Review Article Phytoagents for Cancer Management ...downloads.hindawi.com/journals/omcl/2013/925804.pdf · Review Article Phytoagents for Cancer Management: Regulation of Nucleic

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2013 Article ID 925804 22 pageshttpdxdoiorg1011552013925804

Review ArticlePhytoagents for Cancer Management Regulation of Nucleic AcidOxidation ROS and Related Mechanisms

Wai-Leng Lee1 Jing-Ying Huang2 and Lie-Fen Shyur234

1 School of Science Monash University Sunway Campus Jalan Lagoon Selatan 47500 Bandar SunwaySelangor Darul Ehsan Malaysia

2 Agricultural Biotechnology Research Center Academia Sinica No 128 Sec 2 Academia Road Nankang Taipei 115 Taiwan3Graduate Institute of Pharmacognosy Taipei Medical University No 250 Wu-Hsing Street Taipei 110 Taiwan4Graduate Institute of Biotechnology National Chung Hsing University No 250 Kuo Kuang Rd Taichung 402 Taiwan

Correspondence should be addressed to Lie-Fen Shyur lfshyurccvaxsinicaedutw

Received 3 May 2013 Revised 27 September 2013 Accepted 5 October 2013

Academic Editor Chiung-Wen Hu

Copyright copy 2013 Wai-Leng Lee et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Accumulation of oxidized nucleic acids causes genomic instability leading to senescence apoptosis and tumorigenesis Phytoagentsare known to reduce the risk of cancer development whether such effects are through regulating the extent of nucleic acidoxidation remains unclear Here we outlined the role of reactive oxygen species in nucleic acid oxidation as a driving force incancer progression The consequential relationship between genome instability and cancer progression highlights the importanceof modulation of cellular redox level in cancer management Current epidemiological and experimental evidence demonstratethe effects and modes of action of phytoagents in nucleic acid oxidation and provide rationales for the use of phytoagents aschemopreventive or therapeutic agents Vitamins and various phytoagents antagonize carcinogen-triggered oxidative stress byscavenging free radicals andor activating endogenous defence systems such as Nrf2-regulated antioxidant genes or pathwaysMoreover metal ion chelation by phytoagents helps to attenuate oxidative DNA damage caused by transition metal ions Besidesthe prooxidant effects of some phytoagents pose selective cytotoxicity on cancer cells and shed light on a new strategy of cancertherapy The ldquodouble-edged swordrdquo role of phytoagents as redox regulators in nucleic acid oxidation and their possible roles incancer prevention or therapy are discussed in this review

1 Nucleic Acid Oxidation as a Marker ofOxidative Insult by Reactive Oxygen Speciesand the Driving Force in Cancer Progression

The integrity of the genome is of crucial importance forproper gene expression andDNA replication Loss of genomeintegrity jeopardizes normal cellular physiological activitiesand leads to cellular pathological events such as senescenceapoptosis and tumorigenesis [1] Under oxidative stressthe level of genotoxic reactive oxygen species (ROS) isabnormally elevated ROS interact with and modify thechemical properties of biomolecules inside the cell whichcauses oxidative insults such as oxidation of nucleic acidsperoxidation of lipids [2] and denaturation of proteins [3]Oxidative modification to DNA structure mainly occurs inthe form of base oxidation Guanine which possesses the

lowest oxidation potential of the DNA bases is the mostfrequent target of ROS ROS-elicited changes in biomoleculescan be used as biomarkers to indicate the presence andextent of oxidative insult 8-Oxo-78-dihydroguanine (8-oxoG) the oxidation product of the DNA base guanineis a well-characterized marker for oxidative stress-inducedDNA damage [4] Following the oxidation of a DNA basegenome integrity is at increased risk because the DNA repairprocess base excision repair (BER) can increase the levelof interrupted DNA strands resulting in indirect single-strand break (SSB) [5] subsequently leading to introductionof mismatched base pairing during translesion DNA repair[6] As a consequence genome instability and accumulationof mutations lead to genetic heterogeneity in cancer cellsthat drive the adaptive evolution of cancer colonies withsurvivalexpansion advantages [7] Figure 1 shows the genetic

2 Oxidative Medicine and Cellular Longevity

Accumulation of genetic heterogeneity

Cancer evolutionTumor initiationTumor promotionTumor invasionTumor metastasis

PARP-mediated cell death

Genome instabilitygenome rearrangement

Base pair mismatchpoint mutation

Base excision repair (BER)

Indirect single-strand break (SSB)

Translesion DNA synthesis

ROS

Nucleic acid oxidation(eg 8-oxoG)

SSB-activatedPARP activity

Translesion DNA repair

Carc

inog

enes

is

PARAIF

Restoration of genome integrity

DNA ligase III

PCNA

DNA polymerase 120573

Figure 1 Genetic heterogeneity following nucleic acid oxidation is a major driving force of cancer progression ROS causes the oxidation ofDNA bases Subsequent base excision repair (BER) introduces genetic errors during the repair process and the accumulation of these errorsdrives cancer progression

instability and heterogeneity caused by nucleic acid oxidationin cancer cells which lead to carcinogenesis and cancer evolu-tion During BER indirect SSB are produced as intermediatesafter the removal of oxidized bases and their correspondingnucleotides If SSB takes place at adjacent regions on bothstrands of the same chromosome genome instability canensue Meanwhile poly (ADP-ribose) polymerase (PARP)is activated after binding to SSB and consumes NAD+ tosynthesize polyA chains which then recruit important DNArepair enzymes such as DNA polymerase 120573 and DNAligase III PARP also induces apoptosis through increasedpoly (ADP-ribose) (PAR) levels that facilitate the release ofapoptosis-inducing factor (AIF) frommitochondria and elicitapoptosis Otherwise depletion of NAD due to excessivePARP activity will further deplete the ATP pool and lead tocell lysis (necrosis) Proliferating cell nuclear antigen (PCNA)promotes the switch to a specialized DNA polymerase with alarger active site that tolerates damaged bases at the expenseof sacrificing fidelity during translesion synthesisrepairLower fidelity increases the chance of mismatch which givesrise to point mutations The accumulation of genome insta-bility and point mutations results in genome heterogeneityamong cells and chronologically within cells Tumor initi-ation is triggered by mutations that can activate oncogenesor silence tumor suppressor genes Further mutations thatgive rise to gainloss of function of genes then grant tumorcells the ability to resist growth control Further gainloss

of function continues to drive cancer progression enablingtumor cells to escape layers of control and become capableof invasion and metastasis

Elevated levels of oxidative DNA lesions (8-oxoG) havebeen noted in various tumors supporting the argument thatsuch damage contributes to the etiology of cancer Therefore8-oxoG has been established as an important biomarkerwhich is widely used to measure oxidative stress and assessrisk of tumor initiation after exposure to various carcinogenicsubstances and pollutants [8] In a cohort study involvingesophageal cancer patients more extensive oxidative damageto DNA as indicated by 8-oxoG levels was detected in cancerpatients in comparison to a healthy control group Smokinghabits and alcohol consumption risk factors for esophagealcancer were also correlated with the observed levels ofoxidative DNA damage [9]

Oxidative stress-induced lipid peroxidation is also asso-ciated with the early stages of carcinogenesis [10] Mal-ondialdehyde (MDA) the product of lipid peroxidationcan induce the formation of DNA adducts which leads tomutagenesis In an epidemiological study of breast cancer thelevel of the malondialdehyde-DNA adduct 3-(2-deoxy-120573-D-erythro-pentofuranosyl) pyrimido [12-120572]purin-10(3H) one(M1dG) was significantly higher in breast tissue specimensfrom cancer patients than in those from healthy individuals[11]Therefore other than 8-oxoG the level ofM1dGhas beenemployed as an indicator of cancer-associated oxidative DNA

Oxidative Medicine and Cellular Longevity 3

ROS

8-oxoG

MDA + guanineMDA-DNA adduct

(M1dG)

Elevated levels of oxidative DNA damage markers in cancer patients

Malondialdehyde(MDA)

DNA Lipid Protein

DNA base oxidation Lipid peroxidation

Protein carbonylation

O

O

OO

O

H

N

N

NNN

N

N

N

HN

H2N

Figure 2 Markers of oxidative DNA damage are elevated in cancer patients ROS causes oxidative damage to biomolecules such as DNAlipids and proteins and the resulting end products are often detrimental to normal cell physiological functions As the result of DNA baseoxidation 8-oxo-guanine (8-oxoG) can serve as a biomarker of primary oxidative DNA damageWhen lipids are attacked by ROS secondaryDNA damage arises due to malondialdehyde (MDA) the end production of lipid peroxidation that can covalently bind to guanine and formMDA-DNA adduct (M1dG) In human cancer patients both 8-oxoG and M1dG are found to be elevated suggesting a correlation betweenhigher oxidative stress and cancer

damage These markers are used as measures of antioxidantactivity in studies that assess the chemopreventive efficacyof anticancer agents including phytochemicals [9 12 13](Figure 2)

2 Sources of ROS and CellularAntioxidant Defense

ROS are genotoxic and ubiquitous They include the super-oxide anion radical (O

2

∙minus) hydrogen peroxide (H2O2) the

hydroxyl radical (OH∙) and the nitric oxide radical (NO∙)[14] For maintenance of genome integrity and normal cellphysiological function cells have developed strategies tocontrol ROS levels Such control is known as antioxidantdefense [14] Cellular redox status the level of ROS is the netresult of ROS arising from various origins and the capacityof the cell to remove it by antioxidant defense Many pre-ventivetherapeutic regimens including those phytoagent-based intervene in disease progression by fine-tuning thelevel of ROS and the corresponding antioxidant responses in

the cell [15] and thus shifting the redox balance in favor ofhuman health Introductions of the various origins of ROSand cellular antioxidant defense mechanisms are outlinedbelow

21 Origins of ROS Sources of ROS can be divided into threemajor categories exogenous endogenous metal-catalyzed(Figure 3(a)) Exogenously ROS levels are mainly increasedby environmental and dietary factors These factors mayserve as prooxidants that elicit ROS directly through chem-ical reactions or through the inhibition of cellular anti-oxidant defense or as substrates or stimulators of ROS-producing enzymes Environmental factors that increaseROSproduction include ultraviolet light ionizing radiation airpollutants cigarette smoke pesticides and industrial solventsor chemicals Dietary factors that induce ROS include foodcontaining peroxidized lipids (from rotten oil) polycyclicaromatic hydrocarbons (PAH from high-temperature pro-cessed hydrocarbon-based food) and food additives (preser-vatives)


Exogenous stimuli

(1) Radiation(2) UV(3) Cigarette smoke(4) Industrial solvent(5) Pesticides (6) Induction of inflammation

Endogenous origins through enzyme catalysis

(1) NADPH oxidase (NOX)(2) Cytochrome P450 (CYP)(3) Lipoxygenase (LOX)(4) Xanthine oxidase (XO)(5) Mitochondrial respiratory chain(6) Peroxisomal fatty acid beta-oxidation(7) Inflammation

(a) NADPH oxidase (NOX) (b) Myeloperoxidase (MPO)

Fenton(-like) reaction

Transition metal ion-catalyzed

(1) Fe(II)(2) Cu(I)(3) Co(I)(4) Cr(III)

(5) Cr(IV)(6) Cr(V)(7) V(III)

H2O2 OH∙ + OHminus

M(n) M(n + 1)

(a)

The first layer Nonenzymatic antioxidant defense(a) Radical scavengers

(1) Vit C

(2) Vit E(3) GSH(4) Ubiquinol-10(5) Urate(6) Bilirubin

(b) Metal-chelating proteins(1) Ferritin(2) Transferrin(3) Coeruloplasmin(4) Metallothionein

The second layerEnzymatic antioxidant defense(a) Superoxide dismutase (SOD)(b) Catalase (CAT)

(c) Glutathione system (1) Glutathione synthetase (GSS)(2) Glutathione peroxidase (GPx)(3) Glutathione reductase (GR)

(d) Thioredoxin system(1) Thioredoxin (TRX)(2) Thioredoxin reductase (TRR)(3) Peroxiredoxin (PRX)

(e) NADPH supplying system(1) Glucose-6-phosphate

dehydrogenase (G6PD)(2) Others

SODSuperoxide dismutase

CATCatalase

[Glutamate-glycine] + cysteine GSHGSS

GPxGR

2GSH + X-S-S-X GSSG + 2XSHGPx

Glutathione system

PRXTRR

TRX

PRXTRX

Thioredoxin system

H2O2

H2O2 2H2O + O2

2GSH + H2O2 GSSG + 2H2O2 + O2

2GSH + 2NADP+

TRX-(SH)2 + X-S-S-X 2TRX-S2 + 2XSH

2TRX-(SH)2 + 2NADP+TRX-S2 + 2NADPH

2PRX-(SH)22PRX-S2PRX-(SH)2 + XOOH PRX-S2 + 2XOH + H2O2

PRX-(SH)2 + H2O2 PRX-S2 + 2H2O + O2

GSSG2 + NADPH

O2∙

(b)

