Review Article Redox Control of Multidrug Resistance and Its...

Review ArticleRedox Control of Multidrug Resistance andIts Possible Modulation by Antioxidants

Aysegul Cort1 Tomris Ozben2 Luciano Saso3 Chiara De Luca4 and Liudmila Korkina5

1Department of Nutrition and Dietetics Faculty of Health Sciences Sanko University Incili PınarGazi Muhtar Pasa Bulvarı Sehitkamil 27090 Gaziantep Turkey2Department of Biochemistry Akdeniz University Medical Faculty Campus Dumlupınar Street 07070 Antalya Turkey3Department of Physiology and Pharmacology ldquoVittorio Erspamerrdquo La Sapienza University of RomePiazzale Aldo Moro 5 00185 Rome Italy4Evidence-Based Well-Being (EB-WB) Ltd 31 Alt-Stralau 10245 Berlin Germany5Centre of Innovative Biotechnological Investigations Nanolab 197 Vernadskogo Prospekt Moscow 119571 Russia

Correspondence should be addressed to Liudmila Korkina korkinacibi-nanolabcom

Received 12 August 2015 Revised 14 November 2015 Accepted 18 November 2015

Academic Editor Sidhartha D Ray

Copyright copy 2016 Aysegul Cort 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

Clinical efficacy of anticancer chemotherapies is dramatically hampered by multidrug resistance (MDR) dependent on inheritedtraits acquired defence against toxins and adaptive mechanisms mounting in tumours There is overwhelming evidence thatmolecular events leading to MDR are regulated by redox mechanisms For example chemotherapeutics which overrun the firstobstacle of redox-regulated cellular uptake channels (MDR1 MDR2 andMDR3) induce a concerted action of phase III metabolicenzymes with a temporal redox-regulated axis This results in rapid metabolic transformation and elimination of a toxin Thismetabolic axis is tightly interconnected with the inducible Nrf2-linked pathway a key switch-on mechanism for upregulationof endogenous antioxidant enzymes and detoxifying systems As a result chemotherapeutics and cytotoxic by-products of theirmetabolism (ROS hydroperoxides and aldehydes) are inactivated and MDR occurs On the other hand tumour cells are capableof mounting an adaptive antioxidant response against ROS produced by chemotherapeutics and host immune cells The multipleredox-dependent mechanisms involved in MDR prompted suggesting redox-active drugs (antioxidants and prooxidants) orinhibitors of inducible antioxidant defence as a novel approach to diminish MDR Pitfalls and progress in this direction arediscussed

1 Introduction

It is commonknowledge thatmultiple drug resistance (MDR)has crucial negative impact on the clinical outcomes of con-ventional cytotoxic anticancer therapies and of those basedon specific drugs targeting molecular pathways implicatedin cancer cell functions and survival strategies Since thediscovery of the first ATP-binding cassette (ABC) trans-porter P-glycoprotein (P-gp) ABC drug transporters havebecome targets for improving anticancer chemotherapy Upto now more than 49 different ABC transporters have beenfound and cloned [1] A majority of MDR modulators orreversals are themselves substrates of the transporters thatcompete with anticancer agents for the efflux from tumour

cells [2] Frustrating the great expectations raised ABCtransportermodulatorsreversals proved to have insufficientclinical efficacy and very high toxicity Novel ldquobiologicalrdquoapproaches have been recently developed in laboratoryto modulate ABC transporter-mediated MDR including amonoclonal antibody that binds specifically to P-gp thus sup-pressing drug transport small interfering RNA technologyto decrease the expression of ABCB1 antisense oligonucleot-ides and agents attenuating P-gp transcription [3] Thoughvery promising these ldquobiologicalsrdquo are still lacking clinicalproof-of-concept data

In any case the evident and numerous adverse effects ofMDR modulators stimulated additional studies on physio-logical role(s) of MDR in the human organism It has been

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 4251912 17 pageshttpdxdoiorg10115520164251912

2 Oxidative Medicine and Cellular Longevity

reported that MDR relies not exclusively on transportingsystems for drug uptake and efflux but also on intracellulardrug metabolism and DNA damage [4] Transporting andmetabolic systems definingMDR are expressed in the major-ity of normal cells are essential for nutrients uptake andmetabolites efflux and play a vital role in protecting cellsagainst xenobiotics Hence harsh inhibition of a functionallyessential mechanism results in general intoxication

To gain protection against foreign invasions andmaintainhomeostasis the human organism employs several types ofphysical chemical and biological defence systems For exam-ple skin and other lining epitheliamechanically prevent inva-sion of relatively large organic and inorganic particles Theimmune system has been evolved to fight cellular invadersand high-molecular-weight compounds of biological origin

The chemical defence system consisting of biosensoringtransmitting and responsive elements has been evolvedstarting from primitive eukaryotes and lower plants [5] toprotectmulticellular organisms against environmental chem-ical insults (xenobiotics) and to maintain homeostasis ofendogenous low-molecular-weightmetabolites (endobiotics)[6] Being exposed to xenobiotic (drug) stress an organism ischallenged to rapid and appropriate adaptation by activatingconstitutive and expressing inducible systems thus attenuat-ing negative biological consequences For this purpose anarray of gene families and molecular pathways have beendeveloped during evolution to prevent cellular access todetoxify and eliminate toxins and to repair chemical damageThe active efflux proteins for example P-glycoproteins (P-gp) [7] multidrug resistance (MDR) proteins [8] and multi-xenobiotic resistance (MXR) proteins [9] directly eliminateslightly lipophilic organic xenobiotics from cells serving asthe first line of chemical defence Escaping the first-lineguardians once in the cytoplasm toxic nucleophilic com-pounds undergo biotransformation by the oxidative phaseI enzymes (cytochrome P450 (CYP) flavoprotein monooxy-genase hemeoxygenase amine oxidases xanthine oxi-dase and others) to become electrophilic The electrophileis subjected to reductive or conjugative modification byphase II enzymes (glutathione-S-transferases (GSTs) UDP-glucuronosyltransferases (UGTs) catechol-O-methyl trans-ferases (COMT) N-acetyl transferases (NATs) and manyothers)

Reactive oxygen species (ROS) generated as by-productsof phase I reactions are rapidly reduced to nontoxic ldquophysi-ologicalrdquo levels by antioxidant enzymes (superoxide dismu-tases (SODs) catalase (CAT) glutathione peroxidases (GPx)peroxiredoxins (PRx) and nonenzymatic antioxidants suchas reduced glutathione (GSH) uric acid ascorbic acid andceruloplasmin among others) All these constitutive protec-tive systems are sufficient to cope with low levels of xenobi-otics or endobioticsThe inducible chemical defence relies onthe array of stress responsive genes In this case chemicalstressors like anticancer chemotherapeutics should first berecognised by specific sensors which in turn transmit alarmsignals to activate or express de novo transporting biotrans-forming and detoxifying enzymes

The primary member of mammalian proteins-sensors oforganic chemicals is the aryl hydrocarbon receptor (AhR)

activated by planar aromatic hydrocarbons of natural orsynthetic origin [10ndash12] A second group of chemical sensorscomprises nuclear receptors such as pregnane X constitutiveandrostane peroxisome proliferators-activated liver-X andfarnesoid-X receptors recognising a wide variety of xeno-and endobiotics [12ndash14] Nuclear factor erythroid-derived2-related factors (Nrf1 and Nrf2) and related caprsquonrsquocollar-(CNC-) basic leucine zipper proteins belong to anotherfamily of sensors activated by oxidants and electrophiles[15 16] Activation of such recognition elements after ligandbinding may result in alterations of ion channel conductivitykinase machinery and cytoplasmic and nuclear transcriptionfactors inducing cell response (signal transduction)

Signal transduction is oftenmediated by redox substances(superoxide anion radical hydrogen peroxide lipid perox-ides aldehydes and others) [17ndash21] At moderate concentra-tions they are signals to start gene transcription via activationof transcription factors (nuclear factor 120581B (NF-120581B) activatorprotein 1 (AP-1) and antioxidant response element- (ARE-)binding proteins) or initiating the protein kinase cascade [516 19]The latter pathway leads to the interactionwith specificARE of DNA motifs on promoters of antioxidant defenceenzymes such as GST Mn-superoxide dismutase (MnSOD)and glutamyl-cysteine ligase among others [15]

