187]Other genotoxic chemotherapeutics such as doxorubicin

and 5-Fluorouracil trigger a p53-dependent proapoptoticpathway in order to kill cancer cells The tumor suppressorp53 is involved in the maintenance of DNA integrity andunder normal conditions it is maintained at low levels by theE3 ubiquitin ligase MDM2 Doxorubicin and 5-fluorouracilinduce the stabilization of p53 and the subsequent

transcription of p53 regulated genes including cytochromeoxidase 2 a component of the cellular respiratory chain thathas been shown to generate ROS [188] Another molecularmechanism by which 5-Fluorouracil induces the generationof ROS is by p53-dependent transcription of the ROSmodulator 1 (ROMO1) gene ROMO 1 protein localizes at themitochondrial membrane and induces mitochondrial ROSgeneration [188 189]

Doxorubicin also induces cancer cell apoptosis in a p53-independent way Both doxorubicin and etoposide genotoxicchemotherapeutics promote the accumulation and nucleartranslocation of the forkhead transcription factor FOXO3which activates the transcription of the proapoptotic genesNoxa and BIM This promotes the collapse of the mitochon-drial membrane with the subsequent release of cytochromeC and ROS into the cytosol ultimately inducing apopto-sis [190ndash192] Another mechanism by which doxorubicinproduces ROS involves the addition of one-electron to thequinone moiety of doxorubicin resulting in the formationof a semiquinone that quickly regenerates into a quinoneby reducing O

2to O2

∙minus and H2O2 The one-electron redox

cycling of doxorubicin is accompanied by a release of ironfrom intracellular stores binding of doxorubicin with ironresults in formation of 3 1 drug-iron complexes that convertO2

∙minus and H2O2into more potent ∙OH [193]

Doxorubicin is known to produce serious side effects themost dangerous of which being cardiomyopathy which hasbeen closely associated with abnormalities in mitochondrialfunctions including defects in the respiratory chainoxidativephosphorylation system decreased ATP production mito-chondrialDNAdamagemodulation ofmitochondrial sirtuinactivity and ROS generation [193ndash196] For this reason itis important to take into account that using ROS to killcancer cells might also have serious consequences for thepatient that need to be taken into serious consideration beforeadministration of these chemotherapeutic compounds

The chemotherapeutic drug cisplatin is an alkylatingagent that causesDNA crosslinking ultimately leading to p53-dependent apoptosis It has been shown that DNA damageinduced by cisplatin triggers a p53-dependent upregulation ofROS that activate p38 and JNK signaling pathways inducingapoptosis in a wide variety of cancer cell lines [188 197]

The chemotherapeutic gemcitabine (21015840-21015840 difluorodeoxycytidine dFdC) is a prodrug that is phosphorylated bydeoxycytidine kinase within the cell to form the active com-pounds gemcitabine diphosphate (dFdCDP) and gemcitabinetriphosphate (dFdCTP) The active forms of gemcitabineincorporate into the DNA causing cell cycle arrest andsubsequent apoptosis [198] It has also been shown thatgemcitabine induces ROS as an additional anticancer mecha-nism [199] Interestingly a report has shown that gemcitabineinduced ROS activate the proproliferative and prosurvivalMAPKS ERK12 and AKTThe activation of these pathwaysleads to the enhanced nuclear accumulation of NF-kB andHIF-1120572 transcription factors which induce the transcriptionand subsequent expression of CXCR4 protein [198 200]These authors also demonstrated that increased expressionof CXCR4 enhanced cancer cell invasion and migration toCXCL12 chemokine rich environments namely the stroma


and blood vessels promoting in this way chemoresistancedue to escape from the tumor site [198] For this reasonROS concentrations within the cell should be consideredduring chemotherapy treatment since survival andmetastaticmechanisms can be induced It is crucial that ROS concen-trations are increased until a threshold is reached where thecellular balance is tipped to activate apoptotic pathway(s)to stop tumor progression [176 200] Although high levelsof ROS induced by chemotherapeutics can have dangerousside effects (as seen for doxorubicin) low dosages canalso promote tumor growth instead of death It becomesclear that finding the optimal dosage for the use of thesechemotherapeutic agents is crucial for an effective cancertherapy

All of the chemotherapeutics described above (summa-rized in Table 1) generate ROS that will contribute to tumorcell death This is because excessive ROS can induce sig-nificant DNA damage protein oxidation organelles andormembranes oxidation tipping the cellular balance away fromthe proliferative advantages of lowmoderate ROS levels todrive apoptosis in the presence of high ROS levels [201]

5 Conclusions and Future Directions

Increasing evidence has established that the cellular antioxi-dant systems play a key role not only in regulating (normal)cellular redox homeostasis but also in protecting cancer cellsfrom the increasing oxidative stress that they are subjectedto during tumor progression A large number of antioxidantproteins have been shown to be upregulated in cancer andto promote resistance to chemotherapy These include notonly proteins of the GSH and Trx systems that play amajor role in recyclingreducing REDOX sensitive proteinswhose function is regulated by oxidationreduction of keyreactive cysteine residues but also ROS scavenging proteinsand transcription factors that induce the cellular antioxidantresponse Novel antioxidant proteins such as annexin A2 andDJ-1 have also been identified more recently that contributesignificantly to tumorigenesis In summary since it was estab-lished that tumors are typically under substantial oxidativestress and as such have to adapt to survive in this extremeenvironment increasing interest has been drawn to iden-tifying the antioxidantredox regulatory proteins involvedin the tumor REDOX adaptation and in understanding themolecular mechanisms by which these proteins promotetumor progression and resistance to chemotherapy Takinginto account that many chemotherapeutic drugs currently inuse in the clinic rely to varying degrees on ROS overload tokill the cancer cells the tumor REDOX adaptation presentsa major obstacle for the efficacy of these therapies Oneapproach to overcome this problem could be to deplete thecancer cell from REDOX regulatory potential through thedownregulation of antioxidant protein(s) and peptides thathave been shown to play crucial roles for tumor survival andgrowth in combination with chemotherapeutics that induceROS

Conflict of Interests

The authors declare no conflict of interests

Acknowledgments

Patrıcia Alexandra Madureira has received funding fromthe European Union Seventh Framework Programme(FP72007ndash2013) under Grant agreement no PCOFUND-GA-2009-246542 and from the Foundation for Science andTechnology of Portugal and is a recipient of a Bolsa deCientista Convidado (BCC) (ref SFRHBCC1058312014)from the Foundation for Science and Technology of PortugalFCT Research Center Grant UIDBIM047732013 CBMR1334The authors would like to thank Dr Richard Hill for hiscritical review of the paper The authors would like to thankManuel Borges for his help with generating Figure 3

References

[1] G P Bienert A L B Moslashller K A Kristiansen et al ldquoSpecificaquaporins facilitate the diffusion of hydrogen peroxide acrossmembranesrdquoThe Journal of Biological Chemistry vol 282 no 2pp 1183ndash1192 2007

[2] G P Bienert J K Schjoerring and T P Jahn ldquoMembrane trans-port of hydrogen peroxiderdquo Biochimica et Biophysica ActamdashBiomembranes vol 1758 no 8 pp 994ndash1003 2006

[3] S G Rhee ldquoCell signaling H2O2 a necessary evil for cell

signalingrdquo Science vol 312 no 5782 pp 1882ndash1883 2006[4] M J Marchissio D E A Frances C E Carnovale and R A

Marinelli ldquoMitochondrial aquaporin-8 knockdown in humanhepatoma HepG2 cells causes ROS-induced mitochondrialdepolarization and loss of viabilityrdquo Toxicology and AppliedPharmacology vol 264 no 2 pp 246ndash254 2012

[5] M Bertolotti S Bestetti J M Garcıa-Manteiga et al ldquoTyrosineKinase signal modulation a matter of H

2O2membrane perme-

abilityrdquo Antioxidants and Redox Signaling vol 19 no 13 pp1447ndash1451 2013

[6] E W Miller B C Dickinson and C J Chang ldquoAquaporin-3 mediates hydrogen peroxide uptake to regulate downstreamintracellular signalingrdquo Proceedings of the National Academy ofSciences of the United States of America vol 107 no 36 pp15681ndash15686 2010