Figure 3 The source and clearance of ROS (a) Three major origins of ROS The sources of ROS can be roughly classified into threemajor categories exogenous endogenous and transition metal ion-catalyzed Exogenous sources of ROS can elicit radical chain reactionscontainproduce ROS or stimulate enzymatic ROS production Endogenous sources of ROS include the various enzymes that produceROS as by-products or as signaling mediators or as antimicrobial agents during inflammation Many of these enzymes can be activatedby stimulation by cytokines and growth factors such as NOX LOX XO and MPO Some CYPs are inducible and can be upregulated byenvironmental pollutants dietary phytocompounds or drugs The transition metal ion-catalyzed Fenton-reaction produces highly reactivehydroxyl radical from hydrogen peroxide (b) Layers of antioxidant defense There are several layers of antioxidant defense Basal levelantioxidant defenses provide buffering capacity upon ROS challenge Radical scavengers can directly quench ROS and metal-chelatingproteins can block ROS generation catalyzed by the Fenton or Fenton-like reactions Further antioxidant capacity is provided by inducibleantioxidant enzymes that aremostly under the regulation of Nrf2ARE signaling (see Figure 4) ROS can oxidize the thiol group of amino acidresidues leading to intermolecular or intramolecular disulfide bond formation These disulfide bonds that are caused by oxidation can leadto structuralfunctional alteration of proteins These disulfide bonds can be reduced by the glutathione system and the thioredoxin systemallowing resumption of protein function NADPH plays an indispensable role in the recycling of glutathione and thioredoxin and thereforemetabolic enzymes that are involved in NADPH generation also account for antioxidant defense

Endogenously ROS are generated during metabolic pro-cesses such as mitochondrial oxidative phosphorylationperoxisomal fatty acid beta-oxidation [16] catabolism ofxenobiotics by cytochrome P450monooxygenase (CYP) [17]purine by xanthine oxidase (XO) [18 19] and lipidfatty acidby cyclooxygenase (COX) [20 21] or lipoxygenase (LOX)[22 23] Inflammation is another important endogenoussource of ROS During inflammation ROS are generatedvia NADPH oxidase and myeloperoxidase which can protect

against microbe or virus invasion however they mightalso be injurious to adjacent cells [24ndash27] The positivefeedback loop between oxidative insult inflammation andcarcinogenesis is well recognized and appreciated as one ofthe hallmarks of cancer [28] In metal-catalyzed generationof ROS transition metal ions such as iron copper andchromium catalyze Fenton or Fenton-like reactions [29]that donate electrons and thus promote the production ofhydroxyl radicals from hydrogen peroxide [30]


Nrf2KE

AP1

KEA

P1 SHSH

HSHS

UbUb

E3

PKC MAPK PI3K and PERK

ROS

Antioxidant defense

Proteasome degradation

ARE

Nrf2

P

GR

GPx GSS

PRX

TRX

TRR

ARE

Nrf2

P

KEA

P1

KEA

P1SS

UbUb

Ub

Nucleus

Figure 4 Inducible antioxidant defense regulated by Nrf2Keap1 and the antioxidant response element Under normal physiologicalconditions the transcription factor Nrf2 is sequestered in the cytosol by Keap1 Keap1 recruits ubiquitin ligase E3 which then ubiquitinatesNrf2 and directs it to the proteasome degradation pathway The increased level of ROS promotes the dissociation of Nrf2 and Keap1 eithervia activation of kinases that phosphorylate Nrf2 or by oxidization of key cysteine residues that govern Keap1 activity The dissociated Nrf2is then translocated into the nucleus and binds to the antioxidant response element (ARE) ARE-regulated genes are then transcriptionallyactivated including a panel of antioxidant enzymes or proteins such as glutathione synthetase (GSS) glutathione reductase (GR) glutathioneperoxidase (GPx) thioredoxin (TRX) thioredoxin reductase (TRR) and peroxiredoxin (PRX) These inducible antioxidant enzymes thenprovide further ROS clearance capacity and antioxidant defense mechanism to exert a cytoprotective effect

22 Cellular Antioxidant DefenseMechanisms Control of ROSLevels and Repair of Oxidized DNA Bases Proper controlof ROS is critical for the maintenance of redox balanceand genome integrity Otherwise excessive levels of ROSwould overwrite the roles of ROS as signaling mediators andjeopardize the normal physiological processes inside the cellSeveral layers of antioxidant defense have been proposed aspreventive strategies against nucleic acid oxidation includingnonenzymatic removal of ROS by scavenger moleculeschelation of metals that catalyze ROS formation inducibleenzymatic removal of ROS and the DNA repair systemresponsible for oxidative DNA lesion Cellular moleculesthat can serve as radical scavengers form a first line ofdefense in the control of ROS levels (Figure 3(b)) Thesemolecules include metabolites such as vitamin C vitamin Eubiquinol-10 and urate as well as the tripeptide glutathione(GSH) and the thioredoxin (TRX) system [31] Meanwhilecellular metal-chelating proteins play key roles in controllingthe level of free metal ions and thus enhance or preventROS generation by metal-catalyzed Fenton of Fenton-likereactions These proteins include ferritin [32 33] transferrin[34] coeruloplasmin [35] and metallothionein [36]

ROS scavengers and metal-binding proteins do notprovide complete protection from ROS damage Thereforeanother layer of protection is provided in the form ofenzymatic removal of ROS Superoxide dismutase (SOD)is responsible for the transformation of superoxide anionsinto hydrogen peroxide which is subsequently transformed

into oxygen and water by catalase (CAT) or into water byglutathione peroxidase (GPx) [14] The removal of hydrogenperoxide by GPx consumes the reduced form of glutathione(GSH) and generates the oxidized form (GSSG) GSSG canlater be recycled by glutathione reductase (GR) and so replen-ish the GSH pool Notably metabolic enzymes responsiblefor NADPH production are critical factors in maintainingcellular redox balance because NADPH is an indispensablefactor responsible for the recycling of GSH and TRX byGR and thioredoxin reductase (TRR) Defects in NADPHsupplying enzymes such as glucose-6-phosphate dehydroge-nase (G6PD) deficiency in humans compromise recyclingof glutathione and thioredoxin and so weaken antioxidantcapacity and confer susceptibility toward oxidative insult[37] SOD CAT GPx GR TRR and NADPH producingenzymes together therefore increase the capacity of the cellto remove ROS through enzymatic means (Figure 3(b))

Cellular antioxidant defense is inducible and often up-regulated in response to oxidative stress or plant antioxidantsCells sense and respond to changes in redox status by nuclearfactor (erythroid-derived 2)-like 2 (Nrf2)kelch-like ECH-associated protein 1 (Keap1) complex [38 39] which whendissociated allows Nrf2 nuclear translation and binding tothe antioxidant response element (ARE) to transactivateantioxidant enzymes and thus further elevate antioxidantcapacity [40] (Figure 4) Under normal physiological condi-tions transcription factor Nrf2 is sequestered in the cytosolby Keap1 which recruits ubiquitin ligase E3 that ubiquitinates


PCNA


Genome instability genome heterogeneity

DNA ligase

ROS

Indirect single-strand breakage (SSB)

Seal of SSB

Correct basepoint mutation


Oxidized DNA base(eg 8-oxoG)

Base excision repair

Apurinicapyrimidinic site (AP site)

AP endonuclease

Family YDNA polymerase

PARP

DNA glycosylase D

NA

liga

seD

NA

pol

ymer

ase120573

Figure 5 Repair of oxidative DNA damage introduces genome heterogeneity and instability ROS causes oxidation of DNA bases whichthen elicit base excision repair machineries First the oxidized base is cleaved by glycosylase leaving an apurinicapyrimidinic site (AP site)Second the AP site is recognized by AP endonuclease that cleaves the phosphodiester bonds to remove the AP nucleotide and create thesingle-strand break (SSB) intermediate DNA polymerase then resynthesizes the missing part of the DNA and later DNA ligase seals the nickThe low fidelity of the translesion DNA polymerase increases the chance of mismatched base-pairing and thus leads to accumulation of pointmutations which creates genome heterogeneity

Nrf2 and directs it to the proteasome degradation pathwayIncreased levels of ROS promote the dissociation of Nrf2and Keap1 either by the oxidization of key cysteine residuesthat govern Keap1 activity or via the activation of kinases(eg protein kinase C (PKC) mitogen activated protein-kinase (MAPK) phosphatidylinositide 3-kinases (PI3K) [41]and protein kinase (PKR-) like endoplasmic reticulum kinase(PERK) that phosphorylate Nrf2 [42] The dissociated Nrf2then translocates into the nucleus and binds to the AREARE-regulated genes such as glutathione synthetase (GSS)GR GPx TRX TRR and peroxiredoxin (PRX) are thentranscriptionally activated [40] These inducible antioxidantenzymes provide further ROS clearance capacity and thusconfer cytoprotective effects ensuing Nrf2 activation inresponse to oxidative stress stimulation during inflammation[43] or in the presence of redox-modulating phytoagents[44 45] (Figure 4)

As nonenzymatic and enzymatic control of ROS levelscannot guarantee perfectcomplete protection against ROSdamage oxidative damage continues to occur and accu-mulate in cells To alleviate the negative effects elicited byoxidized biomolecules especially DNA cells have evolved

sophisticated specific enzymatic repair systems One suchsystem base excision repair (BER) repairs oxidized DNAbases (Figure 5) [5] During BER the oxidized base is firstrecognized and removed by DNA glycosylase leaving anapurinicapyrimidinic (AP) site which is later recognized andcleaved by AP endonuclease on the phosphodiester backboneand leaves a DNA single-strand break (SSB) intermediatewith a free 31015840-OH end Subsequently PPAR binds to theSSB and recruits DNA polymerase 120573 and DNA ligase whichsynthesizes the missing nucleic acid and seals the SSB torestore genome integrity Nonetheless PCNA a DNA clampprotein that associates with and coordinates the DNA repairpathway facilitates a DNA polymerase switch to the special-ized Family Y DNA polymerase and increases the potentialof generating point mutation Family Y DNA polymerasecarries out translesion DNA synthesis The low fidelity ofFamily Y DNA polymerase introduces a higher frequency ofmismatched base pairing than in regular DNA synthesis andtherefore increases the incidence of point mutations [46 47]In the last step DNA ligase seals the nick between the de novosynthesized nucleotide and adjacent nucleotides and com-pletes the base excision repair process The point mutations


introduced during translesion DNA repair lead to genomeheterogeneity between different cells and chronologicallywithin the same cell (Figure 5)

3 lsquolsquoDouble-Edged Swordrsquorsquo Role of Phytoagentsas Redox Regulators in Cancer Management

31 Phytoagents in Cancer Management Plants produce aremarkably diverse array of secondary metabolites (phyto-chemicals) many of which have evolved to combat microbialattack resist environmental stress or function as signal-ing molecules in interplant communication [48] Humancivilizations have used botanical preparations for treatingand preventing various human diseases throughout historyToday more than half of the anticancer drugs in clinicaluse are natural products or their derivatives and many areplant-derived phytochemicals [49 50] As cancer remains amajor threat to health worldwide there is global demandfor more affordable and effective therapeutic alternativesMoreover concerns about drug resistance and the side effectsof conventional therapeutic regimens currently used forcancer have renewed interest in phytochemicals derived fromdietary foods and traditional medicines [51ndash55]

The US National Cancer Institute (NCI) has identifiedmore than 1000 different phytoextracts or phytochemicalsthat possess cancer-preventive activity [15] and the compo-nents responsible for many of the cancer chemopreventiveeffects of various edible plants have been determined Forexample the cancer preventive effects of allium species(eg garlic) and cruciferous vegetables (eg broccoli andwatercress) are attributed to organosulfur compounds (egdiallyl trisulfide) and isothiocyanates (eg sulforaphane(SFN) and phenethyl isothiocyanate (PEITC)) respectively[56] Other naturally occurring phytochemicals found infruits vegetables spices herbs beverages and medicinalplants such as resveratrol [57] genistein [58] curcumin [59](ndash)-epigallocatechin gallate (EGCG) [60] and sesquiterpenelactones (eg deoxyelephantopin [61ndash63] artemisinin [64]and parthenolide) [65ndash67] have been reported to modulatemultiple signaling cascades that are known to deregulatecancer cell activities [68] Interestingly these representativephytocompounds (Figure 6) exert their anticancer cell effectsthroughmodulating ROS activity and oxidative stress in can-cer cells by antioxidant pro-oxidant or a dual as antioxidantand prooxidant under certain physiological or pathologicalconditions The important dual seemingly oppositional roleof phytoagents as redox regulators involved in nucleic acidoxidation in cancer cells is discussed below

32 Phytoagents as Antioxidants for Cancer Prevention Ingeneral phytoagents with antioxidant properties are poten-tially useful in cancer prevention because they can protecthealthy cells fromoxidativeDNAdamage through direct rad-ical scavenging upregulation of antioxidant defense systemmetal ion chelation andor additional anti-inflammatoryactivity The latest developments in the evaluation of theantioxidant effects and related defense systems or molecularmechanisms of phytocompounds with focus on oxidative