Inherited or acquired alterations at any key point of thechemical defence system might lead to chronic intoxicationand numerous human pathologies (chronic inflammationdegeneration carcinogenesis multiple chemical sensitivitysyndrome etc) in the inherited or acquired MDR respec-tively (Figure 1) Usually the course of anticancer chemo-therapy induces the overexpression of drug transportersMDRMXRP-gp [3 4] activation of sensoring receptorselectrophileoxidant sensors transcription factors and over-expressionactivation of detoxifyingantioxidant enzymes [1]Collectively it causes rapid metabolism and eliminationof both the anticancer drugs and cytotoxic by-productstargeting tumour cells Since the chemical defence system isubiquitous for all human organs and tissues and central toorganism functions the attempts for its pharmacological sup-pression in order to diminish MDR potentially bear the riskof a multitude of undesired side effects Upon the pharma-cological interaction with components of universal chemicaldefence system the ldquogood guyrdquo evolved on purpose to protectmulticellular organisms from low-molecular-weight chemi-cals could become a ldquobad guyrdquo blocking desired therapeuticaleffects of anticancer drugs (MDR)

On the grounds of our current knowledge redox regu-lation of multiple molecular pathways essential for humanchemical defence system can be implicated differentially innormal host and in tumour cells Owing to the fact that redoxbalance in tumour cells is greatly altered as compared tothat of normal host cells [22 23] selective redox inhibitorstargeting tumour-associated chemical defence as a cause ofMDR should be developed Regarding potential health effectsof redox modulators on tumours they are mainly attributedto cancer chemoprevention direct anticancer action (forcomprehensive review see [23]) cancer sensitisation to con-ventional chemotherapeutics preferentially through MDRsuppressionreversal cancer sensitisation to radio- and

Oxidative Medicine and Cellular Longevity 3

P-gp

Phase II(GSTs UGTs COMT NAT etc)

Antioxidant systems(SOD CAT GPx and

Prx)

MXRMDR

Metaboliteexcretion

XB

EBPhase I(CYPs HO1 and

Prx)

ROS

ROS

(a)

Anticancer drug

AhR

Phase I enzymeinduction

Phase II enzymeinduction

Antioxidant enzymeinduction

PI3-K

NR

Nrf2 ARE

P-gp MDR MXR

Inflammatoryresponse

Transcriptionfactors

ROS

=

(NF-120581B AP-1)

(b)

Figure 1 Inherited and acquired multiple drug resistance (a) In the inherited multiple drug resistance (MDR) chronic exposure ofnormal cells to low levels of unknown xenobiotics (XB) orand endobiotics (EB) takes place It causes upregulation of ATP-bindingcassette transporters such as P-glycoprotein (P-gp) MDR proteins (MDRs) and multiple xenobiotic resistance (MXR) without induction byanticancer drugs Single nucleotide polymorphisms of phase I and II metabolic enzymes and efflux transporters often accompany inheritedMDR and they could also be a causative reason for the resistance Reactive oxygen species-mediated modulation of xenobioticsdrugmetabolism is similar to that in the acquired drug resistance This cellular pattern seems to be associated with high risk of tumourtransformation ROS reactive oxygen species MDRmultiple drug resistance transporters MXRmultiple xenobiotic resistance transportersP-gp P-glycoprotein CYP cytochrome P450 HO1 hemeoxygenase-1 SOD superoxide dismutase CAT catalase GPx glutathioneperoxidase PI3K phosphatidylinositol-3 kinase AhR aromatic hydrocarbon receptor NF-120581B nuclear factor kappa B AP-1 activatorprotein 1 NR nuclear receptor Nrf2 nuclear factor erythroid-derived 2-related factor 2 ARE antioxidant responsive elements (b) In theacquired MDR chemotherapeutics induce redox-dependent MDR expression and activity in tumour cells Chemotherapeutics activate alsoaromatic hydrocarbon receptor- (AhR-) driven and ROS-regulated expression of transcriptional factors (nuclear factor kappa B (NF-120581B) andactivator protein 1 (AP-1)) which initiate inflammatory response Reactive oxygen species (ROS) mediate activation of phosphoinositol-3kinase upstream of inflammatory cytokine transcription and synthesis ROS and AhR-associated stimulation of Nrf2 followed by antioxidantresponsive element of DNAmotif causes upregulation of protective antioxidant and detoxifying systems such as antioxidant phase I and IIenzymes


Redox

Radiotherapy

Host tissues protection

Sensitisation (synergy with

a drug)

Redox

Chemotherapy

MDR suppression

Directantitumour

action Direct photochemical

toxicity

Sensitisation to

radiotherapy

Redox adjuvants

Redox

Photodynamictherapy

Cancerchemoprevention

Cancer therapies

Figure 2 Redox-active substances and cancer A variety of redox-active substances (direct or indirect antioxidants) are known to exhibitcancer chemopreventive properties In the pharmacological anticancer protocols redox-active agents could be used as direct anticancerchemotherapeutics or synergies with cytotoxic effects of conventional anticancer drugs Here we discuss the feasibility of such substances insuppressionreversal of acquired MDR The redox agents are often used for the protection of normal tissuesorgans against toxic effects ofchemotherapy and radiotherapy

photodynamic therapies and protection of normal hostorganstissues against damage by chemo- and radiotherapy(Figure 2)

This review will discuss existing and perspective possibil-ities of differential targeted modulation of redox-dependentcomponentspathways of intrinsic and induced chemicaldefence as an emerging strategy for combinatory anticancertherapies to overcome MDR Molecular pathways-targets forMDR attenuation or even reversal by redox-active substanceswill be described in detail

2 Intrinsic Multidrug Resistance(MDR) Is It Possible to Overcome It byRedox Modulation

21 Inherited Overexpression of Drug Transporters AcceleratesDrug Efflux from Target Cells Some individuals possessthe so-called intrinsic MDR having never been exposed tochemotherapy Genetical predisposition to resist xenobioticstress could in principle be explained in terms of singlenucleotide polymorphisms (SNPs) of complex MDR sys-tem components starting from drug transporters censor-ing receptors and xenobioticdrug metabolising enzymes(see several examples below) On the other hand a lead-ing hypothesis indicates intrinsic MDR as a result ofchronic (ldquosilentrdquo) exposure to low-level xenobiotic stressorsor endogenous disturbances of lipid glucose andor hor-mone metabolism Therefore the molecular pathways of its

regulations are similar to those characteristic for acquiredchemotherapy-induced MDR In this line the developmentof intrinsic MDR correlates with increased risk of carcino-genesis and the process is under network-like redox control(for comprehensive review see [1]) It appears that theclassical paradigm of cancer chemoprevention with redox-active nontoxic substances could be interpreted in terms ofintrinsic MDR prevention Furthermore intrinsic MDR isa hallmark of stem cells both normal and tumour becausehigh resistance to any toxin would guarantee survival andmaintenance of stem cell populations

22 Gene Polymorphisms Influencing Drug MetabolisingEnzymes May Result in Ultrafast Drug Elimination orExtremely Slow Formation of Cytotoxic Redox By-ProductsThe cytochrome P450 (CYP) system is a superfamily ofisozymes located in the smooth endoplasmic reticulummainly in the liver but also in extrahepatic tissues (egintestinalmucosa lung kidney brain lymphocytes placentaand skin) involved in the biotransformation of numerouslipophilic xenobiotics into more hydrophilic less toxic andmore easily excreted metabolites [11 24 25] The major CYPenzymes involved in human drug metabolism belong to fam-ilies 1 2 and 3 the specific drug metabolising isoforms beingCyp1A2 Cyp2C9 Cyp2C19 Cyp2D6 and Cyp3A43A5

Each CYP isoform is a product of specific gene For someisoforms the existence of genetic polymorphisms has beendemonstrated The allelic variants may be due to the deletion


of the entire gene SNPs deletion or insertion of fragments ofDNA within the gene or multiplication of gene copies lead-ing to absent deficient or enhanced enzyme activity Thusthe population can be classified into Extensive Metabolisers(EM individuals with normal capacity) Poor Metabolisers(PM individuals with reducednull metabolic activity) andUltrarapid Metabolisers (UM individuals with a higher-than-normal metabolic activity) It seems that opposite pop-ulations of PM and UM could be at risk of constitutiveMDR because UM would rapidly metaboliseexcrete parentmolecules of anticancer drugs while PM would not produceROS as by-products of anticancer drug metabolism Theseby-products possess strong cytotoxicity against cancer cellsHence the routine clinical diagnostics based on determina-tion of CYP SNPs produce a reliable prediction of individualchemosensitivitychemoresistanceMDR to anticancer ther-apies Several polymorphisms have been connected with theinducibility or enzymatic activity of the abovementioneddrug metabolising CYP isoforms [6]

23 Redox-Active Inhibitors of Drug Transporters and Recep-tors Associated with Drug Detoxifying Enzymes Hopes andReality Notwithstanding the growing interest and greathopes for natural nontoxic redox agents to preventinhibitreverse MDR ([26] in this review) drug developmentremains rather complicated due to low bioavailability definedby restricted absorption through intestine lining epitheliaand skin [24 25] rapid metabolism and excretion AbsorbedMDR inhibitors become themselves targets for the classicalpathways of xenobiotic detoxificationdrug metabolism [27ndash29] In phase I they are predominantlymetabolised bymicro-somal CYPs Then phase II glucuronidation by UGT [30]sulfation by phenol and catecholamine specific sulfotrans-ferases (SULT1A1 and SULT1A3) [11] methylation by COMT[31] and binding with glutathione through GST occur [1228]