[7] E A Veal A M Day and B A Morgan ldquoHydrogen peroxidesensing and signalingrdquo Molecular Cell vol 26 no 1 pp 1ndash142007

[8] D Trachootham W Lu M A Ogasawara N R-D Valle andP Huang ldquoRedox regulation of cell survivalrdquo Antioxidants andRedox Signaling vol 10 no 8 pp 1343ndash1374 2008

[9] P A Madureira and D M Waisman ldquoAnnexin A2 theimportance of being redox sensitiverdquo International Journal ofMolecular Sciences vol 14 no 2 pp 3568ndash3594 2013

[10] A L Jackson and L A Loeb ldquoThe contribution of endogenoussources of DNA damage to the multiple mutations in cancerrdquoMutation Research vol 477 no 1-2 pp 7ndash21 2001

[11] R Rubin and J L Farber ldquoMechanisms of the killing of culturedhepatocytes by hydrogen peroxiderdquo Archives of Biochemistryand Biophysics vol 228 no 2 pp 450ndash459 1984

[12] B Kumar S Koul L Khandrika R B Meacham and H KKoul ldquoOxidative stress is inherent in prostate cancer cells andis required for aggressive phenotyperdquo Cancer Research vol 68no 6 pp 1777ndash1785 2008

[13] K Ishikawa K Takenaga M Akimoto et al ldquoROS-generatingmitochondrial DNA mutations can regulate tumor cell metas-tasisrdquo Science vol 320 no 5876 pp 661ndash664 2008


[14] F Weinberg and N S Chandel ldquoReactive oxygen species-dependent signaling regulates cancerrdquo Cellular and MolecularLife Sciences vol 66 no 23 pp 3663ndash3673 2009

[15] E L Bell T A Klimova J Eisenbart P T Schumacker andN S Chandel ldquoMitochondrial reactive oxygen species triggerhypoxia-inducible factor-dependent extension of the replicativelife span during hypoxiardquo Molecular and Cellular Biology vol27 no 16 pp 5737ndash5745 2007

[16] H J Kim H-Z Chae Y-J Kim et al ldquoPreferential elevation ofPrx I and Trx expression in lung cancer cells following hypoxiaand in human lung cancer tissuesrdquo Cell Biology and Toxicologyvol 19 no 5 pp 285ndash298 2003

[17] C Li M AThompson A T Tamayo et al ldquoOver-expression ofThioredoxin-1 mediates growth survival and chemoresistanceand is a druggable target in diffuse large B-cell lymphomardquoOncotarget vol 3 no 3 pp 314ndash326 2012

[18] N Traverso R Ricciarelli M Nitti et al ldquoRole of glutathionein cancer progression and chemoresistancerdquoOxidativeMedicineand Cellular Longevity vol 2013 Article ID 972913 10 pages2013

[19] A Ooi J-C Wong D Petillo et al ldquoAn antioxidant responsephenotype shared between hereditary and sporadic type 2papillary renal cell carcinomardquo Cancer Cell vol 20 no 4 pp511ndash523 2011

[20] G M Denicola F A Karreth T J Humpton et al ldquoOncogene-induced Nrf2 transcription promotes ROS detoxification andtumorigenesisrdquo Nature vol 475 no 7354 pp 106ndash110 2011

[21] KMHolmstrom andT Finkel ldquoCellularmechanisms and phy-siological consequences of redox-dependent signallingrdquoNatureReviews Molecular Cell Biology vol 15 no 6 pp 411ndash421 2014

[22] P Storz ldquoReactive oxygen species in tumor progressionrdquo Fron-tiers in Bioscience vol 10 no 2 pp 1881ndash1896 2005

[23] M E Cockman N Masson D R Mole et al ldquoHypoxiainducible factor-alpha binding and ubiquitylation by the vonHippel-Lindau tumor suppressor proteinrdquo The Journal of Bio-logical Chemistry vol 275 no 33 pp 25733ndash25741 2000

[24] P H Maxwell M S Wlesener G-W Chang et al ldquoThe tumoursuppressor protein VHL targets hypoxia-inducible factors foroxygen-dependent proteolysisrdquo Nature vol 399 no 6733 pp271ndash275 1999

[25] V Srinivas L-P Zhang X-H Zhu and J Caro ldquoCharacteri-zation of an oxygenredox-dependent degradation domain ofhypoxia-inducible factor alpha (HIF-alpha) proteinsrdquo Biochem-ical and Biophysical Research Communications vol 260 no 2pp 557ndash561 1999

[26] B L Ebert and H F Bunn ldquoRegulation of transcription byhypoxia requires amultiprotein complex that includes hypoxia-inducible factor 1 an adjacent transcription factor and p300CREB binding proteinrdquoMolecular and Cellular Biology vol 18no 7 pp 4089ndash4096 1998

[27] T Klimova and N S Chandel ldquoMitochondrial complex III reg-ulates hypoxic activation of HIFrdquoCell Death andDifferentiationvol 15 no 4 pp 660ndash666 2008

[28] V Catalano A Turdo S Di Franco F Dieli M Todaro and GStassi ldquoTumor and its microenvironment a synergistic inter-playrdquo Seminars in Cancer Biology vol 23 no 6 pp 522ndash5322013

[29] E L Bell T A Klimova J Eisenbart et al ldquoThe Qo site ofthe mitochondrial complex III is required for the transductionof hypoxic signaling via reactive oxygen species productionrdquoJournal of Cell Biology vol 177 no 6 pp 1029ndash1036 2007

[30] N S Chandel D S McClintock C E Feliciano et al ldquoReactiveoxygen species generated at mitochondrial complex III stabilizehypoxia-inducible factor-1alpha during hypoxia a mechanismof O2sensingrdquoThe Journal of Biological Chemistry vol 275 no

33 pp 25130ndash25138 2000[31] P Gao H Zhang R Dinavahi et al ldquoHIF-dependent antitu-

morigenic effect of antioxidants in vivordquoCancer Cell vol 12 no3 pp 230ndash238 2007

[32] R D Guzy B Hoyos E Robin et al ldquoMitochondrial complexIII is required for hypoxia-inducedROSproduction and cellularoxygen sensingrdquo Cell Metabolism vol 1 no 6 pp 401ndash4082005

[33] S Bonello C Zahringer R S BelAiba et al ldquoReactive oxygenspecies activate the HIF-1alpha promoter via a functionalNFkappaB siterdquo Arteriosclerosis Thrombosis and Vascular Biol-ogy vol 27 no 4 pp 755ndash761 2007

[34] M P Murphy ldquoHow mitochondria produce reactive oxygenspeciesrdquo Biochemical Journal vol 417 no 1 pp 1ndash13 2009

[35] G-Y Liou and P Storz ldquoReactive oxygen species in cancerrdquo FreeRadical Research vol 44 no 5 pp 479ndash496 2010

[36] MD Brand ldquoThe sites and topology ofmitochondrial superox-ide productionrdquo Experimental Gerontology vol 45 no 7-8 pp466ndash472 2010

[37] M Schrader and H D Fahimi ldquoPeroxisomes and oxidativestressrdquo Biochimica et Biophysica ActamdashMolecular Cell Researchvol 1763 no 12 pp 1755ndash1766 2006

[38] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007

[39] R Paletta-SilvaN Rocco-Machado and J RMeyer-FernandesldquoNADPH oxidase biology and the regulation of tyrosine kinasereceptor signaling and cancer drug cytotoxicityrdquo InternationalJournal of Molecular Sciences vol 14 no 2 pp 3683ndash3704 2013

[40] K E de Visser A Eichten and L M Coussens ldquoParadoxicalroles of the immune systemduring cancer developmentrdquoNatureReviews Cancer vol 6 no 1 pp 24ndash37 2006

[41] B M Babior ldquoThe respiratory burst oxidaserdquo Current Opinionin Hematology vol 2 no 1 pp 55ndash60 1995

[42] S Cui J S Reichner R B Mateo and J E Albina ldquoActivatedmurine macrophages induce apoptosis in tumor cells throughnitric oxide-dependent or -independent mechanismsrdquo CancerResearch vol 54 no 9 pp 2462ndash2467 1994

[43] C Szabo H Ischiropoulos and R Radi ldquoPeroxynitrite bio-chemistry pathophysiology and development of therapeuticsrdquoNature Reviews Drug Discovery vol 6 no 8 pp 662ndash680 2007