DNA damage as a biomarker in cancer prevention arediscussed below

321 Major Antioxidant Mechanisms of Action of Phytoagents

(a) Direct ROS Scavenging Phytoagents can attenuate ROSinsults on biomolecules through direct scavenging of ROSldquoScavengingrdquo refers to direct chemical modification of ROSand their stabilization by chemical reduction or electron-donation In this way the reduced form of a phytoagentmolecule is consumed to buffer injurious ROS that mightotherwise cause DNA damage Phytoagents might havedifferent scavenging capacity for different ROS and freeradical species For example vitamin E and the caroteneshave long polyunsaturated fatty acid chains while vitaminC flavonoids and polyphenols have ring structures Theyall share one structural commonality conjugated systemscharacterized by intermittent single bonds and double bondswhich together form aligned p orbitals where pi electronscanmove freelyThe conjugated system can therefore donateelectrons more easily and thus have high reducing capacityThis property gives these phytoagents ROS buffering capacitythat protects important biomolecules from ROS attack

(b) Attenuation of the Fenton(-Like) Reaction by Direct MetalIon Chelation Oxidative damage is one of the main forms oftoxicity conferred by transition metal ions In the Fenton(-like) reaction the reduced form of a transition metal ioncatalyzes the generation of the highly reactive hydroxyl freeradical from hydrogen peroxide Therefore the more freeform transition metal ions there are the more hydroxylfree radical formation occurs by the Fenton(-like) reactionand the more serious the oxidative damage to biomoleculesincluding DNA Will be Phytoagents can attenuate Fenton(-like) reaction by reducing the level of transition metal ionThrough direct chelation by phytocompounds containinga catechol or galloyl structure transition metal ions aresequestered from solution and therefore prevented fromparticipating the Fenton(-like) reaction [69 70] This isanother indirect way by which phytoagents exert antioxidanteffects(c) Induction of Antioxidant Response Element-ControlledGenes through Nrf2 ActivationDietary levels of phytochemi-cals have been suggested to trigger induction of low levels ofoxidative stress that may ldquoprimerdquo cellular antioxidant defensesystems to resist higher levels of oxidative insults thus offeringprotection against carcinogenic insult [60] These types ofphytochemicals might have little antioxidant effect in vitroin terms of ROS scavenging capacity nonetheless in somecases they activate themaster transcription factorNrf2whichgoverns the expression of a set of antioxidant-related genesTherefore through activation of Nrf2 and the subsequent up-regulation of endogenous antioxidant defense these phyto-chemicals confer antioxidant effects in an indirect way

Phytoagents from various structural categories havebeen shown to activate Nrf2 with varied potency [71]In general phytoagents with electrophilic groups that arethiol-reactive induce the most potent Nrf2 activation whencompared based on fold of induction of Nrf2-regulated


O

O

OHOH

HO

OH

O

OHOH

HO

OHOH

O

OHOH

HO

OHO

O OH

OHOH

OH

O

O

O

O O

H H

H

OO

O

O

O

O

O

O

O

HO

O

HO

O

OH

OHOH

H

N C S

O

O

OH

OOO

HO

OH

OHHO

NC

SSO

S

SS

SS

S

(b) Curcuminoids

(A) Phenolics

Quercetin

(a) Flavonoids

Catechin

Epigallocatechin gallate(EGCG)

(c) Stilbenoids

Resveratrol

Curcumin

Ascorbic acid (Vit C)

(B) Terpenes (isoprenoids)

(a) Carotenes

(b) Sesquiterpene lactones

Artemisinin Parthenolide

(C) Vitamins

Deoxyelephantopin

Tocopherol (Vit E)

Sulforaphane (SFN)

Phenethyl isothiocyanate (PEITC)

(a) Isothiocyanates

(D) Organosulfides

Diallyl trisulfide

(b) Sulfides

Diallyl sulfide

Diallyl disulfide

120573-carotene

Figure 6 Representative phytocompoundswith redox regulation capabilityThere are fourmajor types of phytocompounds that canmodulateintracellular redox status (A) phenolics (B) terpenes (C) vitamins and (D) organosulfides They show free radical scavenging Nrf2AREactivation andor facilitation of ROS production in cancer cells

NADPH quinone reductase [72] Some phytoagents withoutelectrophilic groups could also induce Nrf2 though to alesser extent These types of phytoagents might activate Nrf2indirectly through modulating signaling pathways whereasthiol-reactive electrophiles can directly modify the redox-sensitive cysteine residues in theNrf2Keap1 complex thereby

promoting the dissociation of the complex and the nucleartranslocation of Nrf2

(d) Attenuation of Inflammation through Inactivation NF-120581Bis the master transcription factor that governs the expressionof many inflammation-related genes Notably the activation


of NF-120581B is redox-sensitive High endogenous ROS levelstimulates NF-120581B activation which then leads to a pro-inflammatory response and further exacerbates the intracel-lular redox status [73ndash77] Such a feedback loop mediatedby redox-sensitive NF-120581B activation often leads to chronicinflammation one of the hallmarks of cancer Many phytoa-gents exhibiting an anti-inflammatory effect have been shownto efficiently suppress NF-120581B activation Suppression of NF-120581B can be achieved by either the aforementioned antioxidantactions or through direct chemical modification of NF-120581B redox-sensitive cysteine residues by phytoagents withelectrophilic groups such as C=O N=C=S or organosulfidegroups to compromise its ability to translocate to the nucleusand bind DNA

322 Antioxidant Effects and Defense Systems of Selected Phy-toagents Vitamins and phenolics (two well-known groupsof antioxidants) as well as electrophilic phytocompoundsare used below to exemplify the latest developments in theevaluation of the antioxidant effects and related defensesystems of phytocompounds with a focus on oxidative DNAdamage as a biomarker in cancer prevention

(a) Vitamins The ability of macronutrients and micronutri-ents present in fruits and vegetables to reduce the risk of can-cer is well known Among these compounds the antioxidantvitamins and their precursors have been extensively studied[15] Vitamin C (ascorbic acid) vitamin E and 120573-caroteneare often referred to as ldquoantioxidant vitaminsrdquo Vitamin Ccooperates with vitamin E to generate 120572-tocopherol from 120572-tocopherol radicals in membranes and lipoproteinsThroughworking along with other antioxidant enzymes these antiox-idants have been suggested to reduce oxidative damage inhumans [78] and thereby minimizing the risk of certainchronic diseases [79ndash81] However early epidemiologicalstudies and clinical trials investigating the efficacy of thesevitamins in affecting disease outcome concluded that therewas insufficient evidence to link supplementation of humanswith vitamin C vitamin E or 120573-carotene with a reductionin in vivo oxidative damage to lipids proteins or DNAbased on the measurement of oxidative biomarkers [82]More recent clinical trials also suggest no correlatable effectbetween individual vitamins and chemoprevention [83 84]Further anticancer properties reported for different vitaminshave been discrepant The history of the most well-knownantioxidant vitamin C in cancer treatment is controversialwhile vitamins A and E only showed dispensable effectsin tumor elimination [85] However the role of vitaminD in cancer treatment and prevention is promising [8687] Interestingly a large-scale randomized double-blindplacebo-controlled trial in male physicians showed thatcompared with placebo men taking a daily multivitaminhad a statistically significant reduction in the incidence oftotal cancer however there was no significant effect on somespecific cancer types such as prostate cancer and colorectalcancer It was therefore concluded that ldquodaily multivitaminsupplementation modestly but significantly reduced the riskof total cancer [88]rdquo

Recently in a large cohort studywith 356 healthy subjectsdietary intake of vitamins was demonstrated to be associatedwith reduced levels ofmarkers of DNAdamage and oxidation(M1dG and 8-oxoG) measured in peripheral white bloodcells Notably the associations were stronger in nonsmokersthan in smokers [89] It is important to keep in mindthat several environmental factors can affect the antioxidantcapacity of these vitamins Environmental factors such assmoking and metal intoxication that causes excessive ROSburden to the body should be avoided because antioxidantphytoagents can prevent de novo oxidation to nucleic acidbut are not able to rescue or reverse oxidized nucleic acidcaused by persistent oxidative insults from environmentalstimulation In another study the protective effects of vitaminC and a natural phenol resveratrol on ethanol-induced oxida-tive DNA damage in human peripheral lymphocytes wereinvestigated Resveratrol showed significant DNA protectionin a 24 h experiment while the protective effect of vitaminC was seen in only 1 h Both compounds were shown todirectly scavenge hydroxyl radicals produced during ethanolmetabolism In addition resveratrol inhibited dehydrogenasegene expression and activated the base excision repair (BER)system mechanisms whichmay underlie its substantial effecton DNA protection Vitamin C however showed no effecton the ethanol metabolic pathway or the BER system [90]The antioxidant properties of vitamins in comparison towhole fruits and vegetables as anticancer agents are also ofinterest The effectiveness of kiwifruit in decreasing oxidativeDNA damage was assessed using comet assay (single-cell gelelectrophoresis) tomeasure damage to lymphocytes collectedfrom a human trial in which subjects drank kiwifruit juiceIt was observed that a simple extract of kiwifruit was moreeffective than a solution of vitamin C in protecting DNAfrom damage in vitro [91] This study demonstrated that thesignificant antioxidant activity of kiwifruit ex vivo and in vitrois not attributable entirely to vitamin C contained in the fruitInstead other components like phenolics and vitamin E mayalso contribute to the antioxidant effect of kiwi fruit extract[92] These studies suggest an undetermined role of vitaminC present in fresh fruits although different vitamin C contentpresent in kiwifruit extractmight result in different protectiveeffects

(b) Phenolics Phenolic compounds are present in high con-centrations in many components of the so-called ldquoMediter-ranean dietrdquo including fruit and vegetables These com-pounds seem to scavenge ROS resulting in protection againstoxidative DNA This assumption was verified by testing theeffect of Mediterranean plant extracts (Crepis vesicaria LOriganumheracleoticum Scandix australis LAmaranthus spScolymus hispanicus L and Thymus piperella L) on oxidativeDNA damage induced in lymphocytes by H

2O2in relation to

their polyphenolic content using comet assay [93]This studyrevealed that the protection of DNA by phenols present inMediterranean plants is only partly due to ROS scavengingproperties Phenols can also attenuate Fenton(-like) reac-tions through metal ion chelation and induce endogenousantioxidant defense through Nrf2 activation ApparentlyROS scavenging only partially contributes to antioxidant


activity of Mediterranean diet-derived phenolics or otherphytochemicals Their protection against oxidative DNAmay involve other redox regulation such as upregulation ofantioxidant enzymes in cells and attenuation of Fenton(-like)reaction by metal ion chelation

In the carcinogenesis of hepatocellular carcinoma (HCC)oxidative stress is a major predisposing condition which isrelevant to the development and progression of the cancerIn search for a dietary chemopreventive approach for thelethal HCC pomegranate an ancient fruit has gained atten-tion owing to its significant antioxidant properties mainlycontributed by the anthocyanins and ellagic acid derivatives[94 95] Pomegranate emulsion a proprietary combinationof aqueous phase extract and pomegranate seed oil contain-ing several polyphenolic compounds mixed with octadeca-trienoic acids sterols steroids and 120574-tocopherol was foundto prevent hepatocarcinogenesis through induction of Nrf2-regulated phase II xenobiotic-metabolizing genes such asseveral GST isozymes that are involved in antagonizingoxidative stress [96] A similar Nrf2-mediated antioxidanteffect was also observed in HCC rats treated with blackcur-rant anthocyanins [97]

Flavonoids are naturally occurring diphenylpropanoidsthat appear in animal and human cells following consump-tion of vegetables fruits and beverages such as tea andwine Flavonoids can be classified into six major subgroupsflavonols (eg quercetin kaempferol) flavones (eg api-genin luteolin) flavanones (eg hesperidin naringenin)flavan-3-ols (eg catechin theaflavin and gallic esters ofcatechin and theaflavins) anthocyanidins (eg pelargonidincyanidin) and isoflavones (eg genistein daidzein) Epi-demiological studies suggest that dietary intake of flavonoidsmay reduce the risk of tumors of the breast colon lungprostate and pancreas However the generalizability of theseanticancer effects remains a subject of study [98]

(c) Electrophilic Phytochemicals Electrophilic phytochemi-cals such as phenethylisothiocyanate (PEITC) sulforaphane(SFN) turmeric curcumin and EGCG prevent oxidativemodification and mutation of genes through activation ofthe Nrf2Keap1 complex [45 99ndash101] These phytochemicalsmodulate Keap1-associated transcriptional regulation whichresults in up-regulation of ARE-bearing genes encodingphase II detoxifying enzymes and transporters that protectnormal cells from ROS reactive nitrogen species (RNS)or reactive metabolites of carcinogenic species [71] Suchresponses are thought to represent a form of cellular adapta-tion to chemicals and oxidative stress that maintains cellularredox homeostasis [15 99] Therefore the use of dietary phy-tochemicals to regulateNrf2-dependent antioxidant responseto counter oxidative DNA damage has emerged as a promis-ing strategy for cancer prevention