To improve candidate MDR inhibitor bioavailability andattenuate its metabolic disruption several approaches havebeen implied such as injectable forms other sophisticateddrug delivery systems combinationwith adjuvants like piper-ine and caffeine to diminish glucuronidation and chem-ical modification of parent molecules to bypass efficientmetabolic guardians [6 24 27]

A very high probability of drug-drug interactionsbetween the adjuvant therapeutics for MDR inhibition andanticancer therapies themselves as inducers of MDR shouldalso be taken into consideration [32] It has been reportedthat potential MDR suppressors of herbal origin may easilyinteract with the same efflux (P-gp) and metabolic (Cyp3A4)pathways as anticancer agents do resulting in oppositeoutcomes inhibition or expression of MDR componentsdepending on timing dosages posology and route of drugadministration [33] Recent findings have shown that thiskind of drug-drug interaction is highly influenced by geneticpolymorphisms of efflux proteins (MDR1) and metabolicenzymes (Cyp3A5) [34]

Emerging evidence shows that MDR could be an evolu-tionary defined mechanism to preserve normal and cancerstem cell populations In this direction redox signalling

becomes a probable candidate to maintain cell stemness[1] Therefore the development of clinically efficient redoxmodulators of MDR should selectively target cancer stemcells while leaving normal stem cells intact

3 Redox Dependence of AcquiredMultidrug Resistance Modulation byDirect and Indirect Antioxidants

Most chemotherapeutic agents generate ROS which bind tospecific structures within the cancer cells and promote celldeath Chemotherapeutic agents disturb the redox homeosta-sis in cells and change their ability to cope with excessive ROSlevels through the production of protective direct antioxi-dants [35] Direct antioxidants are modified in this processand need to be resynthesised [36] Glutathione (GSH) is con-sidered as the main redox buffer in a cell because it supplieslarge amounts (millimolar concentrations) of reducing equiv-alents [37] The intracellular thiol redox status is described asthe ratio of reduced to oxidised forms of thiols (GSHGSSG)which decreases under oxidative stress conditions and GSHreversibly forms mixed disulfide bonds between proteinthiols (S-glutathionylation) to prevent protein oxidation [38]Besides GSH thioredoxin (Trx) another important endoge-nous antioxidant provides protection against oxidative stress[39 40] Nrf2 regulates Trx and sulfiredoxin enzymes whichare involved in the regeneration of the reduced form ofnicotinamide adenine dinucleotide phosphate (NADPH) andsynthesis of GSH [41] Among the potential mediators ofchemoresistance Trx plays critical roles in the regulation ofcellular redox homeostasis and redox-regulated chemoresis-tance [42ndash44]

In a recent study Zhang et al have shown that inhibitingNrf2 expression through the transfection of shRNA plasmidsin non-small-cell lung cancer cells significantly inhibited theexpressions of glutathione pathway genes antioxidants andmultidrug resistance proteins and induced the generation ofROS decreased the level of GSH and inhibited cell prolifera-tion [45] It has been reported that diffuse large B lymphomacells expressed higher-than-normal basal levels of Trx whichwas associated with decreased survival Suppressed Trxinhibited cell growth and clonogenicity and sensitised thelymphoma cells to doxorubicin [44] In a recent studyRaninga et al [46] have reported the cytoprotective role oftTrx1 and thioredoxin reductase 1 (TrxR1) enzyme inmultiplemyeloma Trx inhibitors were utilised in a variety of humancancers including acute myeloid leukemia [47] colorectalcancer [48] and lung cancer [49] to inhibit tumour growthand to stimulate ROS-induced apoptosis Auranofin a TrxR1inhibitor caused oxidative stress-induced cytotoxicity andapoptosis in cancers including chronic myeloid leukemia[50] chronic lymphocytic leukemia [51] prostate cancer [52]and breast cancer [53] Signal transducer and activator oftranscription 3 (STAT3) activation is commonly observedin multiple myeloma chronic lymphocytic leukemia gas-tric cancer lung cancer and laryngeal carcinoma Dietarygamma-tocotrienol inhibited both induced and constitutiveactivation of STAT3 inmultiple myeloma and prostate cancer


cell lines [54] High-dose intravenous ascorbate inhibitedNADPH-oxidase and was selectively toxic to tumours withlow CAT activity [55] Recent study has reported that a naph-thoquinone derivative induced cell death depending on Baxdeficiency In conclusion it has been suggested that naphtho-quinone might be clinically feasible to overcome chemoresis-tance [56]

Plant-origin polyphenols or their synthetic derivativeshave been recognised as redox-active molecules with rel-atively low toxicity Some of them for example luteolinapigenin and chrysin exert both direct and indirect antiox-idant effects by scavenging ROS and increasing Nrf2 activityfollowed by the induction of its target antioxidant genes[57] The natural polyphenols are also substrates for ABCtransporters as they bind to the active sites of the transportersand reduce drug efflux [58]The prooxidant capacity of somepolyphenols (quercetin epigallocatechin gallate) allowedtheir identification as chemotherapeutic adjuvants since theyselectively enhanced cytotoxic effects of chemotherapeutics[59] Shin et al have reported that some specific polyphenolstriggered cell cycle arrest and apoptotic cell death in cisplatin-resistant A2780Cis human ovarian cancer cells [60]

31 Antioxidant-Associated Modification of Drug Transport-ing Systems Elevated GSH levels trigger chemoresistanceby different pathways direct interaction with drugs andROS prevention of protein and DNA damage and induc-tion of DNA repair For example MRP1 causes efflux ofsome xenobiotics (eg vincristine daunorubicin) througha cotransport mechanism with GSH [26 61ndash63] Oxidativestress was more cytotoxic towards B16 melanoma cells withlow GSH concentrations [64] Tumour cells overexpressing120574-glutamyl-transpeptidase were more resistant to H

2O2and

chemotherapeutics such as doxorubicin cisplatin and 5-fluorouracil [65] GST-related chemoresistance modulatedprotein-protein interactions with members of the mitogen-activated protein (MAP) kinases including c-Jun N-terminalkinase 1 and apoptosis signal-regulating kinase 1 and alteredbalance of kinases during drug treatment [66] This complexmechanism involved the interaction of promoter regions forGST andGGT withNF-120581B andNrf2 followed by upregulationof several detoxification genes such as ferritin GSH-S-reductase and hemeoxygenase-1 Hypoxia induced breastcancer resistance protein (BCRP) expression in tissues byinteracting with heme and porphyrins thus increasing levelsof cytoprotective protoporphyrins [67] Overexpression ofBCRP is known to induce resistance to various chemother-apeutic drugs such as topotecan and methotrexate [68]

311 MDR Induction and Possibility to Inhibit It by Redox-Active Substances Affecting Glutathione Metabolism Definiteredox-active compounds such as quinones polyphenolsoligomeric proanthocyanidins ergothioneine ovothiols tan-nins or terpenes behave as redox modulators and triggerredox-related events such as ROS increase and GSH deple-tion causing apoptosis of cancer cells [69] In general redoxmodulations in cancer cells could initiate cell differentiationor could induce apoptosis [70] Acetaminophen a widelyused drug to combat pregnancy-connected toxicity [71]

induced ROS production in human choriocarcinoma cellsby reducing BCRP and GSH content and activating Nrf2-targeted genesNAD(P)Hdehydrogenase quinone 1 (NQO1)and hemeoxygenase-1 On the other hand genetic knockoutof TrxR1 gene resulted in liver insensitivity to acetaminophendue to drastic disruption of the link between redox home-ostasis and drug metabolism in the liver [72] Glyoxalase 1a key enzyme converting 120572-oxoaldehydes into correspond-ing 120572-hydroxy acids has been found to be amplified inmany primary tumours and cancer cell lines [73] In thisregard Young et al [73] have reported that overexpressionof both enzymes glyoxalase 1 and transglutaminase 2 anenzyme catalysing polyamine conjugationdeamidation ledto increased tumour cell survival drug resistance andmetas-tasis [74] The use of photodynamic anticancer therapy isparticularly attractive because of its specificity and selec-tivity [75] Hypericin a naphthodianthrone is a promisingphotosensitizer which is feasible for photodynamic therapyfor fluorescence diagnosis and for topical applications [76]Mikesova et al [77] have shown that hypericin content incells GSH levels and redox status correlated with hypericin-induced photocytotoxicity In contrast resveratrol attenuatedcisplatin toxicity by maintaining GSH levels [78 79] Ithas also been demonstrated that buthionine sulfoximinean inhibitor of GSH biosynthesis increased the sensitivityof the cells to chemotherapeutics while N-acetyl cysteineexhibited the reverse effect particularly in drug-resistant cells[61 62 80]Malabaricone-A a diarylnonanoidwith a potencyof MDR reversal induced depletion of GSH inhibitedGPx activity and caused redox imbalance [81] Collectivelymolecular pathways-targets for MDR modulation by GSHcontrolling agents are schematically presented in Figure 3