[44] P A Riley ldquoFree radicals in biology oxidative stress and theeffects of ionizing radiationrdquo International Journal of RadiationBiology vol 65 no 1 pp 27ndash33 1994

[45] J E Klaunig L M Kamendulis and B A Hocevar ldquoOxidativestress and oxidative damage in carcinogenesisrdquo ToxicologicPathology vol 38 no 1 pp 96ndash109 2010

[46] C Gorrini I S Harris and TWMak ldquoModulation of oxidativestress as an anticancer strategyrdquoNature Reviews DrugDiscoveryvol 12 no 12 pp 931ndash947 2013

[47] B Jiang S Xiao M A Khan and M Xue ldquoDefective antioxi-dant systems in cervical cancerrdquo Tumor Biology vol 34 no 4pp 2003ndash2009 2013

[48] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006


[49] C-C Yeh M-F Hou S-H Wu et al ldquoA study of glutathionestatus in the blood and tissues of patients with breast cancerrdquoCell Biochemistry and Function vol 24 no 6 pp 555ndash559 2006

[50] A Acharya I Das D Chandhok and T Saha ldquoRedox reg-ulation in cancer a double-edged sword with therapeuticpotentialrdquoOxidative Medicine and Cellular Longevity vol 3 no1 pp 23ndash34 2010

[51] J M Estrela A Ortega and E Obrador ldquoGlutathione in cancerbiology and therapyrdquo Critical Reviews in Clinical LaboratorySciences vol 43 no 2 pp 143ndash181 2006

[52] M L OrsquoBrien and K D Tew ldquoGlutathione and related enzymesinmultidrug resistancerdquo European Journal of Cancer Part A vol32 no 6 pp 967ndash978 1996

[53] P Calvert K-S Yao T CHamilton and P J OrsquoDwyer ldquoClinicalstudies of reversal of drug resistance based on glutathionerdquoChemico-Biological Interactions vol 111-112 pp 213ndash224 1998

[54] Z-X Du H-Y Zhang X Meng Y Guan and H-Q WangldquoRole of oxidative stress and intracellular glutathione in the sen-sitivity to apoptosis induced by proteasome inhibitor in thyroidcancer cellsrdquo BMC Cancer vol 9 article 56 2009

[55] B Koberle M T Tomicic S Usanova and B Kaina ldquoCis-platin resistance preclinical findings and clinical implicationsrdquoBiochimica et Biophysica Acta vol 1806 no 2 pp 172ndash182 2010

[56] P-S Ong S-Y Chan and P C Ho ldquoDifferential augmentativeeffects of buthionine sulfoximine and ascorbic acid in As2O3-induced ovarian cancer cell death oxidative stress-independentand -dependent cytotoxic potentiationrdquo International Journal ofOncology vol 38 no 6 pp 1731ndash1739 2011

[57] I S Harris A E Treloar S Inoue et al ldquoGlutathione andthioredoxin antioxidant pathways synergize to drive cancer ini-tiation and progressionrdquo Cancer Cell vol 27 no 2 pp 211ndash2222015

[58] P AMadureira R Hill V AMiller C Giacomantonio PW KLee and D M Waisman ldquoAnnexin A2 is a novel cellular redoxregulatory protein involved in tumorigenesisrdquo Oncotarget vol2 no 12 pp 1075ndash1093 2011

[59] P V Raninga G D Trapani and K F Tonissen ldquoCross talkbetween two antioxidant systems thioredoxin and DJ-1 conse-quences for cancerrdquo Oncoscience vol 1 no 1 pp 95ndash110 2014

[60] E S J Arner and A Holmgren ldquoPhysiological functions ofthioredoxin and thioredoxin reductaserdquo European Journal ofBiochemistry vol 267 no 20 pp 6102ndash6109 2000

[61] M Saitoh H NishitohM Fujii et al ldquoMammalian thioredoxinis a direct inhibitor of apoptosis signal-regulating kinase (ASK)1rdquoThe EMBO Journal vol 17 no 9 pp 2596ndash2606 1998

[62] H Ichijo E Nishida K Irie et al ldquoInduction of apoptosis byASK1 a mammalian MAPKKK that activates SAPKJNK andp38 signaling pathwaysrdquo Science vol 275 no 5296 pp 90ndash941997

[63] K Tobiume A Matsuzawa T Takahashi et al ldquoASK1 isrequired for sustained activations of JNKp38MAP kinases andapoptosisrdquoThe EMBO Reports vol 2 no 3 pp 222ndash228 2001

[64] G Powis D Mustacich and A Coon ldquoThe role of the redoxprotein thioredoxin in cell growth and cancerrdquo Free RadicalBiology amp Medicine vol 29 no 3-4 pp 312ndash322 2000

[65] J Wang M Kobayashi K Sakurada M Imamura T Moriuchiand M Hosokawa ldquoPossible roles of an adult T-cell leukemia(ATL)-derived factorthioredoxin in the drug resistance of ATLto adriamycinrdquo Blood vol 89 no 7 pp 2480ndash2487 1997

[66] N Kawahara T Tanaka A Yokomizo et al ldquoEnhanced coex-pression of thioredoxin and highmobility group protein 1 genes

in humanhepatocellular carcinoma and the possible associationwith decreased sensitivity to cisplatinrdquo Cancer Research vol 56no 23 pp 5330ndash5333 1996

[67] A Yokomizo M Ono H Nanri et al ldquoCellular levels of thiore-doxin associated with drug sensitivity to cisplatin mitomycinC doxorubicin and etoposiderdquo Cancer Research vol 55 no 19pp 4293ndash4296 1995

[68] G N Landis and J Tower ldquoSuperoxide dismutase evolution andlife span regulationrdquo Mechanisms of Ageing and Developmentvol 126 no 3 pp 365ndash379 2005

[69] J C-M Ho S Zheng S A A Comhair C Farver and SC Erzurum ldquoDifferential expression of manganese superoxidedismutase and catalase in lung cancerrdquo Cancer Research vol 61no 23 pp 8578ndash8585 2001

[70] H Hu M-L Luo X-L Du et al ldquoUp-regulated manganesesuperoxide dismutase expression increases apoptosis resistancein human esophageal squamous cell carcinomasrdquo Chinese Med-ical Journal vol 120 no 23 pp 2092ndash2098 2007

[71] R Izutani S Asano M Imano D Kuroda M Kato and HOhyanagi ldquoExpression of manganese superoxide dismutase inesophageal and gastric cancersrdquo Journal of Gastroenterology vol33 no 6 pp 816ndash822 1998

[72] AM L Janssen C B BosmanW van Duijn et al ldquoSuperoxidedismutases in gastric and esophageal cancer and the prognosticimpact in gastric cancerrdquo Clinical Cancer Research vol 6 no 8pp 3183ndash3192 2000

[73] R Salzman K Kankova L Pacal J Tomandl Z Horakovaand R Kostrica ldquoIncreased activity of superoxide dismutasein advanced stages of head and neck squamous cell carcinomawith locoregionalmetastasesrdquoNeoplasma vol 54 no 4 pp 321ndash325 2007

[74] MMalafa JMargenthaler BWebb L Neitzel andM Christo-phersen ldquoMnSOD expression is increased in metastatic gastriccancerrdquo Journal of Surgical Research vol 88 no 2 pp 130ndash134 2000

[75] A Miar D Hevia H Munoz-Cimadevilla et al ldquoMan-ganese superoxide dismutase (SOD2MnSOD)catalase andSOD2GPx1 ratios as biomarkers for tumor progression andmetastasis in prostate colon and lung cancerrdquo Free RadicalBiology and Medicine vol 85 pp 45ndash55 2015

[76] K K Nelson A C Ranganathan J Mansouri et al ldquoElevatedSod2 activity augments matrix metalloproteinase expressionevidence for the involvement of endogenous hydrogen peroxidein regulating metastasisrdquo Clinical Cancer Research vol 9 no 1pp 424ndash432 2003

[77] A C Ranganathan K K Nelson A M Rodriguez et al ldquoMan-ganese superoxide dismutase signals matrix metalloproteinaseexpression viaH