Hormonal factors especially 17szlig-estradiol (E2) play amajor role in the etiology of breast cancer where the cir-culating levels of E2 itself are an independent risk factorE2 can cause both oxidative DNA damage and attenuateDNA repair leading to oncogenic mutagenesis [102] In theliver the metabolism of E2 to its various phase I metabo-lites such as the carcinogenic 4-hydroxy estradiol (4E2)

primarily involves the cytochrome P450 enzymes CYP1A2and CYP3A4 [103] Dietary berries and their chemical con-stituents are known for their cancer preventive potentialwhich were recently shown to affect the enzymes involved incarcinogen metabolism in mouse liver [104] and significantlyreduced hepatic oxidative DNA damage indicated by thelevel of 8-oxoG and other polar adducts validated by P32-postlabeling experiments Compared to crude berry juicesellagic acid one of the bioactive components found in berriesshowed more elimination of oxidative DNA adducts inducedby redox cycling of 4E2 catalyzed by copper chloride in vitro[105]

33 Phytocompounds as Prooxidative Agents for Cancer Ther-apy Prooxidant phytoagents on the other hand are particu-larly effective in treating aggressive tumors with abnormallyradical-reactive cellular environments They act by tippingthe limit of oxidative stress that can be tolerated by tumorcells over a limit thus triggering apoptosis and cell death[106] Although pro-oxidant effects are observed after treat-ment with certain phytoagents generally phytoagents donot produce ROS directly Instead their prooxidant effectis highly dependent on the original redox status of thecell which determines sensitivity to cytotoxicity mediatedby phytoagents The basal redox levels of cancer cells aredifferent from those of normal cells Higher levels of free formmetal ions and higher levels of endogenous ROS productionin cancer cells sensitizes them to phytoagent-mediated proox-idant cytotoxicity [30 107 108] In this section we elaborateon how phytoagents act as prooxidants to selectively killcancer cells and their effects in cancer chemotherapy

331 Major Prooxidant Mechanisms of Action of Phytoagents

(a) Promotion of Fenton(-Like) Reactions byCatalyzing Redox-Cycling of Metal Ions Phytoagents with strong reducingcapacity can reduce not only ROS but also metal ionsUnder normal physiological conditions most metal ionsare complexed with proteins and few exist in free formHowever in the presence of abundant free form metal ionsphytoagents catalyze Fenton(-like) reactions that produceinjurious hydroxyl radicals [29 109] Notably cancer cellsdevelop abnormally high concentrations of metal ions dueto overexpression of the transferrin receptor [110 111] Whenexcessive concentrations of free form metal ions exist clas-sical antioxidant phytoagents catalyze the redox cycling ofmetal ions by reducing their oxidized form As a result aburst of hydroxyl free radical production ensues and thephytoagents become pro-oxidants

(b) Basal ROS Generation through Glutathione Depletion byElectrophiles Phytoagents with electrophilic groups can formcovalent bonds with cysteine resides of proteins Glutathionethe most abundant cysteine-containing peptide thus canbe rapidly depleted due to adduct formation with elec-trophilic phytoagents [112ndash115] Upon glutathione depletionthe buffering capacity of ROS is attenuated so that thebasal ROS production is revealed Therefore electrophilic


phytoagents exhibit pronounced pro-oxidant effect in cancercells with high ROS production and push cancer cells overthe tolerable limit of ROS In contrast the same dosageof phytoagents produces a negligible pro-oxidant effect innormal cells with low basal ROS production and boostsantioxidant response by Nrf2 activation [71 100 116ndash121]

332 Prooxidant Effects and Defense Systems of SelectedPhytoagents ROS and cellular oxidative stress have longbeen associated with cancer [122] Hypoxic condition thatis low ambient oxygen pressure is well described in cancercells particularly in the central area of the tumor noduleor mass [123] These cancer cells act more like anaerobicbacteria showing low levels of mitochondrial oxidative phos-phorylation and generally survive through the generation ofATP in an oxygen-independent manner [124] Many conven-tional anticancer drugs including vinblastine doxorubicincampthotecin cisplatin and inostamycin have been reportedto activate a caspase-3(-like) protease causing generation ofH2O2presumably through the activation of NADPH oxidase

that subsequently induces apoptosis in cancer cells [125]Intriguingly cancer cells are frequently deficient in crucialantioxidative enzymes such as catalase GPx and SOD andtherefore demonstrate a high vulnerability to ROS Oneantitumor strategy is to deliver excess oxidative stress intotumor cells or to target the disruption of the antioxidativedefense systems of tumor cellsThis strategy has been termedldquooxidation therapyrdquo in cancer treatment [126] Several studieshave reported that certain dietary anticancercancer preven-tive agents cause generation of ROS specifically in tumor cellsnot in normal cells [56 127 128]Through adaptation normalcells that are exposed to pro-oxidant chemopreventive agentswhich generate oxidative stress can acquire resistance totransformation via adjusting the normal redox tone of thesecells In contrast transformed cells which typically endurean oxidizing intracellular environment would ultimatelysuccumb due to an excess of ROS caused by the same agentROS and cellular redox tone are exploitable targets in cancerchemoprevention via the stimulation of cytoprotection innormal cells andor the induction of apoptosis in malignantcells [129] Dietary intake of such chemopreventive agentscould be a prefect strategy to achieve this purpose

(a) Sulfur-Containing Compounds Diallyl disulfide (DADS)and diallyltrisulfide (DATS) which are found in abun-dance in garlic are among the dietary factors studiedextensively for their anticancer action involving inductionof oxidative stress in the human body as reviewed else-where [130] The pro-oxidant and thiol-adducting activ-ities of these electrophilic organosulfur compounds areattributed to their reactive isothiocyanate (RndashN=C=S) phar-macophore Dietary isothiocyanates include sulforaphanephenethyl isothiocyanate (PEITC) benzyl-isothiocyanateand 6-methylsulfinylhexyl-isothiocyanate (Figure 6) Origi-nally copper-mediated oxidative DNA damage induced bythese isothiocyanates was considered to be carcinogenic [131]however later studies demonstrated that these phytochem-icals exhibit preferential cytostaticity in premalignant and

tumor cells via their pleiotropic pro-oxidant activities asreviewed elsewhere [106]

(b) Curcumin Curcumin (diferuloylmethane) from turmericlike isothiocyanates is a pleiotropic redox modulator that isinvolved in multiple cellular activities as a proantioxidantand metal chelator as recently reviewed [59] Curcuminwhich contains an electrophilic Michael acceptor as an activemoiety can also mediate strand scission of DNA in thepresence of Cu (II) [132]The compelling anticancer activitiesof curcumin have been widely demonstrated across differentcancer cell lines and animal systems as a function of above-mentioned reactive pharmacophores targeting various cellu-lar molecules Currently the cancer preventivetherapeuticpotential of curcumin as single or combinatorial agent isunder evaluation in various clinical trials including multiplemyeloma rectal cancer metastatic colon cancer advancedosteosarcoma and pancreatic cancer [59]

(c) Sesquiterpene Lactones The sesquiterpene lactones (SLs)have also gained considerable attention for their effective-ness in treating inflammation headaches infections andother human diseases SLs contain Michael acceptors thatact as electrophiles that can increase cellular ROS andmodulate specific redox sensitive targets in cancer cellsArtemisinin and parthenolide (Figure 6) are SL-deriveddrugs now being evaluated in cancer clinical trials [133ndash138] Artemisinin isolated from Artemisia annua (qinhaosweet wormwood) possesses an endoperoxide bridge in thereactive pharmacophore that can be activated and cleavedby endogenous ions leading to the generation of radicalspecies and ROS through the Fenton reaction which wasobserved to be a common mechanism underlying both theantimalarial and anticancer activities of the compound [139]Parthenolide identified from feverfew (Tanacetum parthe-nium) contains an electrophilic 120572-methylene-120574-lactone asthe active moiety underlying its anticancer activity related tothe Michael acceptor electrophile [66 67] Phytochemicalswith prooxidant properties such as the SLs with Michaelacceptor electrophiles have the potential to sensitize tumorsin cancer treatment For example concurrent delivery ofthe SL parthenolide and the clinical drug paclitaxel inmixed micelles greatly improved the therapeutic response ofresistant lung cancer cell lines to paclitaxel treatment [140] Ina mouse peritoneal dissemination model parthenolide alsoimproved the chemosensitivity of paclitaxel against gastriccancer through deregulation of theNF-120581B signalling pathway[141] Nevertheless parthenolide and dehydrocostus lactonecan also suppress cancer cell activity through downregulatingother molecular targets such as mitogen-activated proteinkinase (MAPK) and protein kinase C and induction of c-Jun-N-termial kinase (JNK) [142]

In our laboratory we identified a germacranolide SLdeoxyelephantopin (DET) from a medicinal plant Elephan-topus scaber (Asteraceas) which contains an 120572-methylene-120574-lactone an 120572120573-unsaturated lactone and a methacrylate esterside chain [62] DET could induce ROS in breast cancercells which became the upstream stimulus for the formationof centrosomal ubiquitinated protein aggregates and the


induction of protein carbonylation that might subsequentlyrestrict cancer cell motility [63] DET was also observed toactivate ER stress- and JNK pathway-mediated apoptosis inmammary carcinoma cells triggered by ROS [62] Howeverit is not yet clear whether DET caused oxidative DNAdamagethrough the involvement of transitionmetals Illustration thatthe anticancer activity of DET the same as artemisinin isthrough its role as a pro-oxidant suggests that pro-oxidantintervention using SLsmay constitute a promising anticancerstrategy

34 Cancer-Associated Transition Metals in Phytochemical-Mediated Redox Regulation Several essential transition met-als such as zinc iron copper cobalt and manganese areknown to regulate various metabolic and signaling path-ways For example iron is an essential element in oxygentransportation [143] while copper is an essential componentof several antioxidant enzymes [144] In cancer cells highmetal ion concentration is one factor that contributes to theobserved high base level of oxidative stress which raisesthe possibility of killing cancer cells by dosing with metalsupplements [145] However the prooxidant effect of metalions is also known to initiate carcinogenesis [30] whichraises concerns about applying metal supplementation as atherapeutic strategy against cancer However some studiesindicated that cancer cells are prone to proliferate in envi-ronments with high levels of copper and iron and thereforesuggested that these ions maybe be functionally involved incarcinogenesis [146 147] In a national cohort of the UnitedStates adults serum concentrations of iron and copper wereshown to correlate with mortality rate in cancer patients[148] Due to the significant role of these metal ions in cancerepidemiology their levels in different cancers were reviewedby Gupte and Mumper [145] In comparison to normalindividuals the Cu (Zn Se Fe) ratios are usually higher inpatients suffering from breast [149] cervical [150] ovarian[150] lung [151] prostate [152] bladder [153] and stomachcancer [154] and leukemia [155] Increased levels of copperhave also recently been correlated with poor survival inbreast cancer patients [156]Themajormetal ion contained inchromatin copper is closely associated with the DNA basesespecially guanine [157] As one of the redox active metalscopper can directly catalyze the formation of ROS via theFenton reaction and cause oxidative stress in the cells [158]The intracellular level of transition metal ions can determinewhether phytoantioxidants act as cytoprotective antioxidantsor cytotoxic prooxidants Figure 7 summarizes the currentunderstanding of the interplay between phytoagents andtransition metal ions and the antioxidantpro-oxidant roleswitch of phytoagents in response to the level of metal ionsThe level of transition metal ions determines whether aphytoagent ultimately functions as cytoprotective antioxidantor cytotoxic pro-oxidant Under normal level of transitionmetal ions phytoantioxidants serve as radical scavengersand Nrf2ARE activators that confer a cytoprotective effectthat can be applied in chemoprevention When the level ofintracellular transition metal ion is high such as in cancercells phytoagents recycle the metal ions and thus facilitate

ROS production through the Fenton or Fenton-like reactionsOtherwise metal ions catalyze the cleavage of phytoagentsand generate radical cleavage products that can cause ROSSuch a prooxidant effect further drives the redox-sensitivecancer cells to their antioxidant limit and leads to cytotoxicitythat can be applied as a chemotherapeutic strategy Onthe other hand metal-chelating phytoagents reduce metalion levels and thus block the ROS producing Fenton(-like)reaction and provide a cytoprotective effect