312 Overexpression of ABC Transporters Effects of NADPH-Oxidase and CYP Inhibitors NADPH-oxidase (NOX) is anoxidoreductase and plays crucial roles in cell growth pro-liferation and regulation of phosphatases and transcriptionfactors via redox-sensitive cysteine residues [82] ElevatedNOX expression has been shown in breast cancer [83]colon cancer [84] and neuroblastoma cells [85] Barth et alhave demonstrated that pharmacological block of glucosylce-ramide synthase a stimulator of NOX activity substantiallyimproved cytotoxicity of chemotherapeutics in glioblastomacells [86] The molecular mechanism of anticancer effects ofcisplatin involves activation of AktmTOR pathway regulatedby NOX-generated ROS and NOX inhibition by diphenyliodonium was critical for cisplatin cytotoxicity [87]

Overexpression of the drug and xenobiotic metabolisingcytochrome P450 enzymes for a long time has been con-sidered as one of the major mechanisms of chemoresistancein solid tumours [88 89] Types 1 and 2 CYPs have beenproven to activate procarcinogens into ultimate carcinogens[90] CYPs have become therapeutic targets in anticancerprotocols amid their involvement in the activation andorinactivation of chemotherapeutic drugs [91] Molina-Ortizet al reported that altered CYP expression played a crucialrole in the therapy of Rhabdomyosarcoma patients [92] Thein vitro antitumour action of natural product austocystin D


GPx

LOOH

CAT

NADPHNADPH

NADPHNADPH

GSH

GSSG

LOOH

HOOH

GR

TrxR

HOOHHOOH

NADP+

NADP+

H2O

Prxred

Prxox

TrxredTrxox

Figure 3 Antioxidant and prooxidant systems as molecular targets for redox-active MDRmodulators Glutathione and enzymes involved inthe glutathione metabolism such as glutathione reductase (GR) and glutathione peroxidase (Gpx) as well as gamma-glutamyl cysteine ligasecatalase NADPH-oxidase thioredoxin (Trx) and peroxiredoxins (Prx) are potential molecular targets for future MDR modulators

has been explained by selective activation of CYP enzymesleading to DNA damage [93]

32 Chemotherapy-Induced Inflammatory Responses MayCause Redox-Regulated Multidrug Chemoresistance Toincrease clinical efficacy of chemotherapy and combat MDRmolecular and cellular processes promoting inflammationhave been targeted due to the common knowledge that(i) inflammatory cells are present within tumours and (ii)tumours arise at sites of chronic inflammation [94 95]Cancer promotion and progression stages are accelerated byROS generated by immune cells mediators of inflammation[96] The induction of antioxidant defence enzymes intumours as an adaptation to oxidative attacks from hostimmune cells might contribute to chemoresistance Thushydrogen peroxide-resistant thymic lymphoma cells withincreased catalase and total SOD activities altered GSSGGSH redox potential and oxidised NADP+NADPH poolexhibited resistance to conventional chemotherapeuticssuch as cyclophosphamide doxorubicin vincristine andglucocorticoids [97] Chemotherapeutic agents causedrelease of ATP into the extracellular space as they inducedtumour cell death [98] Following accumulation of adenosinein tumours through CD39 and CD73 immune responseswere suppressed [99] Clayton et al showed that exosome-expressing CD39 and CD73 suppressed T cells throughadenosine production [100] Oxidative stress has putativeimpact on the activation and regulation of protein kinaseC (PKC) with redox-sensitive regions in both N-terminalregulatory domain and C-terminal catalytic domain Rimessiet al [101] have demonstrated that PKC120577 induced resistance toapoptotic agents following its translocation into the nucleusas a result of oxidative stress Nuclear PKC120577 inhibitor restoredthe apoptotic susceptibility of doxorubicin-resistant cells byforming a complex with the proinflammatory transcription

factor NF-120581B and promoting IL-6 synthesis thus favouringtumorigenesis and MDR [102]

321 Activation of NF-120581B-Dependent Pathways and TheirInhibition by Antioxidants NF-120581B is the key transcriptionfactor involved in the inflammatory pathway NF-120581B isconstitutively active in many of the signalling pathwaysimplicated in cancer Hyperactivation of NF-120581B in can-cer cells promotes cancer cell survival by inducing theupregulation of antiapoptotic proteins such as MnSOD andBcl-2 family members and the inhibition of proapoptoticproteins and is linked directly to the inflammation-inducedchemoresistance NF-120581B protects against oxidative stress andactivates transcription factor c-myc MMP gene expressionand tumour angiogenesis and remodels extracellular matrixwhileNF-120581B inhibition blocks cell proliferation [95 103ndash106]NF-120581B is associated with aberrant growth resistance to apop-tosis and overexpression of the genes involved in cell cyclepromotion in cancer cells In a recent study it has been shownthat isorhamnetin a metabolite of quercetin enhancedantitumour effects of chemotherapeutic drug capecitabinethrough negative regulation NF-120581B [107] Singh et al havereported that tea polyphenols inhibited cisplatin enhancedactivity of NF-120581B [108] FADD-like IL-1beta-convertingenzyme inhibitory protein (FLIP) is a potent inhibitor ofcaspase-8-mediated apoptosis involved in NF-120581B activationTalbott et al revealed that FLIP regulates NF-120581B throughprotein S-nitrosylation a key posttranslational mechanismcontrolling cell death and survival strategies [109] Overex-pression of cyclin D1 in cancer cells was reported in cisplatinchemoresistance In contrast reduction of cyclin D1 expres-sion resulted in the increased sensitivity to cisplatin due toreducedNF-120581B activity and apoptosis [110] It was shown thatvitamin E compounds such as 120575- and 120574-tocotrienol inhibitedNF-120581B activity cell growth cell survival and tumour growth


In parallel 120575-tocotrienol augmented sensitivity of pancreaticcancer to gemcitabine [111]

Curcumin a nontoxic food additive extensively used forfood flavouring [112] has been found to suppress humanhepatoma through inhibition of tumour cell proliferation cellcycle arrest in G2M phase and induction of apoptosis [113]Numerous publications have reported curcumin as a sensi-tiser for a number of anticancer drugs [114] first of all cis-platin [115] Results of recent studies have also suggested thatcurcumin was a reversal of induced MDR by multiple mech-anisms such as the inhibition of ABC transporter expressionand function activation of ATPase and modulation of NF-120581B activity during anticancer therapy [116] In contrastcaffeic acid a natural phenolic prevented antiproliferativeand proapoptotic effects induced by paclitaxel in lung cancercells by the activation of NF-120581B-survivin-Bcl-2 axis thuscontributing to acquired MDR [117]

322 Activation of Phosphoinositol-3 Pathway and Its Inhibi-tion in a Redox Fashion The phosphatidylinositol-3 kinase(PI3K) pathway has been widely considered to be associatedwith oncogenesis cancer progression andmultiple hallmarksofmalignancy [118] Consistently PI3K pathway is a commonmechanism of resistance to antineoplastic agents [119] Ofnote resistance to PI3K inhibitors may also develop due toaberrant compensatory signalling through other pathways[120] The three main molecules in this pathway are PI3KAkt and mammalian target of rapamycin (mTOR) Recentlyit has been reported that PI3K-mTOR inhibitor enhanced thecytotoxicity of temozolomide an advanced chemotherapy formalignant gliomas [121]

Since activation of integrins proteins expressed on thecytoplasmic membrane of malignant cells is controlleddirectly by a redox site by disulfide exchange in their extracel-lular domain redox modifications of thiols could alter essen-tial functions of integrins [122] It was suggested that inactiva-tion of VLA-4 integrin by nontoxic tellurium compound wasdue to its binding to the thiol groups of cysteines thatdecreased PI3KAktBcl-2 signalling while enhancing drugsensitivity [123] Gao et al demonstrated that the natu-ral bioflavonoid apigenin reversed drug-resistant pheno-type by its suppressor effect on PI3KAktNrf2 pathway indoxorubicin-resistant Nrf2 overexpressing cells [124]