2O2-dependent ERK12 activationrdquoThe Journal

of Biological Chemistry vol 276 no 17 pp 14264ndash14270 2001[78] T-C Chuang J-Y Liu C-T Lin et al ldquoHuman manganese

superoxide dismutase suppresses HER2neu-mediated breastcancer malignancyrdquo FEBS Letters vol 581 no 23 pp 4443ndash4449 2007

[79] J J Cullen C Weydert M M Hinkhouse et al ldquoThe role ofmanganese superoxide dismutase in the growth of pancreaticadenocarcinomardquoCancer Research vol 63 no 6 pp 1297ndash13032003

[80] Y Hu D G Rosen Y Zhou et al ldquoMitochondrial manganese-superoxide dismutase expression in ovarian cancer role incell proliferation and response to oxidative stressrdquo Journal ofBiological Chemistry vol 280 no 47 pp 39485ndash39492 2005


[81] LWOberley andG R Buettner ldquoRole of superoxide dismutasein cancer a reviewrdquoCancer Research vol 39 no 4 pp 1141ndash11491979

[82] Y Soini M Vakkala K Kahlos P Paakko and V KinnulaldquoMnSOD expression is less frequent in tumour cells of invasivebreast carcinomas than in in situ carcinomas or non-neoplasticbreast epithelial cellsrdquo The Journal of Pathology vol 195 no 2pp 156ndash162 2001

[83] L Behrend A Mohr T Dick and R M Zwacka ldquoManganesesuperoxide dismutase induces p53-dependent senescence incolorectal cancer cellsrdquoMolecular and Cellular Biology vol 25no 17 pp 7758ndash7769 2005

[84] L W Oberley ldquoMechanism of the tumor suppressive effect ofMnSOD overexpressionrdquo Biomedicine and Pharmacotherapyvol 59 no 4 pp 143ndash148 2005

[85] L A Ridnour T D Oberley and L W Oberley ldquoTumor sup-pressive effects of MnSOD overexpression may involve imbal-ance in peroxide generation versus peroxide removalrdquo Anti-oxidants and Redox Signaling vol 6 no 3 pp 501ndash512 2004

[86] Y Zhang B J Smith and L W Oberley ldquoEnzymatic activityis necessary for the tumor-suppressive effects of MnSODrdquoAntioxidants and Redox Signaling vol 8 no 7-8 pp 1283ndash12932006

[87] N Li T D Oberley L W Oberley and W Zhong ldquoOverex-pression of manganese superoxide dismutase in DU145 humanprostate carcinoma cells has multiple effects of cell phenotyperdquoProstate vol 35 no 3 pp 221ndash233 1998

[88] J M McCord B B Keele Jr and I Fridovich ldquoAn enzyme-based theory of obligate anaerobiosis the physiological func-tion of superoxide dismutaserdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 68 no5 pp 1024ndash1027 1971

[89] D Keilin and E F Hartree ldquoCatalase peroxidase and metmyo-globin as catalysts of coupled peroxidatic reactionsrdquo Biochemi-cal Journal vol 60 no 2 pp 310ndash325 1955

[90] M L Kremer ldquoPeroxidatic activity of catalaserdquo Biochimica etBiophysica Acta vol 198 no 2 pp 199ndash209 1970

[91] A M Vetrano D E Heck T M Mariano V Mishin DL Laskin and J D Laskin ldquoCharacterization of the oxidaseactivity in mammalian catalaserdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35372ndash35381 2005

[92] L Gebicka and J Didik ldquoCatalytic scavenging of peroxynitriteby catalaserdquo Journal of Inorganic Biochemistry vol 103 no 10pp 1375ndash1379 2009

[93] S Heinzelmanna and G Bauer ldquoMultiple protective functionsof catalase against intercellular apoptosis-inducing ROS signal-ing of human tumor cellsrdquo Biological Chemistry vol 391 no 6pp 675ndash693 2010

[94] L Brunelli V Yermilov and J S Beckman ldquoModulation ofcatalase peroxidatic and catalatic activity by nitric oxiderdquo FreeRadical Biology and Medicine vol 30 no 7 pp 709ndash714 2001

[95] D AWink and J BMitchell ldquoChemical biology of nitric oxideinsights into regulatory cytotoxic and cytoprotective mecha-nisms of nitric oxiderdquo Free Radical Biology amp Medicine vol25 no 4-5 pp 434ndash456 1998

[96] G C Brown ldquoReversible binding and inhibition of catalase bynitric oxiderdquo European Journal of Biochemistry vol 232 no 1pp 188ndash191 1995

[97] S A Castaldo A P Da Silva A Matos et al ldquoThe role ofCYBA (p22phox) and catalase genetic polymorphisms and theirpossible epistatic interaction in cervical cancerrdquo Tumor Biologyvol 36 no 2 pp 909ndash414 2015

[98] J P Fruehauf and F L Meyskens Jr ldquoReactive oxygen species abreath of life or deathrdquo Clinical Cancer Research vol 13 no 3pp 789ndash794 2007

[99] F Bittinger J L Gonzalez-Garcıa C L Klein C BrochhausenF Offner and C J Kirkpatrick ldquoProduction of superoxide byhuman malignant melanoma cellsrdquoMelanoma Research vol 8no 5 pp 381ndash387 1998

[100] M Lopez-Lazaro ldquoExcessive superoxide anion generation playsa key role in carcinogenesisrdquo International Journal of Cancervol 120 no 6 pp 1378ndash1380 2007

[101] W Bechtel and G Bauer ldquoModulation of intercellular ROSsignaling of human tumor cellsrdquo Anticancer Research vol 29no 11 pp 4559ndash4570 2009

[102] W Bechtel and G Bauer ldquoCatalase protects tumor cells fromapoptosis induction by intercellular ROS signalingrdquo AnticancerResearch vol 29 no 11 pp 4541ndash4557 2009

[103] G Bauer ldquoReactive oxygen and nitrogen species efficientselective and interactive signals during intercellular inductionof apoptosisrdquo Anticancer Research vol 20 no 6 pp 4115ndash41392000

[104] G Bauer ldquoTumor cell-protective catalase as a novel target forrational therapeutic approaches based on specific intercellularROS signalingrdquo Anticancer Research vol 32 no 7 pp 2599ndash2624 2012

[105] B Bohm S Heinzelmann M Motz and G Bauer ldquoExtracel-lular localization of catalase is associated with the transformedstate of malignant cellsrdquo Biological Chemistry 2015

[106] C McDonald J Muhlbauer G Perlmutter K Taparra and SA Phelan ldquoPeroxiredoxin proteins protectMCF-7 breast cancercells from doxorubicin-induced toxicityrdquo International Journalof Oncology vol 45 no 1 pp 219ndash226 2014

[107] H C Whitaker D Patel W J Howat et al ldquoPeroxiredoxin-3is overexpressed in prostate cancer and promotes cancer cellsurvival by protecting cells fromoxidative stressrdquoBritish Journalof Cancer vol 109 no 4 pp 983ndash993 2013

[108] J Park S Lee S Lee and S W Kang ldquo2-cys peroxiredoxinsemerging hubs determining redox dependency of mammaliansignaling networksrdquo International Journal of Cell Biology vol2014 Article ID 715867 10 pages 2014

[109] T Ishii E Warabi and T Yanagawa ldquoNovel roles of peroxire-doxins in inflammation cancer and innate immunityrdquo Journalof Clinical Biochemistry and Nutrition vol 50 no 2 pp 91ndash1052012

[110] L Li Y-G Zhang and C-L Chen ldquoAnti-apoptotic role ofperoxiredoxin III in cervical cancer cellsrdquo FEBS Open Bio vol3 pp 51ndash54 2013

[111] J H Park Y S Kim H L Lee et al ldquoExpression of peroxire-doxin and thioredoxin in human lung cancer and paired normallungrdquo Respirology vol 11 no 3 pp 269ndash275 2006

[112] V L Kinnula S Lehtonen R Sormunen et al ldquoOverexpressionof peroxiredoxins I II III V and VI in malignant mesothe-liomardquo Journal of Pathology vol 196 no 3 pp 316ndash323 2002

[113] G Poschmann M Grzendowski A Stefanski E Bruns HE Meyer and K Stuhler ldquoRedox proteomics reveal stressresponsive proteins linking peroxiredoxin-1 status in glioma tochemosensitivity and oxidative stressrdquo Biochimica et BiophysicaActamdashProteins and Proteomics vol 1854 no 6 pp 624ndash6312015