341 Ion Chelation by Phytoagents Increasing numbers ofstudies are evaluating the antioxidant properties of phyto-chemicals through assessment of their ability to chelate metalions that lead to attenuated reactivity of free radicals Waterextracts of pine needles inhibited oxidative DNA damageprobably due to their stronghydroxyl radical and intracellularROS scavenging activity and the chelating action of theiron (Fe2+) ion [159] Antioxidant activity was reported forlunasin a novel preventive peptide purified from Solanumnigrum L which is also found in soy barley and wheatThe peptide did not scavenge endogenous hydroxyl radicalsbut inhibited the Fenton reaction by chelating iron ionsthus protecting DNA from oxidative damage [160] Theantioxidant properties of phenolic compounds are clearhowever the contribution of metal ion chelation to theantioxidative effect of these compounds is not yet conclusiveOne study showed that the orthodihydroxy polyphenols bear-ing catechol or galloyl groups exhibit strong metal chelatingactivity [161] In the study by Andjelkovic and colleagues theability of the phenolic compounds which chelate iron wasranked based on iron binding constants in ascending orderProtocatechuic acid was the weakest chelator followed byhydroxytyrosol gallic acid and caffeic acid with chlorogenicacid as the strongest chelator [162] Iron chelation by phenoliccompounds phytochemicals in pine needle extracts or bythe peptide lunasin which subsequently inhibited DNAoxidation may deserve further exploration for their potentialin cancer prevention

The reactivity of metal ions can be attenuated indi-rectly through inhibition of their transportation Dihy-droartemisinin was reported to decrease iron uptake anddisturb iron homeostasis in cancer cells through downregulating cell-surface transferrin receptor-1 which may bea novel mechanism of dihydroartemisinin independent ofoxidative damage that has been previously mentioned asanticancer property of artemisinin [163] The disturbanceof iron homeostasis in cancer cells via irondepletion bynatural or synthetic iron chelators has recently been shownto inhibit tumor growth by therapeutically manipulating ironlevel [164] The effect of phytocompounds on deregulationof reactive ion metabolism in tumor cells is worth furtherexploration

It is interesting to note that a prokaryotic glutathioneanalog namely ergothioneine can protect cells from oxida-tive damage as measured by 4-HNE and partially rescue celldeath caused by irradiation [165] Another report showed thatergothioneine forms a chelation complex with copper andtherefore protects cells from copper-induced DNA damage[166]


Phenolics lunasin etc

Metal ion chelation

Block ROS production through fenton reaction

Cytoprotective effect

Chemopreventiveapplication

Prooxidant effectsFacilitating fenton reaction by recycling of metal ions

ROS production

Cytotoxic effect

Chemotherapeuticapplication

Medium level

High levelTransition metal ions

Normallevel

Cancer cellsPhytoagents

Antioxidant effectsScavenging ROS

activating Nrf2ARE and

ROS clearance



Vitamin C resveratrol quercetin caffeic acid and

Phytoagents


Phytoagents

so forth

so forth

so forth

Figure 7 Role switches under different conditionsmdashphytoagents function as both antioxidants and prooxidants in concert with transitionmetal ions The level of transition metal ions determines whether a phyto-antioxidant ultimately functions as cytoprotective antioxidant orcytotoxic prooxidant Under normal levels of transition metal ions phytoantioxidants serve as radical scavengers and Nrf2ARE activatorsthat confer a cytoprotective effect that can be applied in chemoprevention When the level of intracellular transition metal ion is high suchas in cancer cells phytoantioxidants recycle the metal ions and thus facilitate ROS production through the Fenton or Fenton-like reactionsOtherwisemetal ions catalyze the cleavage of phytoagents and generate radical cleavage products that can cause ROS Such a prooxidant effectfurther drives the redox-sensitive cancer cells to their antioxidant limit and leads to cytotoxicity that can be applied as a chemotherapeuticstrategy On the other hand metal-chelating phytoagents reduce metal ion levels and thus block the ROS producing Fenton(-like) reactionand provide a cytoprotective effect

342 Transition Metal-Mediated Prooxidant Properties ofPhytochemicals in Anticancer Activity Under certaincon-ditions antioxidants can act as prooxidants [167] Caffeicacid produces hydrogen peroxide which is activated bytransition metals to cause oxidative DNA damage in vitroand in cultured human cells in the presence of Mn(II)or Cu(II) [168] In another study using DNA fragmentsisolated from the human p53 gene quercetin increased8-oxoG levelsignificantly in the presence of copper ions(Cu2+) whereas 8-oxoG formation by kaempferol or luteolinwas insignificant [169] These early studies raised concernabout whether ingestion of these phytochemicals may leadto increased risk of cancer Lately rats treated with 712-dimethylbenz[a]anthracene (DMBA) have become a widelyusedmodel formammary carcinogenesis and in recent studydietary supplementation with copper alone or together withthe grape polyphenol resveratrol was found to promotecarcinogenesis through increased frequency of microsatelliteinstability [170] Later a similar result was observed in theDMBA-model treated with combined supplementation withzinc ions and resveratrol [171] However a different mecha-nism was reported for resveratrol action in another cancermodel with different stage of carcinogenesis Resveratroland its derivatives increase copper-mediated oxidative DNA

damage by their pro-oxidant properties coupled with higherapoptosis induction in human leukemia cell lines [172]

The well-known antioxidant vitamin C for example wasalso found to act as a pro-oxidant in vitro when mixed withtransition metal ions [173] In healthy humans Rehman andcolleagues observed an increased level of oxidative DNAdamage after 6-week supplementation of a mixture of ferroussulphate andvitamin C suggesting that this combinationacts as a pro-oxidant however a longer period of sup-plementation by 12 weeks did not show significant effect[174] Intriguingly catalytic therapy that involves hydroxylradical induction through a redox active mixture of vitaminCmedicinal herbal extracts and copper has been employedto improve the treatment of cancer patients [175 176] TheBhat group that established a model that involves humanperipheral lymphocytes and comet assay carried out a seriesof studies on plant-derived polyphenolic antioxidants andproved that the mechanism is not restricted to vitamin C[177ndash179] The most recent finding from the group is that thepolyphenolic compound gossypol from the cotton plant andits derivative apogossypolone also cause oxidative damageto DNA by mobilizing endogenous copper in lymphocytes[180] Although the reported mechanism was mainly theresult obtained from lymphocytes nevertheless it could


PAPA

PA

PAPARP

Protein denaturationProtein carboxylationSulfhydrate disulfide bond

TRX

GPx

PRX

GPx

PRXLipid peroxidation

MDA

Oxidative DNA damage8-oxoG

Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE

O2 + e∙minus + 2 2H2O2 2H2O2 + eminus

Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2

Figure 8 Summary of mechanisms of action of phytoagents in chemoprevention and chemotherapeutics through modulating oxidativestress In the presence of ferrous ions (or other transition metal ions) phytoagents recycle the metal ion and thus promote the Fentonreaction that generates the highly reactive hydroxyl radical from hydrogen peroxide Such prooxidant effects of phytoagents in the presenceof metal ion can overwrite their cytoprotective roles because the production of ROS may be faster than the induction of antioxidant defenseHydrogen peroxide imposes oxidative damage on biomolecules such as proteins lipids and DNA and leads to protein carbonylation lipidperoxidation and DNA base oxidation which can be prevented by phytoantioxidants Phytoantioxidants can activate Nrf2ARE signalingand thus transcriptionally upregulate a panel of antioxidant genes that can provide further antioxidant capacity Glutathione synthetase (GSS)can raise the level of glutathione (GSH) which can reduce oxidative damage by scavenging hydroxyl radicals which otherwise cause oxidativeDNA damage and increase the chance of point mutation and genome instability during the DNA repair process while glutathione reductase(GR) recycles the oxidized form of GSH and maintains the level of the reduced form of GSH Glutathione peroxidase (GPx) thioredoxin(TRX) and peroxiredoxin (PRX) can prevent oxidative insults on proteins and lipids

imply the anticancer property of polyphenols based onthe abundant copper detected in different types of tumors[145 153] The enhanced electron transfer between transi-tion metals and phytochemicals probably occurs in cancercells with higher levels of copper ions which may induceROS generation subsequently leading to DNA damage [178180]

However the mixture of a polyphenol and a transitionmetal was shown to promote tumor growth in mice withcarcinogen induction that mimics the process of cancerinitiation [170 171] These studies raise concerns about thepotential carcinogenic activities of phytoagents It is notclear whether the mixture of antioxidant phytochemical andtransition metal resembles the oxidative stress that couldpossibly initiate tumorigenesis in normal cells but that sucha prooxidant effect drives the redox-sensitive cancer cellsto their antioxidant limit and leads to cytotoxicity that hasbeen applied in catalytic therapyMore studies are required toclarify the interaction of phytoagents and redox active metalsas their oxidative potential may initiate tumors in a healthyindividual

4 Future Prospects

This review provides updated and integrative informationabout the regulation of nucleic acid oxidation by phytoagentsin cancer Animalmodels and human epidemiological studieshave revealed that phytochemicals prevent carcinogenesisthrough direct ROS scavenging or induction of cellularantioxidant defense systems that consist of detoxifyingenzymes defense machinery mediated by Nrf2-antioxidativestress and inhibiting inflammatory signaling pathways thattogether protect cells fromDNAdamage by ROS and reactivemetabolites of carcinogens [42 57 58] (Figure 8) Inves-tigation of oxidative modulation of proteins and lipids aswell as DNA by phytochemicals provides a comprehensivepicture of their functions as redox regulators in cancer Ingeneral antioxidant phytoagents are potentially useful incancer prevention because they can protect healthy cells fromoxidative DNA damage through radical scavenging antiox-idant defense system stimulation and metal ion chelationprooxidant phytoagents on the other hand are particu-larly effective in treating aggressive tumors with abnormally


radical-reactive cellular environments by exceeding the limitof oxidative stress that can be tolerated by tumor cells Cancercells in general have a higher basal redox level due to eitherdefects in antioxidant defense or increased production ofROS during oncogenic transformation [122 126] Thereforewhen challenged with similar quantities of ROS cancer cellsfail to bufferclear excessive ROS and cell death ensues Incontrast normal cells with lower redox levels are capableof bufferingclearing ROS by inducible antioxidant defenseregulated by Nrf2ARE signaling and are thus protected fromcell death Recently dietary levels of phytochemicals havebeen suggested to trigger induction of low levels of oxidativestress that may ldquoprimerdquo cellular antioxidant defense systemsto resist higher level of oxidative insults thus offering greaterprotection against carcinogenic insult [60]

However several studies have also hinted at a ldquodarkrdquoside of these cell-protective mechanisms For example thecytotoxicity of the anticancer drug platinum was attenuatedby base excision repair of ROS-induced formation of 8-oxoGindicating that repairing genotoxic damage could contributeto multidrug resistance of cancer cells [181] Restoration ofglutathione level by overexpression of 120574-glutamylcysteinesynthetase was found to prevent DNA damage and subse-quent apoptosis caused by genotoxic agents in a resistanthuman ovarian carcinoma cell line [182] Overexpression ofcatalase was found to cause drug resistance in breast cancercell lines in chemotherapy [183] These findings imply thatalteration of the expression of antioxidant enzymes could bea mechanism through which cancer-cell resistance to redox-based chemotherapeutic agents is promoted On the otherhand several phytochemicals have been indicated to upreg-ulate the Nrf2 pathway which stimulates the defense systemand leads to cancer prevention However overexpression ofNrf2 and its downstream genes was also observed in severalcancer cell lines and human tumors rendering cancer cellsat an advantage for survival and unlimited proliferation Inaddition increased Nrf2 activity was found in some resistantcancer cells in other words to overcome chemoresistance intumors the Nrf2 pathway has to be deregulated [184] There-fore sophisticated design is necessary and caution has to betaken when administrating and handling Nrf2-dependent (asdiscussed above) phytochemicals in cancer patients giventhat transformed cancer cells that are ldquooverprotectedrdquo byantioxidants could possibly develop drug resistance

Nrf2 is one of the key players in phytoagent-mediatedantioxidant defensewhose activation confers a chemopreven-tive effect However recent studies indicate that Nrf2 itselfalso plays a double-bladed-sword role in cancer manage-ment [185] On one hand Nrf2 orchestrates gene expressionthat protects cells from oxidative damage and detoxifiesxenobiotics on the other hand the same effects conferchemoresistance to cancer cells It is important to discernwhen and how tomanipulate Nrf2 and so we canmake use ofits advantages while minimizing potential disadvantagesThemajor negative sides of Nrf2 activation include promotingbioactivation of xenobiotics whose glucuronide conjugationform is genotoxic and forms adducts with DNA [186ndash188]neutralizing the chemotherapeutic effects in which oxidativestress plays a significant role in mediating cytotoxicity to

cancer cells and facilitating drug excretion from cell throughincreasing the expression levels ofmultidrug resistant pumpsThereby to minimize potential disadvantages the use ofphytoagents as Nrf2 activators for chemoprevention shouldcarefully avoid coadministration of drugs that are bioacti-vated by Nrf2-regulated phase II enzyme processing Onthe other hand for pro-oxidant cancer chemotherapy Nrf2activation is deemed as a side-effect and should be suppressedby coadministration of Nrf2 inhibitor [185] Still more futurestudies are required to confirm these points and thus providea more accurate prediction and therefore application ofphytoagents in cancer management