323 Activation of Toll-Like Receptors (TLRs) by Chemother-apeutics and Inhibitory Effects of Redox Modulators Recentstudies implicate bacterial parasitic and viral infections as apossible link between inflammation and carcinogenesis [125]One possible redox-sensitive signalling pathway connect-ing infection-associated inflammation and carcinogenesis ismediated by Toll-like receptors (TLRs)The hypothesis is thatbacterial products such as lipopolysaccharide could activateTLR4-MyD88 axis in tumour cells followedby the productionof proinflammatory cytokines overexpression of antiapop-totic signals (XIAP and pAkt) and finally acquisition ofchemoresistance by ovarian cancer cells [126] Both in vivoand in vitro experiments have shown that anticancer drugpaclitaxel exerted two opposite modes of action killing ofbreast cancer cells and enhancement of their survival through

activation of TLR4 pathway [127]The authors suggested thatsimultaneous TLR4 block could reverse MDR to paclitaxeland improve efficacy of the anticancer therapy

Activation of TLRs in cancer cells seems to contributeto the tumour growth cancer cell survival and MDR via asignalling cascade involving cytokinechemokine production[128] It was shown that ligation to the TLR2 in lung cancercells induced activation of mitogen-activated protein kinases(MAPK) and NF-120581B a classical pathway of survival strategy[129] Stimulation of TLR7TLR8 in pancreas cancer cellsresulted in elevated NF-120581B and COX-2 expression increasedcancer cell proliferation and reduced chemosensitivity [130]Active TLR-4MyD88 signalling was also found in epithelialovarian cancer cells and influenced the drug response [131]The relationships between the expressions of TLR-4 MyD88and NF-120581B have been examined in epithelial ovarian cancerpatients Increased MyD88 expression was found to beassociated with poor survival rate [132]

33 Chemotherapy-Induced Redox-Dependent Stress Re-sponses Leading to Adaptation Along with killing cancercells chemotherapeutic agents induce their stress andadaptive responses Signalling pathways and gene expressionin response to chemotherapeutics play pivotal roles in thedevelopment of acquired MDR [133] Key functional aspectsof cellular stress response include damage to membranelipids proteins and DNA and alterations in the redox statusenergy metabolism cell cycle and proliferation [134] Thusthere is clear-cut evidence that upregulation of nonenzymaticand enzymatic antioxidant defence molecular chaperonesand stress responsive proteins are responsible for acquiredMDR [135] These molecular pathways are potential targetsto enhance the cytotoxic effects of chemotherapeutics and toovercome drug resistance

331 Nrf2 as a Perspective Target to Overcome MDR inTumours Nrf2 a redox-sensitive transcription factor playsa crucial role in redox homeostasis during oxidative stressNrf2 is sequestered in cytosol by an inhibitory protein Keap1causing its proteosomal degradation [136] In response tooxidative stress Nrf2 translocates to nucleus and binds toARE that increases the expression of antioxidant genes suchas hemeoxygenase-1 NAD(P)H quinone oxidoreductase 1aldo-keto reductases and several ATP-dependent drug effluxpumps [137] Many genes involved in phase II metabolismare also induced by Nrf2 including GSTs UGT and UDP-glucuronic acid synthesis enzymes [138] While Nrf2 upregu-lation causes chemoresistance its blockade sensitises a varietyof cancer cells including neuroblastoma breast ovarianprostate lung and pancreatic cancer cells to chemothera-peutic drugs [139] Several flavonoid compounds have beenreported to be potent Nrf2 inhibitors such as epigallocat-echin 3-gallate luteolin and brusatol [140 141] Nrf2 wasupregulated in hepatocellular carcinoma and positive corre-lation was found between Nrf2 expression and antiapoptoticBcl-xL and MMP-9 [142] Quercetin treatment increasedthe total cellular amount and nuclear accumulation of Nrf2protein in malignant mesothelioma cells [143] In vitro


suppression of Keap1 in human prostate and non-small-cell lung carcinoma cell lines elevated Nrf2 activity andincreased sensitisation to various chemotherapeutic agentsand radiotherapy [144 145] These results demonstrated thatNrf2 inhibitors are effective adjuvants of chemotherapeuticdrugs

34 Chemotherapy-Induced Prosurvival and AntiapoptoticCellular Strategies Roles for Anti- and Prooxidants Cellularredox homeostasis is maintained by the balance betweenendogenous antioxidant defence system including antiox-idant enzymes such as SOD catalase (CAT) GPX GSHproteins and low-molecular-weight scavengers such as uricacid coenzyme Q and lipoic acid and the prooxidantmolecules leading to the formation of several highly oxidis-ing derivatives

341 p53 Proapoptotic Protein p53 is considered as theguardian of the genome and several genemutations encodingp53 have been detected in several tumour cells Underphysiological conditions activated p53 plays a key role intumour prevention by promoting synthesis of antioxidantenzymes ROS-induced DNA damage activates p53 leadingto apoptosis via the mitochondrial intrinsic pathway andincreasing the synthesis of prooxidant enzymes Since p53 isa redox-sensitive factor ROS negativelymodulates its activityvia oxidative modification of the cysteine residues at theDNA-binding site It has been proposed that the loss of p53function in cancer cells is associatedwith their ability to avoidapoptosis [146] Mutations of p53 are involved in resistance tochemotherapy [147] It was demonstrated that p53 regulatedNrf2 negatively and interfered with the ability of Nrf2 to bindto DNA A low level of p53 favoured binding of Nrf2 to DNAIn a recent study the treatment with bortezomib which isa selective proteasome inhibitor induced MyelocytomatosisViral OncogeneNeuroblastoma (MYCN) downregulated p53expression leading to cell survival in neuroblastoma [148]

342 Bcl-2 Antiapoptotic Protein Bcl-2 protein is a memberof a family of apoptosis-modulating proteins which pro-tects against a variety of apoptotic stimuli mainly actingat the mitochondrial level In addition to its antiapoptoticaction Bcl-2 has been shown to exert potent antioxidanteffects [149] such as protection of lipid membranes againstperoxidation reactions maintenance of cellular redox status(ie NADHNAD+ and GSHGSSG in a reduced state) inresponse to oxidative stress [150] and elevation of cellularlevels of glutathione and reducing equivalents [151] Bcl-2upregulates antioxidant defence systems and its mitochon-drial localisation contributes to achieving this effect Bcl-2 iscapable of forming ion channels as a regulator of mitochon-drial permeability transition [152] Mitochondrial permeabil-ity transition blockade prevents release of cytochrome c anapoptosis initiating factor Herrmann et al reported that Bcl-2 selectively regulates nuclear localisation of cell death reg-ulators such as p53 and NF-120581B [153] Cellular redox state viathiols plays amajor role in regulatingmitochondria-mediatedevents during apoptosis and oxidation of mitochondrialthiols is an apoptotic sensor GSH is involved in detoxifying

reactions and it has a high intracellular concentration Itserves as the major reducing peptide within all of the cellsdue to its sulfhydryl group buffering and removing free radi-cals generated duringmetabolic processes such as respirationGSH is an important factor for Bcl-2 ability to suppressapoptosis Chaiswing et al observed that thiol redox statusand activities and expression of several antioxidant enzymesexhibited distinct patterns in two prostate cancer cell linesat different growth phases suggesting that modulation ofthiol redox status might be useful as a therapeutic tool tomodify cancer cell proliferation and tumour aggressiveness[154] Mitochondrial metabolism is altered in malignant cellsso that in contrast to normal or benign cells malignantcells accumulate citrate due to low activity of mitochondrialaconitase become citrate-oxidising cells and exhibit lowamounts of citrateThe higher rate ofmitochondrial substratemetabolism explains the increased levels of ROS associatedwith malignancy and metastasis The foregoing discussionillustrates the importance of GSH in mitochondrial functionand redox status in determining the metastatic aggressive-ness and sensitivity of cancer cells to chemotherapeuticagents and provides the rationale for mitochondrial GSH asa potential therapeutic target in cancer [155]

35 Chemotherapy-Induced Transcription and Activity of Aro-matic Hydrocarbons (Ah) Receptor AhR is a basic helix-loop-helix transcription factor that prior to ligand binding isstabilised in the cytoplasm by direct interaction with severalproteins such as heat shock protein 90 its cochaperon andX-associated protein 2 Upon binding to aromatic ligandstoxins drugs phytochemicals and sterols the AhR-ligandcomplex shuttles from cytoplasm to the nucleus where itheteromerises with the AhR nuclear translocator (Arnt) toform the transcription complex able to bind to xenobioticresponsive elements (XRE) DNA-binding motifs located inthe promoter region of the target drug metabolising genessuch as phase I (mainly Cyp1 subfamily) and II metabolisingenzymes and Nrf2 [156ndash158] One of the downstream targetsfor AhR is BCRP encoded by ABCC3 gene [159ndash161] Thecoordinate AhR- and Nrf2-dependent transcriptional regula-tion of humanUGTs by utilising bothXRE- andARE-bindingmotifs takes place to protect cells from xenobiotic and oxida-tive stresses [162]The elegant studywith geneticallymodifiedmice has clearly demonstrated that Nrf2 is required forligand-associated induction of classical ldquoAhR batteryrdquo genesNQO1 GST isoforms and UGTs [163] Apart frommetabolicenzymes a number of growth factors cytokines chemokinesand their receptors are downstream gene targets for activatedAhR [164 165] AhR is also functionally connected with epi-dermal growth factor receptor presumably through NF-120581B-regulated pathway [166] thus influencing the epithelial cellproliferation AhR can also cross-talk and directly interactwith proteins involved in major redox-regulated signallingpathways such as NF-120581B and various kinases such as SrcJNK p38 and MAPK [167] and with oestrogen receptorsto mediate oestrogen metabolism [168 169] Recent studieshave unraveled unsuspected physiological roles and novelalternative ligand-specific pathways for this receptor thatallowed hypothesising numerous pharmacological roles of