[114] T Wang A J G Diaz and Y Yen ldquoThe role of peroxiredoxin IIin chemoresistance of breast cancer cellsrdquoBreast Cancer Targetsand Therapy vol 6 pp 73ndash80 2014


[115] M L Fishel and M R Kelley ldquoThe DNA base excision repairprotein Ape1Ref-1 as a therapeutic and chemopreventive tar-getrdquoMolecular Aspects of Medicine vol 28 no 3-4 pp 375ndash3952007

[116] M L Fishel X Wu C M Devlin et al ldquoApurinicapyrimidinicendonucleaseredox factor-1 (APE1Ref-1) redox function neg-atively regulates NRF2rdquoThe Journal of Biological Chemistry vol290 no 5 pp 3057ndash3068 2015

[117] Y Zhang J Wang D Xiang D Wang and X Xin ldquoAlterationsin the expression of the apurinicapyrimidinic endonuclease-1redox factor-1 (APE1Ref-1) in human ovarian cancer andindentification of the therapeutic potential of APE1Ref-1inhibitorrdquo International Journal of Oncology vol 35 no 5 pp1069ndash1079 2009

[118] Z T Kelleher A Matsumoto J S Stamler and H E MarshallldquoNOS2 regulation of NF-120581B by S-nitrosylation of p65rdquo TheJournal of Biological Chemistry vol 282 no 42 pp 30667ndash30672 2007

[119] S J Wei A Botero K Hirota et al ldquoThioredoxin nucleartranslocation and interaction with redox factor-1 activates theactivator protein-1 transcription factor in response to ionizingradiationrdquo Cancer Research vol 60 no 23 pp 6688ndash66952000

[120] G Kaur R P Cholia A KMantha and R Kumar ldquoDNA repairand redox activities and inhibitors of apurinicapyrimidinicendonuclease 1redox effector factor 1 (APE1Ref-1) a compar-ative analysis and their scope and limitations toward anticancerdrug developmentrdquo Journal of Medicinal Chemistry vol 57 no24 pp 10241ndash10256 2014

[121] Z Yang S Yang B J Misner F Liu-Smith and F L MeyskensldquoThe role of APERef-1 signaling pathway in hepatocellularcarcinoma progressionrdquo International Journal of Oncology vol45 no 5 pp 1820ndash1828 2014

[122] M S Bobola A Blank M S Berger B A Stevens and J RSilber ldquoApurinicapyrimidinic endonuclease activity is elevatedin human adult gliomasrdquo Clinical Cancer Research vol 7 no 11pp 3510ndash3518 2001

[123] M S Bobola P P Jankowski M E Gross et al ldquoApurinicapyrimidinic endonuclease is inversely associatedwith responseto radiotherapy in pediatric ependymomardquo International Jour-nal of Cancer vol 129 no 10 pp 2370ndash2379 2011

[124] G S Xiong H L Sun S M Wu and J Z Mo ldquoSmall inter-fering RNA against the apurinic or apyrimidinic endonucleaseenhances the sensitivity of human pancreatic cancer cells togemcitabine in vitrordquo Journal of Digestive Diseases vol 11 no4 pp 224ndash230 2010

[125] A M Minisini C Loreto M Mansutti et al ldquoTopoisomeraseII120572 and APEref-1 are associated with pathologic response toprimary anthracycline-based chemotherapy for breast cancerrdquoCancer Letters vol 224 no 1 pp 133ndash139 2005

[126] S Yang and F L Meyskens Jr ldquoApurinicapyrimidinic endonu-cleaseredox effector factor-1(APERef-1) a unique target forthe prevention and treatment of human melanomardquo Antioxi-dants and Redox Signaling vol 11 no 3 pp 639ndash650 2009

[127] I Ganan-Gomez Y Wei H Yang M C Boyano-Adanez andG Garcıa-Manero ldquoOncogenic functions of the transcriptionfactor Nrf2rdquo Free Radical Biology andMedicine vol 65 pp 750ndash764 2013

[128] A Sakurai M Nishimoto S Himeno et al ldquoTranscriptionalregulation of thioredoxin reductase 1 expression by cadmiumin vascular endothelial cells role of NF-E2-related factor-2rdquoJournal of Cellular Physiology vol 203 no 3 pp 529ndash537 2005

[129] T Ramprasath and G S Selvam ldquoPotential impact of geneticvariants in Nrf2 regulated antioxidant genes and risk predictionof diabetes and associated cardiac complicationsrdquo CurrentMedicinal Chemistry vol 20 no 37 pp 4680ndash4693 2013

[130] E Kansanen S M Kuosmanen H Leinonen and A-LLevonenn ldquoTheKeap1-Nrf2 pathwaymechanisms of activationand dysregulation in cancerrdquo Redox Biology vol 1 no 1 pp 45ndash49 2013

[131] Y R Kim J EOhM S Kim et al ldquoOncogenicNRF2mutationsin squamous cell carcinomas of oesophagus and skinrdquo Journalof Pathology vol 220 no 4 pp 446ndash451 2010

[132] T Shibata T Ohta K I Tong et al ldquoCancer related mutationsinNRF2 impair its recognition byKeap1-Cul3 E3 ligase and pro-mote malignancyrdquo Proceedings of the National Academy of Sci-ences of the United States of America vol 105 no 36 pp 13568ndash13573 2008

[133] J D Hayes and M McMahon ldquoNRF2 and KEAP1 mutationspermanent activation of an adaptive response in cancerrdquo Trendsin Biochemical Sciences vol 34 no 4 pp 176ndash188 2009

[134] A Sunters P A Madureira K M Pomeranz et al ldquoPaclitaxel-induced nuclear translocation of FOXO3a in breast cancer cellsis mediated by c-Jun NH2-terminal kinase and Aktrdquo CancerResearch vol 66 no 1 pp 212ndash220 2006

[135] B Vurusaner G Poli and H Basaga ldquoTumor suppressorgenes and ROS complex networks of interactionsrdquo Free RadicalBiology and Medicine vol 52 no 1 pp 7ndash18 2012

[136] I Ciechomska B Pyrzynska P Kazmierczak and B KaminskaldquoInhibition of Akt kinase signalling and activation of Forkheadare indispensable for upregulation of FasL expression in apop-tosis of glioma cellsrdquo Oncogene vol 22 no 48 pp 7617ndash76272003

[137] V Modur R Nagarajan B M Evers and J Milbrandt ldquoFOXOproteins regulate tumor necrosis factor-related apoptosis induc-ing ligand expression Implications for PTEN mutation inprostate cancerrdquoThe Journal of Biological Chemistry vol 277 no49 pp 47928ndash47937 2002

[138] S M Sykes S W Lane L Bullinger et al ldquoAKTFOXO sig-naling enforces reversible differentiation blockade in myeloidleukemiasrdquo Cell vol 146 no 5 pp 697ndash708 2011

[139] B M T Burgering and R H Medema ldquoDecisions on life anddeath FOXO Forkhead transcription factors are in commandwhen PKBAkt is off dutyrdquo Journal of Leukocyte Biology vol 73no 6 pp 689ndash701 2003

[140] C M Linardic ldquoPAX3-FOXO1 fusion gene in rhabdomyosar-comardquo Cancer Letters vol 270 no 1 pp 10ndash18 2008

[141] M E Olanich and F G Barr ldquoA call to ARMS targetingthe PAX3-FOXO1 gene in alveolar rhabdomyosarcomardquo ExpertOpinion onTherapeutic Targets vol 17 no 5 pp 607ndash623 2013

[142] L del Peso V M Gonzalez R Hernandez F G Barr and GNunez ldquoRegulation of the forkhead transcription factor FKHRbut not the PAX3-FKHR fusion protein by the serinethreoninekinase Aktrdquo Oncogene vol 18 no 51 pp 7328ndash7333 1999

[143] K I Block A C Koch M NMead P K Tothy R A Newmanand C Gyllenhaal ldquoImpact of antioxidant supplementation onchemotherapeutic toxicity a systematic review of the evidencefrom randomized controlled trialsrdquo International Journal ofCancer vol 123 no 6 pp 1227ndash1239 2008