For phytochemicals that function as both antioxidantsand prooxidants further characterization of the factors thatdetermine the transition from antioxidative to prooxidativeeffects in the biosystem is essential One contributing factoris the presence of transition metals In addition the doses ofphytochemicals used in each treatment at different timesmaybe crucial In this regard we propose some considerationson context-dependent dual function of phytoagents thatmayhelp to understand and to predict the chemotherapeutic roleof phytoagents By comparing normal and cancer-bearingindividuals we know that the oxidative DNAmarker 8-oxoGcorrelates well with basal redox level [8 189] Cancer cellswith higher basal redox level demonstrated elevated levels of8-oxoG whereas normal cells had lower levels of basal redoxlevel and 8-oxoG The overexpression of transferrin receptorin cancer cells increased intracellular level of ferrous ionsand presumably increased the rate of the Fenton reactionIt can be assumed that high levels of ferrous ions in cancercells switch the functions of phyto-antioxidants to those ofpro-oxidants resulting in further elevation of ROS level incancer cells but not in normal cells and the selective killing ofcancer cells More studies are required to determine the con-centration threshold of metal ions that switche phytoagentsto their prooxidant roles so that potential chemotherapeuticapplications can be better characterized In summary twomain points form the base of the concept of the context-dependent dual role of phytoagents One is the level ofintracellular level of transition metal ions and the other isthe basal redox level The higher the two the more likelythe agent to produce a pro-oxidant effect whereas the lowerthe two the more likely the agent to produce an antioxidanteffect

Continued rigorous research to identifymolecular targetsand conduct human studies with bioactive phytochemicalsare important to provide potential alternatives or novelapproaches for plant-based cancer prevention or therapy It islikely that the anticancer properties of phytochemicals resultfrommodulation of a number of molecular mechanisms thatregulate different stages of carcinogenesis In this regardincreased antioxidant strength may be important prior todysregulation of signaling pathways during tumorigenesiswhereas prooxidant cytotoxicity may be critical in eliminat-ing transformed tumor cells that exhibit dysregulated redoxbalance and metal ion absorption In conclusion carefuldose-response and stage-dependent studies that compareenhancement of antioxidant capacity and induction of oxida-tive stress by phytochemicals are essential to clarify when


and to what extent these phytoagents can be used in cancerprevention or therapy

Authorsrsquo Contribution

Wai-Leng Lee and Jing-Ying Huang contributed equally tothis paper as the co-first authors

References

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[2] H Yin L Xu and N A Porter ldquoFree radical lipid peroxidationmechanisms and analysisrdquoChemical Reviews vol 111 no 10 pp5944ndash5972 2011

[3] S Grimm A Hohn and T Grune ldquoOxidative protein damageand the proteasomerdquoAminoAcids vol 42 no 1 pp 23ndash38 2012

[4] M Dizdaroglu P Jaruga M Birincioglu and H RodriguezldquoFree radical-induced damage to DNA mechanisms and mea-surementrdquo Free Radical Biology andMedicine vol 32 no 11 pp1102ndash1115 2002

[5] S Maynard S H Schurman C Harboe N C de Souza-Pintoand V A Bohr ldquoBase excision repair of oxidative DNA damageand association with cancer and agingrdquo Carcinogenesis vol 30no 1 pp 2ndash10 2009

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[7] S Jones W-D Chen G Parmigiani et al ldquoComparative lesionsequencing provides insights into tumor evolutionrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 11 pp 4283ndash4288 2008

[8] A Valavanidis T Vlachogianni and C Fiotakis ldquo8-hydroxy-21015840-deoxyguanosine (8-OHdG) a critical biomarker of oxidativestress and carcinogenesisrdquo Journal of Environmental Science andHealth Part C vol 27 no 2 pp 120ndash139 2009

[9] S Lagadu M Lechevrel F Sichel et al ldquo8-oxo-78-dihydro-21015840-deoxyguanosine as a biomarker of oxidative damage inoesophageal cancer patients lack of association with antioxi-dant vitamins and polymorphism of hOGG1 and GSTrdquo Journalof Experimental and Clinical Cancer Research vol 29 no 157pp 1756ndash9966 2010

[10] H Bartsch and J Nair ldquoOxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesisrdquoCancer Detection and Prevention vol 28 no 6 pp 385ndash3912004

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[12] S Kaur P Greaves D N Cooke et al ldquoBreast cancer preventionby green tea catechins and black tea theaflavins in the C3(1)SV40 Tt antigen transgenic mouse model is accompanied byincreased apoptosis and a decrease in oxidative DNA adductsrdquoJournal of Agricultural and Food Chemistry vol 55 no 9 pp3378ndash3385 2007

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2O2NF-120581B signal-

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against the oxidative DNA damage The role of the radical oxy-gen species and the polyphenol contentrdquo Journal of Physiologyand Pharmacology vol 56 supplement 1 pp 183ndash197 2005

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[101] Y-J Surh J K Kundu and H-K Na ldquoNrf2 as a master redoxswitch in turning on the cellular signaling involved in theinduction of cytoprotective genes by some chemopreventivephytochemicalsrdquo Planta Medica vol 74 no 13 pp 1526ndash15392008

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[107] J-C Yang M-C Lu C-L Lee et al ldquoSelective targeting ofbreast cancer cells through ROS-mediated mechanisms poten-tiates the lethality of paclitaxel by a novel diterpene gelomulideKrdquo Free Radical Biology andMedicine vol 51 no 3 pp 641ndash6572011

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[111] T R Daniels E Bernabeu J A Rodrıguez et al ldquoThe trans-ferrin receptor and the targeted delivery of therapeutic agentsagainst cancerrdquo Biochimica et Biophysica Acta vol 1820 no 3pp 291ndash317 2012

[112] B R You S Z Kim S H Kim and W H Park ldquoGallicacid-induced lung cancer cell death is accompanied by ROSincrease and glutathione depletionrdquo Molecular and CellularBiochemistry vol 357 no 1-2 pp 295ndash303 2011

[113] G Chen Z Chen Y Hu and P Huang ldquoInhibition ofmitochondrial respiration and rapid depletion ofmitochondrialglutathione by 120573-phenethyl isothiocyanate mechanisms foranti-leukemia activityrdquo Antioxidants and Redox Signaling vol15 no 12 pp 2911ndash2921 2011

[114] C Locatelli P C Leal R A Yunes R J Nunes and T BCreczynski-Pasa ldquoGallic acid ester derivatives induce apoptosisand cell adhesion inhibition in melanoma cells the relationshipbetween free radical generation glutathione depletion and celldeathrdquo Chemico-Biological Interactions vol 181 no 2 pp 175ndash184 2009

[115] K Piwocka E Jaruga J Skierski I Gradzka and E SikoraldquoEffect of glutathione depletion on caspase-3 independentapoptosis pathway induced by curcumin in Jurkat cellsrdquo FreeRadical Biology and Medicine vol 31 no 5 pp 670ndash678 2001

[116] M K Pandey S Kumar R K Thimmulappa V S Parmar SBiswal and A C Watterson ldquoDesign synthesis and evaluationof novel PEGylated curcumin analogs as potent Nrf2 activatorsin human bronchial epithelial cellsrdquo European Journal of Phar-maceutical Sciences vol 43 no 1-2 pp 16ndash24 2011

[117] C Yang X Zhang H Fan and Y Liu ldquoCurcumin upregulatestranscription factor Nrf2 HO-1 expression and protects ratbrains against focal ischemiardquo Brain Research vol 1282 pp 133ndash141 2009

[118] E S Kang G H Kim H J Kim et al ldquoNrf2 regulatescurcumin-induced aldose reductase expression indirectly vianuclear factor-120581Brdquo Pharmacological Research vol 58 no 1 pp15ndash21 2008

[119] D-X Hou Y Korenori S Tanigawa et al ldquoDynamics of Nrf2and Keap1 in ARE-mediated NQO1 expression by wasabi 6-(methylsulfinyl)hexyl isothiocyanaterdquo Journal of Agriculturaland Food Chemistry vol 59 no 22 pp 11975ndash11982 2011

[120] A E Wagner C Boesch-Saadatmandi J Dose G Schultheissand G Rimbach ldquoAnti-inflammatory potential of allyl-isothiocyanatemdashrole of Nrf2 NF-120581B and microRNA-155rdquoJournal of Cellular and Molecular Medicine vol 16 no 4 pp836ndash843 2012

[121] I M Ernst A E Wagner C Schuemann et al ldquoAllyl-butyl- and phenylethyl-isothiocyanate activate Nrf2 in culturedfibroblastsrdquo Pharmacological Research vol 63 no 3 pp 233ndash240 2011

[122] P T Schumacker ldquoReactive oxygen species in cancer cells liveby the sword die by the swordrdquo Cancer Cell vol 10 no 3 pp175ndash176 2006


[123] OWarburg ldquoOn the origin of cancer cellsrdquo Science vol 123 no3191 pp 309ndash314 1956

[124] Y Yoshii T Furukawa H Yoshii et al ldquoCytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxiathe possible function in tumor acetyl-CoAacetatemetabolismrdquoCancer Science vol 100 no 5 pp 821ndash827 2009

[125] S Simizu M Takada K Umezawa and M Imoto ldquoRequire-ment of caspase-3(-like) protease-mediated hydrogen peroxideproduction for apoptosis induced by various anticancer drugsrdquoJournal of Biological Chemistry vol 273 no 41 pp 26900ndash26907 1998

[126] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009

[127] L Raj T Ide A U Gurkar et al ldquoSelective killing of cancercells by a small molecule targeting the stress response to ROSrdquoNature vol 475 no 7355 pp 231ndash234 2011

[128] D Trachootham Y Zhou H Zhang et al ldquoSelective killingof oncogenically transformed cells through a ROS-mediatedmechanism by 120573-phenylethyl isothiocyanaterdquo Cancer Cell vol10 no 3 pp 241ndash252 2006

[129] N Hail Jr M Cortes E N Drake and J E Spallholz ldquoCancerchemoprevention a radical perspectiverdquo Free Radical Biologyand Medicine vol 45 no 2 pp 97ndash110 2008

[130] A A Powolny and S V Singh ldquoMultitargeted preventionand therapy of cancer by diallyl trisulfide and related Alliumvegetable-derived organosulfur compoundsrdquo Cancer Lettersvol 269 no 2 pp 305ndash314 2008

[131] M Murata N Yamashita S Inoue and S Kawanishi ldquoMech-anism of oxidative DNA damage induced by carcinogenic allylisothiocyanaterdquo Free Radical Biology and Medicine vol 28 no5 pp 797ndash805 2000

[132] H Ahsan and S M Hadi ldquoStrand scission in DNA induced bycurcumin in the presence of Cu(II)rdquoCancer Letters vol 124 no1 pp 23ndash30 1998

[133] A Ghantous H Gali-Muhtasib H Vuorela N A Saliba andN Darwiche ldquoWhat made sesquiterpene lactones reach cancerclinical trialsrdquoDrugDiscovery Today vol 15 no 15-16 pp 668ndash678 2010

[134] N P Singh and K B Verma ldquoCase report of a laryngealsquamous cell carcinoma treated with artesunaterdquo Archive ofOncology vol 10 no 4 pp 279ndash280 2002

[135] E A Curry III D J Murry C Yoder et al ldquoPhase I dose esca-lation trial of feverfew with standardized doses of parthenolidein patients with cancerrdquo Investigational New Drugs vol 22 no3 pp 299ndash305 2004

[136] M L As ldquoCompleted phase 2 clinical trials for parthenolide intreating allergic contact dermatitisrdquo 2006 httpclinicaltrialsgovct2showNCT00133341term=Parthenolideamprank=1

[137] N P Singh and V K Panwar ldquoCase report of a pituitarymacroadenoma treated with artemetherrdquo Integrative CancerTherapies vol 5 no 4 pp 391ndash394 2006

[138] Z-Y Zhang S-Q Yu L-Y Miao et al ldquoArtesunate combinedwith vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer a randomized controlled trialrdquo Zhong XiYi Jie He Xue Bao vol 6 no 2 pp 134ndash138 2008

[139] T Efferth ldquoWillmar Schwabe Award 2006 antiplasmodial andantitumor activity of artemisininmdashfrom bench to bedsiderdquoPlanta Medica vol 73 no 4 pp 299ndash309 2007

[140] K K Gill A Kaddoumi and S Nazzal ldquoMixed micelles ofPEG2000-DSPE and vitamin-E TPGS for concurrent delivery

of paclitaxel and parthenolide enhanced chemosenstizationand antitumor efficacy against non-small cell lung cancer(NSCLC) cell linesrdquo European Journal of Pharmaceutical Sci-ences vol 46 no 1-2 pp 64ndash71 2012

[141] I Sohma Y Fujiwara Y Sugita et al ldquoParthenolide an NF-120581B inhibitor suppresses tumor growth and enhances responseto chemotherapy in gastric cancerrdquo Cancer Genomics andProteomics vol 8 no 1 pp 39ndash47 2011

[142] M R Kreuger S Grootjans M W Biavatti P Vandenabeeleand K Drsquoherde ldquoSesquiterpene lactones as drugs with multipletargets in cancer treatment focus on parthenoliderdquoAnti-CancerDrugs vol 23 no 9 pp 883ndash896 2012