AhR ligands useful for the development of a new generationof anti-inflammatory and anticancer drugs [159 170]

The AhR-mediated regulation of aromatic hydrocarbonsmetabolism has been implicated in a variety of cancers [164171] affecting different stages of carcinogenesis If metabolicactivation of the organic molecules increased the levels oftheir adducts with DNA thus promoting cancer initiationanticancer drug- or toxin-induced AhR activation playeda pivotal role in cancer promotion and progression [172173] Elevated AhR expression associated with constitutivenonligand activation has been found in several cancers asevidenced by the nuclear localisation of AhR and induceddownstream gene Cyp1A1 [174 175] Stable knockdown ofAhR decreased the tumorigenic and metastatic properties ofbreast cancer cell line in vitro and in vivo On the other handAhR overexpression in nontumour humanmammary epithe-lial cells transformed them in cells withmalignant phenotype[176] Of importance AhR knockdown downregulated theexpression of ABCC3 overexpression of this gene in breastcancer has been strongly associated with acquired MDR[177] and resistance to paclitaxel a drug widely used in thetreatment of metastatic breast cancer [178] Inherited poly-morphisms inAhR for example substitutionArg554Lys andits machinery [179 180] or presence of endogenous ligands-stimulators for the receptor (cAMP bilirubin prostaglandinsoxidative lipids etc) could be implicated into inheritedMDR

To suppress AhR transcription pharmacologically severalapproaches have been proposed including the modulationof protein-protein interaction between transcription factorcoactivators and corepressors [160 167 181] A number ofdietary polyphenols with redox properties (resveratrol quer-cetin curcumin etc) indoles tryptophane metabolitesbilirubin and oxidised products of lipid metabolism havebeen suggested as nontoxic ligands-activators or ligands-inhibitors of AhR expression by competitive and noncom-petitive pathways [181 182] If ligands-activators of AhR areregarded as potential anti-inflammatory agents [181ndash184]redox-active ligands able to suppress AhR expressionfunctions could be candidates for MDR reversals Forexample 7-ketocholesterol a major dietary oxysterol mayactually strongly inhibit AhR activation [185] Alpha-naphthoflavone is considered as a classical AhR antagonistblocking activation of XRE-containing reporter gene andCyp1 upregulation in hepatoma cells [186] However alpha-naphthoflavone is also a partial agonist of AhR and acts as acompetitive inhibitor exclusively in the presence of anotheragonist Recently more selective pure ligands-antagonists ofAhR have been developed such as 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide 31015840-methoxy-41015840-nitroflavone 3101584041015840-dimethoxyflavone and 62101584041015840-trimethoxyflavoneThese were able to block the inductionof Cyp1A1-dependent ethoxyresorufin O-deethylase (EROD)activity [187ndash190] They all belong to redox-active flavonesand after proper clinical studies on safety and efficacy couldbe feasible for combinatory anticancer therapy to combatMDR Among a number of plant polyphenols used for topicalapplication exclusively the phenylpropanoid verbascosideand flavonoid quercetin proved to be strong inhibitors of

UV- or FICZ-upregulated AhR-Cyp1A1-Cyp1B1 axis inhuman keratinocytes [184] suggesting their potency astopical MDR suppressorsreversals

4 Conclusions

The multiple pleiotropic interactions of redox-activemolecules so far demonstrated on the molecular pathwayscontrolling cellular MDR from xenobiotic cellular uptakeinhibition to the modulation of phase III enzymedetoxification to the inhibition of Toll-like receptoractivation andor AhR expression and function provide aconsistent rationale for the necessity of more intense andsystematic research efforts in the field of anti-prooxidantadjuvants for anticancer chemotherapy to attempt clinicallyeffective MDR inhibition with tolerable toxicity

The design and implementation of more selected andtargeted clinical studies centred on redox-active candidateMDR-interfering molecules will possibly contribute to over-coming the presently dominating clinical practice whichconfers a constantly growing interest in redox modulatorsand antioxidants as a mere palliative against the potentcytotoxicity of conventional and biologic anticancer drugs

Abbreviations

ABC ATP-binding cassetteAhR Aryl hydrocarbon receptorAkt Protein kinase BAP-1 Activator protein 1ARE Antioxidant response elementBcl2 Apoptosis regulator Bcl-2BCRP Breast cancer resistance proteinCAT CatalaseCOMT Catechol-O-methyl transferaseCYP Cytochrome P450EM Extensive MetabolisersFLIP FADD-like IL-1beta-converting enzyme

inhibitory proteinGPx Glutathione peroxidaseGSHGSSG Reduced glutathioneoxidised glutathioneGST Glutathione-S-transferaseJNK1 c-Jun N-terminal kinase 1Keap 1 Kelch-like ECH-associated protein 1MDR Multiple drug resistanceMMP Matrix metalloproteinasemTOR Mammalian target of rapamycinMXR Multiple xenobiotic resistanceNADPH Nicotinamide dinucleotide phosphate

reduced formNAT N-Acetyl transferaseNF-120581B Nuclear factor kappa BNQO1 NAD(P)H quinone oxidoreductase 1NOX NADPH-oxidaseNrf12 Nuclear factor E2-related factor 12P-gp P-glycoproteinPPI3K Phosphoinositol-3-kinasePKC Protein kinase CPM Poor Metabolisers


Prx PeroxiredoxinsRNS Reactive nitrogen speciesROS Reactive oxygen speciesSNP Single nuclear polymorphismSOD Superoxide dismutaseSTAT3 Signal transducer and activator of

transcription 3SULT1A1A3 Sulfotransferases A1A3TNF120572 Tumour necrosis factor alphaTLR Toll-like receptorTrx ThioredoxinTrxR Thioredoxin reductaseUGT UDP-glucuronosyltransferaseUM Ultrarapid MetabolisersXRE Xenobiotic responsive elements

Conflict of Interests

The authors declare that they have no conflict of interests

References

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[2] S Shukla S Ohnuma and S V Ambudkar ldquoImproving cancerchemotherapy with modulators of ABC drug transportersrdquoCurrent Drug Targets vol 12 no 5 pp 621ndash630 2011

[3] WWMa andA A Adjei ldquoNovel agents on the horizon for can-cer therapyrdquo CA A Cancer Journal for Clinicians vol 59 no 2pp 111ndash137 2009

[4] T Nakanishi and D D Ross ldquoBreast cancer resistance protein(BCRPABCG2) its role inmultidrug resistance and regulationof its gene expressionrdquo Chinese Journal of Cancer vol 31 no 2pp 73ndash99 2012

[5] J V Goldstone A Hamdoun B J Cole et al ldquoThe chemicaldefensome environmental sensing and response genes in theStrongylocentrotus purpuratus genomerdquo Developmental Biol-ogy vol 300 no 1 pp 366ndash384 2006

[6] L Korkina M G Scordo I Deeva E Cesareo and C DeLuca ldquoThe chemical defensive system in the pathobiology ofidiopathic environmentmdashassociated diseasesrdquo Current DrugMetabolism vol 10 no 8 pp 914ndash931 2009

[7] S V Ambudkar S Dey C AHrycynaM Ramachandra I Pas-tan andMM Gottesman ldquoBiochemical cellular and pharma-cological aspects of the multidrug transporterrdquo Annual Reviewof Pharmacology and Toxicology vol 39 pp 361ndash398 1999

[8] S P C Cole and R G Deeley ldquoMultidrug resistance mediatedby the ATP-binding cassette transporter protein MRPrdquo BioEs-says vol 20 no 11 pp 931ndash940 1998

[9] B Sarkadi C Ozvegy-Laczka K Nemet and A VaradildquoABCG2mdasha transporter for all seasonsrdquo FEBS Letters vol 567no 1 pp 116ndash120 2004

[10] M S Denison and S R Nagy ldquoActivation of the aryl hydrocar-bon receptor by structurally diverse exogenous and endogenouschemicalsrdquoAnnual Review of Pharmacology and Toxicology vol43 pp 309ndash334 2003