[144] MGoodmanRMBostickOKucuk andD P Jones ldquoClinicaltrials of antioxidants as cancer prevention agents past presentand futurerdquo Free Radical Biology andMedicine vol 51 no 5 pp1068ndash1084 2011


[145] V I Sayin M X Ibrahim E Larsson J A Nilsson PLindahl and M O Bergo ldquoAntioxidants accelerate lung cancerprogression in micerdquo Science Translational Medicine vol 6 no221 Article ID 221ra15 2014

[146] M J McConnell and P M Herst ldquoAscorbate combination ther-apy new tool in the anticancer toolboxrdquo Science TranslationalMedicine vol 6 no 222 Article ID 222fs6 2014

[147] Y Ma J Chapman M Levine K Polireddy J Drisko and QChen ldquoHigh-dose parenteral ascorbate enhanced chemosensi-tivity of ovarian cancer and reduced toxicity of chemotherapyrdquoScience Translational Medicine vol 6 no 222 Article ID222ra18 2014

[148] C Luo Q Liu P Zhang M Li Z Chen and Y Liu ldquoPrognosticsignificance of annexin II expression in non-small cell lungcancerrdquo Clinical and Translational Oncology vol 15 no 11 pp938ndash946 2013

[149] X H Xu W Pan L Kang H Feng and Y Song ldquoAssociationof annexin A2 with cancer development (review)rdquo OncologyReports vol 33 no 5 pp 2121ndash2128 2015

[150] Z D Zhang Y Li L Q Fan Q Zhao B B Tan and X F ZhaoldquoAnnexin A2 is implicated in multi-drug-resistance in gastriccancer through p38MAPK and AKT pathwayrdquo Neoplasma vol61 no 6 pp 627ndash637 2014

[151] P A Madureira A P Surette K D Phipps M A S TaboskiV A Miller and D M Waisman ldquoThe role of the annexin A2heterotetramer in vascular fibrinolysisrdquo Blood vol 118 no 18pp 4789ndash4797 2011

[152] K M Waters D L Stenoien M B Sowa et al ldquoAnnexinA2modulates radiation-sensitive transcriptional programmingand cell faterdquo Radiation Research vol 179 no 1 pp 53ndash61 2013

[153] P A Madureira R Hill P W K Lee and D M Wais-man ldquoGenotoxic agents promote the nuclear accumulation ofannexin A2 role of annexin A2 in mitigating DNA damagerdquoPLoS ONE vol 7 no 11 Article ID e50591 2012

[154] R M Canet-Aviles M A Wilson D W Miller et al ldquoTheParkinsonrsquos disease protein DJ-1 is neuroprotective due tocysteine-sulfinic acid-driven mitochondrial localizationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 101 no 24 pp 9103ndash9108 2004

[155] T Kinumi J Kimata T Taira H Ariga and E Niki ldquoCysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogenperoxide-mediated oxidation in vivo in human umbilical veinendothelial cellsrdquo Biochemical and Biophysical Research Com-munications vol 317 no 3 pp 722ndash728 2004

[156] J-Y Im K-W Lee E Junn and M M Mouradian ldquoDJ-1 pro-tects against oxidative damage by regulating the thioredoxinASK1 complexrdquo Neuroscience Research vol 67 no 3 pp 203ndash208 2010

[157] Y-C Kim H Kitaura T Taira S M M Iguchi-Ariga andH Ariga ldquoOxidation of DJ-1-dependent cell transformationthrough direct binding of DJ-1 to PTENrdquo International Journalof Oncology vol 35 no 6 pp 1331ndash1341 2009

[158] S Shendelman A Jonason C Martinat T Leete and AAbeliovich ldquoDJ-1 is a redox-dependent molecular chaperonethat inhibits 120572-synuclein aggregate formationrdquo PLoS Biologyvol 2 no 11 Article ID e362 2004

[159] W Zhou and C R Freed ldquoDJ-1 up-regulates glutathionesynthesis during oxidative stress and inhibits A53T 120572-synucleintoxicityrdquoThe Journal of Biological Chemistry vol 280 no 52 pp43150ndash43158 2005

[160] J Waak S S Weber K Gorner et al ldquoOxidizable residuesmediating protein stability and cytoprotective interaction of

DJ-1 with apoptosis signal-regulating kinase 1rdquo The Journal ofBiological Chemistry vol 284 no 21 pp 14245ndash14257 2009

[161] C M Clements R S McNally B J Conti T W Mak and JP-Y Ting ldquoDJ-1 a cancer- and Parkinsonrsquos disease-associatedprotein stabilizes the antioxidant transcriptionalmaster regula-tor Nrf2rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 103 no 41 pp 15091ndash15096 2006

[162] H-H Yu Q Xu H-P Chen et al ldquoStable overexpression of DJ-1 protects H9c2 cells against oxidative stress under a hypoxiaconditionrdquo Cell Biochemistry and Function vol 31 no 8 pp643ndash651 2013

[163] P Kumar S Nandi T Z Tan et al ldquoHighly sensitive and specificnovel biomarkers for the diagnosis of transitional bladdercarcinomardquo Oncotarget vol 6 no 15 pp 13539ndash13549 2015

[164] I A Ismail A B Abdel Shakor and S H Hong ldquoDJ-1 pro-tects breast cancer cells against 21015840-benzoyloxycinnamaldehyde-induced oxidative stress independent of Nrf2rdquo Journal of Cellu-lar Physiology vol 230 no 9 pp 2262ndash2269 2015

[165] H Zhu S-D Liao J-J Shi et al ldquoDJ-1 mediates the resistanceof cancer cells to dihydroartemisinin through reactive oxygenspecies removalrdquo Free Radical Biology and Medicine vol 71 pp121ndash132 2014

[166] S DallrsquoAcqua M A Linardi R Bortolozzi et al ldquoNaturaldaucane esters induces apoptosis in leukaemic cells throughROS productionrdquo Phytochemistry vol 108 pp 147ndash156 2014

[167] J E Klaunig and L M Kamendulis ldquoThe role of oxidativestress in carcinogenesisrdquo Annual Review of Pharmacology andToxicology vol 44 pp 239ndash267 2004

[168] A P Fernandes and V Gandin ldquoSelenium compounds astherapeutic agents in cancerrdquo Biochimica et Biophysica ActamdashGeneral Subjects vol 1850 no 8 pp 1642ndash1660 1850

[169] J M An S S Kim J H Rhie D M Shin S R Seo and J TSeo ldquoCarmustine induces ERK- and JNK-dependent cell deathof neuronally-differentiated PC12 cells via generation of reactiveoxygen speciesrdquo Toxicology in Vitro vol 25 no 7 pp 1359ndash13652011

[170] S S Roy P Chakraborty and S Bhattacharya ldquoIntervention incyclophosphamide induced oxidative stress and DNA damageby a flavonyl-thiazolidinedione based organoselenocyanate andevaluation of its efficacy during adjuvant therapy in tumor bear-ing micerdquo European Journal of Medicinal Chemistry vol 73 pp195ndash209 2014

[171] L P Billen A Shamas-Din andDWAndrews ldquoBid a Bax-likeBH3 proteinrdquo Oncogene vol 27 supplement 1 no 1 pp S93ndashS104 2008

[172] D W Litchfield ldquoProtein kinase CK2 structure regulation androle in cellular decisions of life and deathrdquo Biochemical Journalvol 369 no 1 pp 1ndash15 2003

[173] C C Schneider A Hessenauer C Gotz and M MontenarhldquoDMAT an inhibitor of protein kinase CK2 induces reactiveoxygen species and DNA double strand breaksrdquo OncologyReports vol 21 no 6 pp 1593ndash1597 2009

[174] S M Jeon S-J Lee T K Kwon K-J Kim and Y-S BaeldquoNADPH oxidase is involved in protein kinase CKII down-regulation-mediated senescence through elevation of the levelof reactive oxygen species in human colon cancer cellsrdquo FEBSLetters vol 584 no 14 pp 3137ndash3142 2010

[175] Y-H Lee B S Kang and Y-S Bae ldquoPremature senescencein human breast cancer and colon cancer cells by tamoxifen-mediated reactive oxygen species generationrdquo Life Sciences vol97 no 2 pp 116ndash122 2014