[143] P Ponka C Beaumont and D R Richardson ldquoFunction andregulation of transferrin and ferritinrdquo Seminars in Hematologyvol 35 no 1 pp 35ndash54 1998

[144] E D Harris ldquoRegulation of antioxidant enzymesrdquo The FASEBJournal vol 6 no 9 pp 2675ndash2683 1992

[145] A Gupte and R J Mumper ldquoElevated copper and oxidativestress in cancer cells as a target for cancer treatmentrdquo CancerTreatment Reviews vol 35 no 1 pp 32ndash46 2009

[146] R J Coates N S Weiss J R Daling R L Rettmer and GR Warnick ldquoCancer risk in relation to serum copper levelsrdquoCancer Research vol 49 no 15 pp 4353ndash4356 1989

[147] J C Kwok and D R Richardson ldquoThe iron metabolism ofneoplastic cells alterations that facilitate proliferationrdquoCriticalReviews in OncologyHematology vol 42 no 1 pp 65ndash78 2002

[148] T Wu C T Sempos J L Freudenheim P Muti and E SmitldquoSerum iron copper and zinc concentrations and risk of cancermortality in US adultsrdquo Annals of Epidemiology vol 14 no 3pp 195ndash201 2004

[149] H W Kuo S F Chen C C Wu D R Chen and J H LeeldquoSerum and tissue trace elements in patients with breast cancerin Taiwanrdquo Biological Trace Element Research vol 89 no 1 pp1ndash11 2002

[150] A Chan F Wong and M Arumanayagam ldquoSerum ultrafil-trable copper total copper and caeruloplasmin concentrationsin gynaecological carcinomasrdquo Annals of Clinical Biochemistryvol 30 no 6 pp 545ndash549 1993

[151] M Diez M Arroyo F J Cerdan M Munoz M A Martinand J L Balibrea ldquoSerum and tissue trace metal levels in lungcancerrdquo Oncology vol 46 no 4 pp 230ndash234 1989

[152] F K Habib T C Dembinski and S R Stitch ldquoThe zinc andcopper content of blood leucocytes and plasma from patientswith benign andmalignant prostatesrdquoClinica ChimicaActa vol104 no 3 pp 329ndash335 1980

[153] H Mazdak F Yazdekhasti A Movahedian N Mirkheshti andM Shafieian ldquoThe comparative study of serum iron copperand zinc levels between bladder cancer patients and a controlgrouprdquo International Urology and Nephrology vol 42 no 1 pp89ndash93 2010

[154] A Scanni L Licciardello M Trovato M Tomirotti and MBiraghi ldquoSerum copper and ceruloplasmin levels in patientswith neoplasias localized in the stomach large intestine orlungrdquo Tumori vol 63 no 2 pp 175ndash180 1977

[155] X L Zuo J M Chen X Zhou X Z Li and G Y Mei ldquoLevelsof selenium zinc copper and antioxidant enzyme activity inpatients with leukemiardquo Biological Trace Element Research vol114 no 1ndash3 pp 41ndash54 2006

[156] M P SilvaD F SoaveA Ribeiro-Silva andME Poletti ldquoTraceelements as tumor biomarkers and prognostic factors in breastcancer a study through energy dispersive x-ray fluorescencerdquoBMC Research Notes vol 5 article 194 2012


[157] S E Bryan D L Vizard D A Beary R A Labiche and KJ Hardy ldquoPartitioning of zinc and copper within subnuclearnucleoprotein particlesrdquo Nucleic Acids Research vol 9 no 21pp 5811ndash5824 1981

[158] J Prousek ldquoFenton chemistry in biology and medicinerdquo Pureand Applied Chemistry vol 79 no 12 pp 2325ndash2338 2007

[159] J B Jeong E W Seo and H J Jeong ldquoEffect of extractsfrom pine needle against oxidative DNA damage and apoptosisinduced by hydroxyl radical via antioxidant activityrdquo Food andChemical Toxicology vol 47 no 8 pp 2135ndash2141 2009

[160] J B Jeong B O De Lumen and H J Jeong ldquoLunasin peptidepurified from Solanum nigrum L protects DNA from oxidativedamage by suppressing the generation of hydroxyl radical viablocking fenton reactionrdquo Cancer Letters vol 293 no 1 pp 58ndash64 2010

[161] S Khokhar and R K O Apenten ldquoIron binding characteristicsof phenolic compounds some tentative structure-activity rela-tionsrdquo Food Chemistry vol 81 no 1 pp 133ndash140 2003

[162] M Andjelkovic J V Camp B D Meulenaer et al ldquoIron-chelation properties of phenolic acids bearing catechol andgalloyl groupsrdquo Food Chemistry vol 98 no 1 pp 23ndash31 2006

[163] Q Ba N Zhou J Duan et al ldquoDihydroartemisinin exerts itsanticancer activity through depleting cellular iron via transfer-rin receptor-1rdquo PLoS One vol 7 no 8 Article ID e42703 2012

[164] A M Merlot D S Kalinowski and D R Richardson ldquoNovelchelators for cancer treatment where are we nowrdquo AntioxidRedox Signal vol 18 no 8 pp 973ndash1006 2013

[165] N G Markova N Karaman-Jurukovska K K Dong NDamaghi K A Smiles and D B Yarosh ldquoSkin cells and tissueare capable of using l-ergothioneine as an integral componentof their antioxidant defense systemrdquo Free Radical Biology andMedicine vol 46 no 8 pp 1168ndash1176 2009

[166] B-Z Zhu L Mao R-M Fan et al ldquoErgothioneine preventscopper-induced oxidative damage toDNAand protein by form-ing a redox-inactive ergothioneine-copper complexrdquo ChemicalResearch in Toxicology vol 24 no 1 pp 30ndash34 2011

[167] B Halliwell ldquoAntioxidant defencemechanisms from the begin-ning to the end (of the beginning)rdquo Free Radical Research vol31 no 4 pp 261ndash272 1999

[168] S Inoue K Ito K Yamamoto and S Kawanishi ldquoCaffeic acidcauses metal-dependent damage to cellular and isolated DNAthrough H

2O2formationrdquo Carcinogenesis vol 13 no 9 pp

1497ndash1502 1992[169] N Yamashita H Tanemura and S Kawanishi ldquoMechanism of

oxidative DNA damage induced by quercetin in the presence ofCu(II)rdquoMutation Research vol 425 no 1 pp 107ndash115 1999

[170] B Bobrowska D Skrajnowska and A Tokarz ldquoEffect of Cusupplementation on genomic instability in chemically-inducedmammary carcinogenesis in the ratrdquo Journal of BiomedicalScience vol 18 article 95 2011

[171] B Bobrowska-Korczak D Skrajnowska and A Tokarz ldquoTheeffect of dietary zincmdashand polyphenols intake on DMBA-inducedmammary tumorigenesis in ratsrdquo Journal of BiomedicalScience vol 19 article 43 2012

[172] L-F Zheng Q-Y Wei Y-J Cai et al ldquoDNA damage inducedby resveratrol and its synthetic analogues in the presence of Cu(II) ions mechanism and structure-activity relationshiprdquo FreeRadical Biology andMedicine vol 41 no 12 pp 1807ndash1816 2006

[173] B Halliwell ldquoVitamin C antioxidant or pro-oxidant in vivordquoFree Radical Research vol 25 no 5 pp 439ndash454 1996

[174] A Rehman C S Collis M Yang et al ldquoThe effects of iron andvitamin C co-supplementation on oxidative damage to DNAin healthy volunteersrdquo Biochemical and Biophysical ResearchCommunications vol 246 no 1 pp 293ndash298 1998

[175] N R Torshina J Z Zhang and D E Heck ldquoCatalytic therapyof cancer with porphyrins and ascorbaterdquo Cancer Letters vol252 no 2 pp 216ndash224 2007

[176] N R Torshina J Z Zhang and D E Heck ldquoCatalytic therapyof cancer with ascorbate and extracts of medicinal herbsrdquoEvidence-Based Complementary and Alternative Medicine vol7 no 2 pp 203ndash212 2010

[177] A S Azmi S H Bhat S Hanif and S M Hadi ldquoPlantpolyphenols mobilize endogenous copper in human peripherallymphocytes leading to oxidative DNA breakage a putativemechanism for anticancer propertiesrdquo The FEBS Letters vol580 no 2 pp 533ndash538 2006

[178] S M Hadi M F Ullah U Shamim S H Bhatt and A S AzmildquoCatalytic therapy of cancer by ascorbic acid involves redoxcycling of exogenousendogenous copper ions and generationof reactive oxygen speciesrdquo Chemotherapy vol 56 no 4 pp280ndash284 2010

[179] H Y Khan H Zubair M F Ullah A Ahmad and S MHadi ldquoOral administration of copper to rats leads to increasedlymphocyte cellular DNA degradation by dietary polyphenolsImplications for a cancer preventive mechanismrdquo BioMetalsvol 24 no 6 pp 1169ndash1178 2011

[180] H Zubair H Y Khan M F Ullah A Ahmad D Wu andS M Hadi ldquoApogossypolone derivative of gossypol mobilizesendogenous copper in human peripheral lymphocytes leadingto oxidative DNA breakagerdquo European Journal of Pharmaceuti-cal Sciences vol 47 no 1 pp 280ndash286 2012

[181] T J Preston J T Henderson G P McCallum and P G WellsldquoBase excision repair of reactive oxygen species-initiated 78-dihydro-8-oxo-21015840-deoxyguanosine inhibits the cytotoxicity ofplatinum anticancer drugsrdquoMolecular CancerTherapeutics vol8 no 7 pp 2015ndash2026 2009

[182] G C Das A Bacsi M Shrivastav T K Hazra andI Boldogh ldquoEnhanced gamma-glutamylcysteine synthetaseactivity decreases drug-induced oxidative stress levels andcytotoxicityrdquo Molecular Carcinogenesis vol 45 no 9 pp 635ndash647 2006

[183] C Glorieux N Dejeans B Sid R Beck P B Calderon andJ Verrax ldquoCatalase overexpression in mammary cancer cellsleads to a less aggressive phenotype and an altered response tochemotherapyrdquo Biochemical Pharmacology vol 82 no 10 pp1384ndash1390 2011

[184] A Lau N F Villeneuve Z Sun P K Wong and D D ZhangldquoDual roles ofNrf2 in cancerrdquoPharmacological Research vol 58no 5-6 pp 262ndash270 2008

[185] M B Sporn andK T Liby ldquoNRF2 and cancer the good the badand the importance of contextrdquo Nature Reviews Cancer vol 12no 8 pp 564ndash571 2012

[186] R Ghaoui B C Sallustio P C Burcham and F RFontaine ldquoUDP-glucuronosyltransferase-dependent bioactiva-tion of clofibric acid to aDNA-damaging intermediate inmousehepatocytesrdquoChemico-Biological Interactions vol 145 no 2 pp201ndash211 2003

[187] B C Sallustio ldquoGlucuronidation-dependent toxicity and bioac-tivationrdquo in Advances in Molecular Toxicology J C FishbeinEd vol 2 pp 57ndash86 Elsevier Cambridge Mass USA 2008

[188] B C Sallustio L A Harkin M C Mann S J Krivickas andP C Burcham ldquoGenotoxicity of acyl glucuronide metabolites


formed from clofibric acid and gemfibrozil a novel role forphase-II-mediated bioactivation in the hepatocarcinogenicityof the parent aglyconesrdquoToxicology and Applied Pharmacologyvol 147 no 2 pp 459ndash464 1997

[189] V Peddireddy B Siva Prasad S D Gundimeda P R Pena-galuru andH PMundluru ldquoAssessment of 8-oxo-7 8-dihydro-21015840-deoxyguanosine and malondialdehyde levels as oxidativestress markers and antioxidant status in non-small cell lungcancerrdquo Biomarkers vol 17 no 3 pp 261ndash268 2012

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


Accumulation of genetic heterogeneity

Cancer evolutionTumor initiationTumor promotionTumor invasionTumor metastasis

PARP-mediated cell death

Genome instabilitygenome rearrangement

Base pair mismatchpoint mutation

Base excision repair (BER)

Indirect single-strand break (SSB)


ROS

Nucleic acid oxidation(eg 8-oxoG)