[11] P Pavek and Z Dvorak ldquoXenobiotic-induced transcrip-tional regulation of xenobiotic metabolizing enzymes of the

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[12] D Kluth A Banning I Paur R Blomhoff and R Brigelius-Flohe ldquoModulation of pregnane X receptor- and electrophileresponsive element-mediated gene expression by dietarypolyphenolic compoundsrdquo Free Radical Biology and Medicinevol 42 no 3 pp 315ndash325 2007

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[14] C D Klaassen and A L Slitt ldquoRegulation of hepatic trans-porters by xenobiotic receptorsrdquo Current Drug Metabolism vol6 no 4 pp 309ndash328 2005

[15] T Nguyen P J Sherratt and C B Pickett ldquoRegulatory mecha-nisms controlling gene expression mediated by the antioxidantresponse elementrdquo Annual Review of Pharmacology and Toxi-cology vol 43 pp 233ndash260 2003

[16] A K Jaiswal ldquoNrf2 signaling in coordinated activation ofantioxidant gene expressionrdquoFree Radical Biology andMedicinevol 36 no 10 pp 1199ndash1207 2004

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[21] A Ayala M F Munoz and S Arguelles ldquoLipid peroxidationproduction metabolism and signaling mechanisms of malon-dialdehyde and 4-hydroxy-2-nonenalrdquo Oxidative Medicine andCellular Longevity vol 2014 Article ID 360438 31 pages 2014

[22] CM CabelloW B Bair III andG TWondrak ldquoExperimentaltherapeutics targeting the redox Achilles heel of cancerrdquo Cur-rent Opinion in Investigational Drugs vol 8 no 12 pp 1022ndash1037 2007

[23] G TWondrak ldquoRedox-directed cancer therapeuticsmolecularmechanisms and opportunitiesrdquo Antioxidants and Redox Sig-naling vol 11 no 12 pp 3013ndash3069 2009

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[26] A Cort and T Ozben ldquoNatural product modulators to over-comemultidrug resistance in cancerrdquoNutrition and Cancer vol67 no 3 pp 411ndash423 2015

[27] PAnandA BKunnumakkara RANewman andB BAggar-wal ldquoBioavailability of curcumin problems and promisesrdquoMolecular Pharmaceutics vol 4 no 6 pp 807ndash818 2007

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[29] R Cermak ldquoEffect of dietary flavonoids on pathways involvedin drug metabolismrdquo Expert Opinion on Drug Metabolism andToxicology vol 4 no 1 pp 17ndash35 2008

[30] S Muranaka H Fujita T Fujiwara et al ldquoMechanism andcharacteristics of stimuli-dependent ROS generation in undif-ferentiated HL-60 cellsrdquo Antioxidants and Redox Signaling vol7 no 9-10 pp 1367ndash1376 2005

[31] J Axelrod and R Tomchick ldquoEnzymatic O-methylation ofepinephrine and other catecholsrdquo The Journal of BiologicalChemistry vol 233 no 3 pp 702ndash705 1958

[32] R S Rapaka andPMCoates ldquoDietary supplements and relatedproducts a brief summaryrdquo Life Sciences vol 78 no 18 pp2026ndash2032 2006

[33] D Pal and A K Mitra ldquoMDR- and CYP3A4-mediated drug-herbal interactionsrdquo Life Sciences vol 78 no 18 pp 2131ndash21452006

[34] D Li A Abudula M Abulahake A-P Zhu Y-Q Lou andG-L Zhang ldquoInfluence of CYP3A5 and MDR1 genetic poly-morphisms on urinary 6120573-hydroxycortisolcortisol ratio aftergrapefruit juice intake in healthy Chineserdquo Journal of ClinicalPharmacology vol 50 no 7 pp 775ndash784 2010

[35] V J Victorino L Pizzatti P Michelletti and C Panis ldquoOxida-tive stress redox signaling and cancer chemoresistance puttingtogether the pieces of the puzzlerdquo Current Medicinal Chemistryvol 21 no 28 pp 3211ndash3226 2014

[36] L E Tebay H Robertson S T Durant et al ldquoMechanisms ofactivation of the transcription factor Nrf2 by redox stressorsnutrient cues and energy status and the pathways throughwhich it attenuates degenerative diseaserdquo Free Radical Biologyamp Medicine vol 88 pp 108ndash146 2015

[37] K Aoyama and T Nakaki ldquoGlutathione in cellular redoxhomeostasis association with the excitatory amino acid carrier1 (EAAC1)rdquoMolecules vol 20 no 5 pp 8742ndash8758 2015

[38] H F Gilbert ldquoThioldisulfide exchange equilibria and disulfidebond stabilityrdquoMethods in Enzymology vol 251 pp 8ndash28 1995

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[40] A Perkins L B Poole and P A Karplus ldquoTuning of perox-iredoxin catalysis for various physiological rolesrdquo Biochemistryvol 53 no 49 pp 7693ndash7705 2014

[41] Y Hirotsu F Katsuoka R Funayama et al ldquoNrf2-MafGheterodimers contribute globally to antioxidant and metabolicnetworksrdquo Nucleic Acids Research vol 40 no 20 pp 10228ndash10239 2012

[42] D T Lincoln E M Ali Emadi K F Tonissen and F M ClarkeldquoThe thioredoxin-thioredoxin reductase system over-expres-sion in human cancerrdquo Anticancer Research vol 23 no 3 pp2425ndash2433 2003

[43] S J Kim Y Miyoshi T Taguchi et al ldquoHigh thioredoxinexpression is associated with resistance to docetaxel in primarybreast cancerrdquoClinical Cancer Research vol 11 no 23 pp 8425ndash8430 2005

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

[45] B Zhang C Xie J Zhong H Chen H Zhang and X WangldquoA549 cell proliferation inhibited by RNAi mediated silencingof the Nrf2 generdquo Bio-Medical Materials and Engineering vol24 no 6 pp 3905ndash3916 2014

[46] P V Raninga G Di Trapani S Vuckovic M Bhatia and KF Tonissen ldquoInhibition of thioredoxin 1 leads to apoptosis indrug-resistant multiple myelomardquo Oncotarget vol 6 no 17 pp15410ndash15424 2015

[47] Y Tan L Bi P Zhang et al ldquoThioredoxin-1 inhibitor PX-12 induces human acute myeloid leukemia cell apoptosis andenhances the sensitivity of cells to arsenic trioxiderdquo Interna-tional Journal of Clinical and Experimental Pathology vol 7 no8 pp 4765ndash4773 2014

[48] F Wang F Lin P Zhang et al ldquoThioredoxin-1 inhibitor1-methylpropyl 2-imidazolyl disulfide inhibits the growthmigration and invasion of colorectal cancer cell linesrdquoOncologyReports vol 33 no 2 pp 967ndash973 2015

[49] B R YouH R Shin andWH Park ldquoPX-12 inhibits the growthof A549 lung cancer cells via G2M phase arrest and ROS-dependent apoptosisrdquo International Journal of Oncology vol 44no 1 pp 301ndash308 2014

[50] J-J Liu Q Liu H-L Wei J Yi H-S Zhao and L-P GaoldquoInhibition of thioredoxin reductase by auranofin inducesapoptosis in adriamycin-resistant humanK562 chronicmyeloidleukemia cellsrdquoDie Pharmazie vol 66 no 6 pp 440ndash444 2011

[51] W Fiskus N Saba M Shen et al ldquoAuranofin induces lethaloxidative and endoplasmic reticulum stress and exerts potentpreclinical activity against chronic lymphocytic leukemiardquoCan-cer Research vol 74 no 9 pp 2520ndash2532 2014

[52] N Park and Y-J Chun ldquoAuranofin promotes mitochondrialapoptosis by inducing annexin A5 expression and translocationin human prostate cancer cellsrdquo Journal of Toxicology andEnvironmental HealthmdashPart A Current Issues vol 77 no 22ndash24 pp 1467ndash1476 2014

[53] N-H Kim H J Park M-K Oh and I-S Kim ldquoAntiprolifera-tive effect of gold(I) compound auranofin through inhibition ofSTAT3 and telomerase activity in MDA-MB 231 human breastcancer cellsrdquo BMB Reports vol 46 no 1 pp 59ndash64 2013

[54] R Kannappan V R Yadav and B B Aggarwal ldquo120574-tocotrienolbut not 120574-tocopherol blocks STAT3 cell signaling pathwaythrough induction of protein-tyrosine phosphatase SHP-1 andsensitizes tumor cells to chemotherapeutic agentsrdquoThe Journalof Biological Chemistry vol 285 no 43 pp 33520ndash33528 2010