[176] R L Lee J Westendorf and M R Gold ldquoDifferential role ofreactive oxygen species in the activation of mitogen-activatedprotein kinases and akt by key receptors on b-lymphocytesCD40 the b cell antigen receptor and CXCR4rdquo Journal of CellCommunication and Signaling vol 1 no 1 pp 33ndash43 2007

[177] J Alexandre F Batteux C Nicco et al ldquoAccumulation of hydro-gen peroxide is an early and crucial step for paclitaxel-inducedcancer cell death both in vitro and in vivordquo International Journalof Cancer vol 119 no 1 pp 41ndash48 2006

[178] J Alexandre Y Hu W Lu H Pelicano and P Huang ldquoNovelaction of paclitaxel against cancer cells bystander effect medi-ated by reactive oxygen speciesrdquo Cancer Research vol 67 no 8pp 3512ndash3517 2007

[179] C Jin S Wu X Lu et al ldquoConditioned medium fromactinomycin D-treated apoptotic cells induces mitochondria-dependent apoptosis in bystander cellsrdquo Toxicology Letters vol211 no 1 pp 45ndash53 2012

[180] C Yan D Kong D Ge et al ldquoMitomycin C induces apop-tosis in rheumatoid arthritis fibroblast-like synoviocytes viaa mitochondrial-mediated pathwayrdquo Cellular Physiology andBiochemistry vol 35 no 3 pp 1125ndash1136 2015

[181] Y Wang X Li X Wang et al ldquoGinsenoside Rd attenuatesmyocardial ischemiareperfusion injury via AktGSK-3120573 sig-naling and inhibition of themitochondria-dependent apoptoticpathwayrdquo PLoS ONE vol 8 no 8 Article ID e70956 2013

[182] P Korge G Calmettes and J N Weiss ldquoIncreased reac-tive oxygen species production during reductive stress theroles of mitochondrial glutathione and thioredoxin reductasesrdquoBiochimica et Biophysica ActamdashBioenergetics vol 1847 no 6-7pp 514ndash525 2015

[183] V Probin YWang andD Zhou ldquoBusulfan-induced senescenceis dependent on ROS production upstream of the MAPK path-wayrdquo Free Radical Biology andMedicine vol 42 no 12 pp 1858ndash1865 2007

[184] D M Townsend and K D Tew ldquoThe role of glutathione-S-transferase in anti-cancer drug resistancerdquo Oncogene vol 22no 47 pp 7369ndash7375 2003

[185] E A Sausville R W Stein J Peisach and S B Horwitz ldquoProp-erties and products of the degradation of DNA by bleomycinand iron(II)rdquo Biochemistry vol 17 no 14 pp 2746ndash2754 1978

[186] H Ekimoto H Kuramochi K Takahashi A Matsuda andH Umezawa ldquoKinetics of the reaction of bleomycin-Fe(II)-O

2

complex with DNArdquoThe Journal of Antibiotics vol 33 no 4 pp426ndash434 1980

[187] S Tobwala W Fan T Stoeger and N Ercal ldquoN-acetylcysteineamide a thiol antioxidant prevents bleomycin-induced toxicityin human alveolar basal epithelial cells (A549)rdquo Free RadicalResearch vol 47 no 9 pp 740ndash749 2013

[188] P Bragado A Armesilla A Silva and A Porras ldquoApoptosisby cisplatin requires p53 mediated p38alpha MAPK activationthroughROS generationrdquoApoptosis vol 12 no 9 pp 1733ndash17422007

[189] Y M Chung J S Kim and Y D Yoo ldquoA novel protein Romo1induces ROS production in themitochondriardquo Biochemical andBiophysical Research Communications vol 347 no 3 pp 649ndash655 2006

[190] J Hagenbuchner A Kuznetsov M Hermann B Hausott PObexer and M J Ausserlechner ldquoFOXO3-induced reactiveoxygen species are regulated by BCL2L11 (Bim) and SESN3rdquoJournal of Cell Science vol 125 part 5 pp 1191ndash1203 2012

[191] N O Karpinich M Tafani T Schneider M A Russo and JL Farber ldquoThe course of etoposide-induced apoptosis in Jurkat

cells lacking p53 and Baxrdquo Journal of Cellular Physiology vol208 no 1 pp 55ndash63 2006

[192] J-X Wang S Kaieda S Ameri et al ldquoIL-33ST2 axis promotesmast cell survival via BCLXLrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 111 no28 pp 10281ndash10286 2014

[193] G Minotti P Menna E Salvatorelli G Cairo and L GiannildquoAnthracyclines molecular advances and pharmacologic devel-opments in antitumor activity and cardiotoxicityrdquo Pharmaco-logical Reviews vol 56 no 2 pp 185ndash229 2004

[194] R D Olson and P S Mushlin ldquoDoxorubicin cardiotoxicityanalysis of prevailing hypothesesrdquoTheFASEB Journal vol 4 no13 pp 3076ndash3086 1990

[195] M Tokarska-SchlattnerM Zaugg C Zuppinger TWallimannand U Schlattner ldquoNew insights into doxorubicin-inducedcardiotoxicity the critical role of cellular energeticsrdquo Journal ofMolecular and Cellular Cardiology vol 41 no 3 pp 389ndash4052006

[196] M Verma N Shulga and J G Pastorino ldquoSirtuin-4 modulatessensitivity to induction of the mitochondrial permeabilitytransition porerdquo Biochimica et Biophysica Acta vol 1827 no 1pp 38ndash49 2013

[197] J Chen C Solomides H Parekh F Simpkins andH SimpkinsldquoCisplatin resistance in human cervical ovarian and lung cancercellsrdquo Cancer Chemotherapy and Pharmacology vol 75 no 6pp 1217ndash1227 2015

[198] S Arora A Bhardwaj S Singh et al ldquoAn undesiredeffect of chemotherapy gemcitabine promotes pancreaticcancer cell invasiveness through reactive oxygen species-dependent nuclear factor 120581B- and hypoxia-inducible factor 1120572-mediated up-regulation of CXCR4rdquo The Journal of BiologicalChemistry vol 288 no 29 pp 21197ndash21207 2013

[199] M Donadelli C Costanzo S Beghelli et al ldquoSynergistic inhi-bition of pancreatic adenocarcinoma cell growth by trichostatinA and gemcitabinerdquo Biochimica et Biophysica Acta vol 1773 no7 pp 1095ndash1106 2007

[200] M A Chetram and C V Hinton ldquoROS-mediated regulation ofCXCR4 in cancerrdquo Frontiers in Biology vol 8 no 3 pp 273ndash2782013

[201] A Gajek M Denel B Bukowska A Rogalska and AMarczakldquoPro-apoptotic activity of new analog of anthracyclinesmdashWP631 in advanced ovarian cancer cell linerdquo Toxicology in Vitrovol 28 no 2 pp 273ndash281 2014

[202] P Koedrith and Y R Seo ldquoEnhancement of the efficacy of mito-mycin C-mediated apoptosis in human colon cancer cells withRNAi-based thioredoxin reductase 1 deficiencyrdquo Experimentaland Therapeutic Medicine vol 2 no 5 pp 873ndash878 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Tumorigenesis

Catalase

SOD ROS

Trx

Proteinoxidation

GSHGR

Lipidperoxidation

Cancer cell death

DNAdamage

Trx peroxidases

GSH peroxidases

Figure 1 The cellular antioxidant systems Tumor progressioninduces increasing oxidative stress Cells have several antioxidantsystems to directly inactivate ROS (eg Trx peroxidases GSHperoxidases catalase and SOD) as well as REDOX regulatory sys-tems that recyclereactivate the ROS scavenging proteins and otherREDOX sensitive proteins (eg PTPs PTEN and transcriptionfactors)

(eg protein tyrosine phosphatases (PTPs) transcriptionfactors and the phosphatase and tensin homolog PTEN)(Figure 1)

Several studies have shown an important role for ROSin tumor development [12 13] Cancer cells generally dis-play elevated ROS compared to normal counterparts thatgive them a proliferative advantage and promote malignantprogression [14] In the tumor site the hypoxic cancer cells(in a low oxygen environment) typically show even higherlevels of ROS compared to nonhypoxic cancer cells [15]To deal with the increasing oxidative stress experienced asthe tumor progresses cancer cells upregulate the cellularantioxidant systems This allows the cancer cells to maintainlow to moderate levels of ROS (important for the activationof proliferative signaling pathways) while avoiding high levelsof ROS that have damaging effects and can induce cell death[16ndash18]