SSB-activatedPARP activity

Translesion DNA repair

Carc

inog

enes

is

PARAIF


DNA ligase III

PCNA

DNA polymerase 120573

Figure 1 Genetic heterogeneity following nucleic acid oxidation is a major driving force of cancer progression ROS causes the oxidation ofDNA bases Subsequent base excision repair (BER) introduces genetic errors during the repair process and the accumulation of these errorsdrives cancer progression

instability and heterogeneity caused by nucleic acid oxidationin cancer cells which lead to carcinogenesis and cancer evolu-tion During BER indirect SSB are produced as intermediatesafter the removal of oxidized bases and their correspondingnucleotides If SSB takes place at adjacent regions on bothstrands of the same chromosome genome instability canensue Meanwhile poly (ADP-ribose) polymerase (PARP)is activated after binding to SSB and consumes NAD+ tosynthesize polyA chains which then recruit important DNArepair enzymes such as DNA polymerase 120573 and DNAligase III PARP also induces apoptosis through increasedpoly (ADP-ribose) (PAR) levels that facilitate the release ofapoptosis-inducing factor (AIF) frommitochondria and elicitapoptosis Otherwise depletion of NAD due to excessivePARP activity will further deplete the ATP pool and lead tocell lysis (necrosis) Proliferating cell nuclear antigen (PCNA)promotes the switch to a specialized DNA polymerase with alarger active site that tolerates damaged bases at the expenseof sacrificing fidelity during translesion synthesisrepairLower fidelity increases the chance of mismatch which givesrise to point mutations The accumulation of genome insta-bility and point mutations results in genome heterogeneityamong cells and chronologically within cells Tumor initi-ation is triggered by mutations that can activate oncogenesor silence tumor suppressor genes Further mutations thatgive rise to gainloss of function of genes then grant tumorcells the ability to resist growth control Further gainloss

of function continues to drive cancer progression enablingtumor cells to escape layers of control and become capableof invasion and metastasis

Elevated levels of oxidative DNA lesions (8-oxoG) havebeen noted in various tumors supporting the argument thatsuch damage contributes to the etiology of cancer Therefore8-oxoG has been established as an important biomarkerwhich is widely used to measure oxidative stress and assessrisk of tumor initiation after exposure to various carcinogenicsubstances and pollutants [8] In a cohort study involvingesophageal cancer patients more extensive oxidative damageto DNA as indicated by 8-oxoG levels was detected in cancerpatients in comparison to a healthy control group Smokinghabits and alcohol consumption risk factors for esophagealcancer were also correlated with the observed levels ofoxidative DNA damage [9]

Oxidative stress-induced lipid peroxidation is also asso-ciated with the early stages of carcinogenesis [10] Mal-ondialdehyde (MDA) the product of lipid peroxidationcan induce the formation of DNA adducts which leads tomutagenesis In an epidemiological study of breast cancer thelevel of the malondialdehyde-DNA adduct 3-(2-deoxy-120573-D-erythro-pentofuranosyl) pyrimido [12-120572]purin-10(3H) one(M1dG) was significantly higher in breast tissue specimensfrom cancer patients than in those from healthy individuals[11]Therefore other than 8-oxoG the level ofM1dGhas beenemployed as an indicator of cancer-associated oxidative DNA


ROS

8-oxoG


(M1dG)



DNA Lipid Protein



O

O

OO

O

H

N

N

NNN

N

N

N

HN

H2N





2






Exogenous stimuli








(5) Cr(IV)(6) Cr(V)(7) V(III)


M(n) M(n + 1)

(a)


(1) Vit C









CATCatalase


GPxGR


Glutathione system

PRXTRR

TRX

PRXTRX

Thioredoxin system

H2O2

H2O2 2H2O + O2


2GSH + 2NADP+





GSSG2 + NADPH

O2∙

(b)





Nrf2KE

AP1

KEA

P1 SHSH

HSHS

UbUb

E3


ROS

Antioxidant defense


ARE

Nrf2

P

GR

GPx GSS

PRX

TRX

TRR

ARE

Nrf2

P

KEA

P1

KEA

P1SS

UbUb

Ub

Nucleus







PCNA



DNA ligase

ROS


Seal of SSB






AP endonuclease


PARP

DNA glycosylase D

NA

liga

seD

NA

pol

ymer

ase120573

















O

O

OHOH

HO

OH

O

OHOH

HO

OHOH

O

OHOH

HO

OHO

O OH

OHOH

OH

O

O

O

O O

H H

H

OO

O

O

O

O

O

O

O

HO

O

HO

O

OH

OHOH

H

N C S

O

O

OH

OOO

HO

OH

OHHO

NC

SSO

S

SS

SS

S

(b) Curcuminoids

(A) Phenolics

Quercetin

(a) Flavonoids

Catechin


(c) Stilbenoids

Resveratrol

Curcumin



(a) Carotenes



(C) Vitamins

Deoxyelephantopin

Tocopherol (Vit E)

Sulforaphane (SFN)


(a) Isothiocyanates

(D) Organosulfides

Diallyl trisulfide

(b) Sulfides

Diallyl sulfide

Diallyl disulfide

120573-carotene











2O2in relation to































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ROS

8-oxoG


(M1dG)



DNA Lipid Protein



O

O

OO

O

H

N

N

NNN

N

N

N

HN

H2N





2






Exogenous stimuli








(5) Cr(IV)(6) Cr(V)(7) V(III)


M(n) M(n + 1)

(a)


(1) Vit C









CATCatalase


GPxGR


Glutathione system

PRXTRR

TRX

PRXTRX

Thioredoxin system

H2O2

H2O2 2H2O + O2


2GSH + 2NADP+





GSSG2 + NADPH

O2∙

(b)





Nrf2KE

AP1

KEA

P1 SHSH

HSHS

UbUb

E3


ROS

Antioxidant defense


ARE

Nrf2

P

GR

GPx GSS

PRX

TRX

TRR

ARE

Nrf2

P

KEA

P1

KEA

P1SS

UbUb

Ub

Nucleus







PCNA



DNA ligase

ROS


Seal of SSB






AP endonuclease


PARP

DNA glycosylase D

NA

liga

seD

NA

pol

ymer

ase120573

















O

O

OHOH

HO

OH

O

OHOH

HO

OHOH

O

OHOH

HO

OHO

O OH

OHOH

OH

O

O

O

O O

H H

H

OO

O

O

O

O

O

O

O

HO

O

HO

O

OH

OHOH

H

N C S

O

O

OH

OOO

HO

OH

OHHO

NC

SSO

S

SS

SS

S

(b) Curcuminoids

(A) Phenolics

Quercetin

(a) Flavonoids

Catechin


(c) Stilbenoids

Resveratrol

Curcumin



(a) Carotenes



(C) Vitamins

Deoxyelephantopin

Tocopherol (Vit E)

Sulforaphane (SFN)


(a) Isothiocyanates

(D) Organosulfides

Diallyl trisulfide

(b) Sulfides

Diallyl sulfide

Diallyl disulfide

120573-carotene











2O2in relation to































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Exogenous stimuli








(5) Cr(IV)(6) Cr(V)(7) V(III)


M(n) M(n + 1)

(a)


(1) Vit C









CATCatalase


GPxGR


Glutathione system

PRXTRR

TRX

PRXTRX

Thioredoxin system

H2O2

H2O2 2H2O + O2


2GSH + 2NADP+





GSSG2 + NADPH

O2∙

(b)





Nrf2KE

AP1

KEA

P1 SHSH

HSHS

UbUb

E3


ROS

Antioxidant defense


ARE

Nrf2

P

GR

GPx GSS

PRX

TRX

TRR

ARE

Nrf2

P

KEA

P1

KEA

P1SS

UbUb

Ub

Nucleus







PCNA



DNA ligase

ROS


Seal of SSB






AP endonuclease


PARP

DNA glycosylase D

NA

liga

seD

NA

pol

ymer

ase120573

















O

O

OHOH

HO

OH

O

OHOH

HO

OHOH

O

OHOH

HO

OHO

O OH

OHOH

OH

O

O

O

O O

H H

H

OO

O

O

O

O

O

O

O

HO

O

HO

O

OH

OHOH

H

N C S

O

O

OH

OOO

HO

OH

OHHO

NC

SSO

S

SS

SS

S

(b) Curcuminoids

(A) Phenolics

Quercetin

(a) Flavonoids

Catechin


(c) Stilbenoids

Resveratrol

Curcumin



(a) Carotenes



(C) Vitamins

Deoxyelephantopin

Tocopherol (Vit E)

Sulforaphane (SFN)


(a) Isothiocyanates

(D) Organosulfides

Diallyl trisulfide

(b) Sulfides

Diallyl sulfide

Diallyl disulfide

120573-carotene











2O2in relation to































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Nrf2KE

AP1

KEA

P1 SHSH

HSHS

UbUb

E3


ROS

Antioxidant defense


ARE

Nrf2

P

GR

GPx GSS

PRX

TRX

TRR

ARE

Nrf2

P

KEA

P1

KEA

P1SS

UbUb

Ub

Nucleus







PCNA



DNA ligase

ROS


Seal of SSB






AP endonuclease


PARP

DNA glycosylase D

NA

liga

seD

NA

pol

ymer

ase120573

















O

O

OHOH

HO

OH

O

OHOH

HO

OHOH

O

OHOH

HO

OHO

O OH

OHOH

OH

O

O

O

O O

H H

H

OO

O

O

O

O

O

O

O

HO

O

HO

O

OH

OHOH

H

N C S

O

O

OH

OOO

HO

OH

OHHO

NC

SSO

S

SS

SS

S

(b) Curcuminoids

(A) Phenolics

Quercetin

(a) Flavonoids

Catechin


(c) Stilbenoids

Resveratrol

Curcumin



(a) Carotenes



(C) Vitamins

Deoxyelephantopin

Tocopherol (Vit E)

Sulforaphane (SFN)


(a) Isothiocyanates

(D) Organosulfides

Diallyl trisulfide

(b) Sulfides

Diallyl sulfide

Diallyl disulfide

120573-carotene











2O2in relation to































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















PCNA



DNA ligase

ROS


Seal of SSB






AP endonuclease


PARP

DNA glycosylase D

NA

liga

seD

NA

pol

ymer

ase120573

















O

O

OHOH

HO

OH

O

OHOH

HO

OHOH

O

OHOH

HO

OHO

O OH

OHOH

OH

O

O

O

O O

H H

H

OO

O

O

O

O

O

O

O

HO

O

HO

O

OH

OHOH

H

N C S

O

O

OH

OOO

HO

OH

OHHO

NC

SSO

S

SS

SS

S

(b) Curcuminoids

(A) Phenolics

Quercetin

(a) Flavonoids

Catechin


(c) Stilbenoids

Resveratrol

Curcumin



(a) Carotenes



(C) Vitamins

Deoxyelephantopin

Tocopherol (Vit E)

Sulforaphane (SFN)


(a) Isothiocyanates

(D) Organosulfides

Diallyl trisulfide

(b) Sulfides

Diallyl sulfide

Diallyl disulfide

120573-carotene











2O2in relation to































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























O

O

OHOH

HO

OH

O

OHOH

HO

OHOH

O

OHOH

HO

OHO

O OH

OHOH

OH

O

O

O

O O

H H

H

OO

O

O

O

O

O

O

O

HO

O

HO

O

OH

OHOH

H

N C S

O

O

OH

OOO

HO

OH

OHHO

NC

SSO

S

SS

SS

S

(b) Curcuminoids

(A) Phenolics

Quercetin

(a) Flavonoids

Catechin


(c) Stilbenoids

Resveratrol

Curcumin



(a) Carotenes



(C) Vitamins

Deoxyelephantopin

Tocopherol (Vit E)

Sulforaphane (SFN)


(a) Isothiocyanates

(D) Organosulfides

Diallyl trisulfide

(b) Sulfides

Diallyl sulfide

Diallyl disulfide

120573-carotene











2O2in relation to































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

O

OHOH

HO

OH

O

OHOH

HO

OHOH

O

OHOH

HO

OHO

O OH

OHOH

OH

O

O

O

O O

H H

H

OO

O

O

O

O

O

O

O

HO

O

HO

O

OH

OHOH

H

N C S

O

O

OH

OOO

HO

OH

OHHO

NC

SSO

S

SS

SS

S

(b) Curcuminoids

(A) Phenolics

Quercetin

(a) Flavonoids

Catechin


(c) Stilbenoids

Resveratrol

Curcumin



(a) Carotenes



(C) Vitamins

Deoxyelephantopin

Tocopherol (Vit E)

Sulforaphane (SFN)


(a) Isothiocyanates

(D) Organosulfides

Diallyl trisulfide

(b) Sulfides

Diallyl sulfide

Diallyl disulfide

120573-carotene











2O2in relation to































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















2O2in relation to































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Metal ion chelation





ROS production

Cytotoxic effect


Medium level


Normallevel




ROS clearance




Phytoagents


Phytoagents

so forth

so forth

so forth






PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















PAPA

PA

PAPARP


TRX

GPx

PRX

GPx


MDA


Indirect SSB

Mutation

BER

Translesion repair

Cell death

Genome instability

MutationPCNA


GPx

GR

TRR

TRXPRX

GSS

GSH

GSH GSSG

CATSOD

Fenton reaction

GPx

OncogenesisPA

PA

Nrf2ARE


Fe2+

Fe3+

PA Phytoagents

Prooxidant role

Antioxidant role

Inhibition

∙OH + OHminus

H+ O + O2




4 Future Prospects













References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















References

















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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Review Article Phytoagents for Cancer Management ...downloads.hindawi.com/journals/omcl/2013/925804.pdf · Review Article Phytoagents for Cancer Management: Regulation of Nucleic