A large number of currently used chemotherapeuticagents kill cancer cells in part through the generation of ROSThese drugs are less toxic to normal cells that have lowerendogenous levels of ROS Consequently the upregulation ofantioxidant proteins within the cancer cells will render themmore resistant to chemotherapy [17ndash20]

In this reviewwewill make a comprehensive examinationof the current literature regarding the redox regulatory sys-tems that become upregulated in cancer and their role in pro-moting tumor progression and resistance to chemotherapy Abetter understanding of the molecular mechanisms used bycancer cells to adapt and survive to oxidative stress may also

allow the development of more efficient chemotherapeutictreatments

2 Sources of ROS in Cancer

The existing high levels of ROS typically observed in cancercells are the result of accumulation of intrinsic andorenvironmental factors

21 Intrinsic Sources of ROS Several factors within thetumor site contribute to the generation of high levels ofROS in the cancer cells The more relevant factors includehypoxia (low levels of oxygen) enhanced cellular metabolicactivity mitochondrial dysfunction increased growth factorreceptor mediated signaling transduction oncogene activ-ity increased activity of oxidases lipoxygenases cyclooxy-genases and thymidine phosphorylase and the crosstalkbetween cancer cells and immune cells recruited to the tumorsite (Figure 2) [21 22]

Within the tumor mass it has been well established thathypoxic cancer cells generally have higher levels of ROScompared to nonhypoxic counterparts Hypoxia contributesto the production of ROS through different mechanismsThemajor regulator of the hypoxic response is the transcriptionfactor Hypoxia Inducible Factor (HIF) The regulation ofthe alpha subunit of this transcription factor (HIF-120572) isdependent on intracellular levels of oxygen HIF-120572 regulationis mediated by the action of prolyl hydroxylases (PHDs)enzymes that in the presence of normal concentrations ofoxygen (normoxia) are able to hydroxylate HIF-120572 at twoprolyl residues allowing the binding of the protein vonHippel-Lindau (pVHL) VHL in its turn recruits E3 ubiquitinligases which target HIF-1120572 for proteasomal degradation [23ndash25] Low levels of oxygen lead to the inhibition of PHDsand subsequent stabilization and accumulation of the HIF-120572 subunit HIF-120572 translocates to the nucleus and bindsto the HIF-1120573 subunit and cofactors such as CBPp300inducing the transcription of more than one hundred genesinvolved in promoting angiogenesis (formation of new bloodvessels from preexisting blood vessels) glycolysis epithelial-mesenchymal transition (EMT) proliferation invasion andrecruitment of inflammatory cells to the tumor site [26 27]

Hypoxia induced glycolysis and subsequent inhibitionof oxidative phosphorylation at the mitochondrial mem-brane leads to an increase in ROS levels mediated by themitochondrial complex III [28ndash30] The hypoxic responsealso promotes the elevation of intracellular ROS via HIFdependent transcriptional activation of genes that encode forgrowth factors and their receptors Binding of these growthfactors to their receptors at the surface of cancer cells triggerssignaling pathways that induce the activation of NADPHoxidases (NOX) NOX are responsible for the production ofO2

∙minus which is then converted into H2O2

HIF-1120572 and HIF-2120572 stabilization are also dependent onROS Gao et al showed for the first time a decrease in tumorgrowth inmice treated with the antioxidant N-acetyl cysteine(NAC) that was traced to a redox mediated reduction in thelevels of HIF [31] In this way ROS is not only a by-product


HIF

Protein oxidation


Oncogene activity


oxygen


Mitochondria

Nucleus

Peroxisomes


Noncancerous cells

Ionizing radiation




ROS

ROS

ROS

ROS


Hypoxia

NOX


Glycolysis





2

∙minus [27 34]O2



2





2O2into O

2and H

2O)





∙minus The O2





2




2) and



2)


∙minus) and NO2

[42 43]













Intercellular ROS

ROS

DNA damage and

cell proliferation

CytoplasmNucleus

Peroxisomes

CAT


TRX

DJ-1GSH

ANXA2 PRDX


Ref-1 HIFP53

NF-120581B

Mitochondria

MnSOD

DNA damage

MnSOD

H2O2

H2O2

O2∙minus

O2∙minus




2) [9






2


2O2(that is less

reactive than O2



2






2


2





2




2O2dependent



2O2into water and O

2 This notion






+ 2NO2





















2










39 Others




2 Oxidized annexin





2O2[9 152 153]














2

[185 187]








[190]









[177 178]






2




2

∙minus which




2O2can






2

∙minus





2to O2














Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















HIF

Protein oxidation


Oncogene activity


oxygen


Mitochondria

Nucleus

Peroxisomes


Noncancerous cells

Ionizing radiation




ROS

ROS

ROS

ROS


Hypoxia

NOX


Glycolysis





2

∙minus [27 34]O2



2





2O2into O

2and H

2O)





∙minus The O2





2




2) and



2)


∙minus) and NO2

[42 43]













Intercellular ROS

ROS

DNA damage and

cell proliferation

CytoplasmNucleus

Peroxisomes

CAT


TRX

DJ-1GSH

ANXA2 PRDX


Ref-1 HIFP53

NF-120581B

Mitochondria

MnSOD

DNA damage

MnSOD

H2O2

H2O2

O2∙minus

O2∙minus




2) [9






2


2O2(that is less

reactive than O2



2






2


2





2




2O2dependent



2O2into water and O

2 This notion






+ 2NO2





















2










39 Others




2 Oxidized annexin





2O2[9 152 153]














2

[185 187]








[190]









[177 178]






2




2

∙minus which




2O2can






2

∙minus





2to O2














Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















∙minus The O2





2




2) and



2)


∙minus) and NO2

[42 43]













Intercellular ROS

ROS

DNA damage and

cell proliferation

CytoplasmNucleus

Peroxisomes

CAT


TRX

DJ-1GSH

ANXA2 PRDX


Ref-1 HIFP53

NF-120581B

Mitochondria

MnSOD

DNA damage

MnSOD

H2O2

H2O2

O2∙minus

O2∙minus




2) [9






2


2O2(that is less

reactive than O2



2






2


2





2




2O2dependent



2O2into water and O

2 This notion






+ 2NO2





















2










39 Others




2 Oxidized annexin





2O2[9 152 153]














2

[185 187]








[190]









[177 178]






2




2

∙minus which




2O2can






2

∙minus





2to O2














Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Intercellular ROS

ROS

DNA damage and

cell proliferation

CytoplasmNucleus

Peroxisomes

CAT


TRX

DJ-1GSH

ANXA2 PRDX


Ref-1 HIFP53

NF-120581B

Mitochondria

MnSOD

DNA damage

MnSOD

H2O2

H2O2

O2∙minus

O2∙minus




2) [9






2


2O2(that is less

reactive than O2



2






2


2





2




2O2dependent



2O2into water and O

2 This notion






+ 2NO2





















2










39 Others




2 Oxidized annexin





2O2[9 152 153]














2

[185 187]








[190]









[177 178]






2




2

∙minus which




2O2can






2

∙minus





2to O2














Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















2


2





2




2O2dependent



2O2into water and O

2 This notion






+ 2NO2





















2










39 Others




2 Oxidized annexin





2O2[9 152 153]














2

[185 187]








[190]









[177 178]






2




2

∙minus which




2O2can






2

∙minus





2to O2














Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























2










39 Others




2 Oxidized annexin





2O2[9 152 153]














2

[185 187]








[190]









[177 178]






2




2

∙minus which




2O2can






2

∙minus





2to O2














Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















39 Others




2 Oxidized annexin





2O2[9 152 153]














2

[185 187]








[190]









[177 178]






2




2

∙minus which




2O2can






2

∙minus





2to O2














Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























2

[185 187]








[190]









[177 178]






2




2

∙minus which




2O2can






2

∙minus





2to O2














Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















2O2can






2

∙minus





2to O2














Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























Acknowledgments


References







2O2membrane perme-


































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































































































































































































2
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article the tumorigenic roles of the...

Documents