[55] M F McCarty J Barroso-Aranda and F Contreras ldquoA two-phase strategy for treatment of oxidant-dependent cancersrdquoMedical Hypotheses vol 69 no 3 pp 489ndash496 2007

[56] J Wang W Guo H Zhou et al ldquoMitochondrial p53 phospho-rylation induces Bak-mediated and caspase-independent celldeathrdquo Oncotarget vol 6 no 19 pp 17192ndash17205 2015

[57] L M Shelton B K Park and I M Copple ldquoRole of Nrf2 inprotection against acute kidney injuryrdquo Kidney Internationalvol 84 no 6 pp 1090ndash1095 2013

[58] C-PWu SOhnuma and SVAmbudkar ldquoDiscovering naturalproductmodulators to overcomemultidrug resistance in cancerchemotherapyrdquo Current Pharmaceutical Biotechnology vol 12no 4 pp 609ndash620 2011

[59] V Stepanic AGasparovic K Troselj DAmic andN ZarkovicldquoSelected attributes of polyphenols in targeting oxidative stressin cancerrdquo Current Topics in Medicinal Chemistry vol 15 no 5pp 496ndash509 2015

[60] S Y Shin H Jung S Ahn et al ldquoPolyphenols bearing cin-namaldehyde scaffold showing cell growth inhibitory effects onthe cisplatin-resistant A2780Cis ovarian cancer cellsrdquo Bioor-ganic ampMedicinal Chemistry vol 22 no 6 pp 1809ndash1820 2014

[61] I Akan S Akan H Akca B Savas and T Ozben ldquoMultidrugresistance-associated protein 1 (MRP1) mediated vincristine


resistance effects of N-acetylcysteine and Buthionine sulfox-iminerdquo Cancer Cell International vol 5 no 1 article 22 2005

[62] I Akan S Akan H Akca B Savas and T Ozben ldquoN-acetyl-cysteine enhances multidrug resistance-associated protein 1mediated doxorubicin resistancerdquo European Journal of ClinicalInvestigation vol 34 no 10 pp 683ndash689 2004

[63] M Yildiz C Celik-Ozenci S Akan et al ldquoZoledronic acid issynergic with vinblastine to induce apoptosis in a multidrugresistance protein-1 dependent way an in vitro studyrdquo CellBiology International vol 30 no 3 pp 278ndash282 2006

[64] M Benlloch A Ortega P Ferrer et al ldquoAcceleration of glu-tathione efflux and inhibition of 120574- glutamyltranspeptidase sen-sitize metastatic B16 melanoma cells to endothelium-inducedcytotoxicityrdquoThe Journal of Biological Chemistry vol 280 no 8pp 6950ndash6959 2005

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

[66] K Itoh T Chiba S Takahashi et al ldquoAn Nrf2small Mafheterodimer mediates the induction of phase II detoxifyingenzyme genes through antioxidant response elementsrdquo Bio-chemical and Biophysical Research Communications vol 236no 2 pp 313ndash322 1997

[67] P Krishnamurthy and J D Schuetz ldquoRole of ABCG2BCRPin biology and medicinerdquo Annual Review of Pharmacology andToxicology vol 46 pp 381ndash410 2006

[68] K Noguchi K Katayama and Y Sugimoto ldquoHuman ABCtransporter ABCG2BCRP expression in chemoresistancebasic and clinical perspectives for molecular cancer therapeu-ticsrdquo Pharmacogenomics and Personalized Medicine vol 7 no1 pp 53ndash64 2014

[69] C Jacob V Jamier and L A Ba ldquoRedox active secondarymetabolitesrdquo Current Opinion in Chemical Biology vol 15 no1 pp 149ndash155 2011

[70] F Q Schafer and G R Buettner ldquoRedox environment of thecell as viewed through the redox state of the glutathione disul-fideglutathione couplerdquo Free Radical Biology andMedicine vol30 no 11 pp 1191ndash1212 2001

[71] A G Blazquez O Briz E Gonzalez-Sanchez M J Perez C IGhanem and J J GMarin ldquoThe effect of acetaminophen on theexpression of BCRP in trophoblast cells impairs the placentalbarrier to bile acids duringmaternal cholestasisrdquoToxicology andApplied Pharmacology vol 277 no 1 pp 77ndash85 2014

[72] S V Iverson S Eriksson J Xu et al ldquoA Txnrd1-dependentmetabolic switch alters hepatic lipogenesis glycogen storageand detoxificationrdquo Free Radical Biology and Medicine vol 63pp 369ndash380 2013

[73] T W Young F C Mei G Yang J A Thompson-Lanza JLiu and X Cheng ldquoActivation of antioxidant pathways in ras-mediated oncogenic transformation of human surface ovarianepithelial cells revealed by functional proteomics and massspectrometryrdquo Cancer Research vol 64 no 13 pp 4577ndash45842004

[74] D-Y Lee and G-D Chang ldquoMethylglyoxal in cells elicits anegative feedback loop entailing transglutaminase 2 and glyox-alase 1rdquo Redox Biology vol 2 no 1 pp 196ndash205 2014

[75] P Agostinis K Berg KA Cengel et al ldquoPhotodynamic therapyof cancer an updaterdquo CA A Cancer Journal for Clinicians vol61 no 4 pp 250ndash281 2011

[76] B Krammer and T Verwanger ldquoMolecular response to hyper-icin-induced photodamagerdquo Current Medicinal Chemistry vol19 no 6 pp 793ndash798 2012

[77] L Mikesova J Mikes J Kovalrsquo et al ldquoConjunction of glu-tathione level NAD(P)HFAD redox status and hypericin con-tent as a potential factor affecting colon cancer cell resistanceto photodynamic therapy with hypericinrdquo Photodiagnosis andPhotodynamic Therapy vol 10 no 4 pp 470ndash483 2013

[78] J-H Kim C Chen and A-N Tony Kong ldquoResveratrol inhibitsgenistein-induced multi-drug resistance protein 2 (MRP2)expression in HepG2 cellsrdquo Archives of Biochemistry and Bio-physics vol 512 no 2 pp 160ndash166 2011

[79] M A Valentovic J G Ball J M Brown et al ldquoResveratrolattenuates cisplatin renal cortical cytotoxicity by modifyingoxidative stressrdquo Toxicology in Vitro vol 28 no 2 pp 248ndash2572014

[80] D-J Tai W-S Jin C-S Wu et al ldquoChanges in intracellularredox status influence multidrug resistance in gastric adeno-carcinoma cellsrdquo Experimental and Therapeutic Medicine vol4 no 2 pp 291ndash296 2012

[81] A Manna A K Bauri S Chattopadhyay and M ChatterjeeldquoGeneration of redox imbalance mediates the cytotoxic effect ofMalabaricone-A in a multidrug resistant cell linerdquo Anti-CancerAgents inMedicinal Chemistry vol 15 no 9 pp 1156ndash1163 2015

[82] K Bedard and K-H Krause ldquoThe NOX family of ROS-generatingNADPHoxidases physiology and pathophysiologyrdquoPhysiological Reviews vol 87 no 1 pp 245ndash313 2007

[83] K A Graham M Kulawiec K M Owens et al ldquoNADPHoxidase 4 is an oncoprotein localized to mitochondriardquo CancerBiology ampTherapy vol 10 no 3 pp 223ndash231 2010

[84] R Wang W-M Dashwood H Nian et al ldquoNADPH oxidaseoverexpression in human colon cancers and rat colon tumorsinduced by 2-amino-1-methyl-6-phenylimidazo[45-b]pyridine(PhIP)rdquo International Journal of Cancer vol 128 no 11 pp2581ndash2590 2011

[85] B M Barth S Stewart-Smeets and T B Kuhn ldquoProinflamma-tory cytokines provoke oxidative damage to actin in neuronalcells mediated by Rac1 and NADPH oxidaserdquo Molecular andCellular Neuroscience vol 41 no 2 pp 274ndash285 2009

[86] B M Barth S J Gustafson M M Young et al ldquoInhibitionof NADPH oxidase by glucosylceramide confers chemoresis-tancerdquo Cancer Biology amp Therapy vol 10 no 11 pp 1126ndash11362010

[87] J Su Y Xu L Zhou et al ldquoSuppression of chloride chan-nel 3 expression facilitates sensitivity of human glioma U251cells to cisplatin through concomitant inhibition of Akt andautophagyrdquo Anatomical Record vol 296 no 4 pp 595ndash6032013

[88] M C E McFadyen W T Melvin and G I Murray ldquoCyto-chrome P450 enzymes novel options for cancer therapeuticsrdquoMolecular Cancer Therapeutics vol 3 no 3 pp 363ndash371 2004

[89] T Oyama N Kagawa N Kunugita et al ldquoExpression ofcytochrome P450 in tumor tissues and its association withcancer developmentrdquo Frontiers in Bioscience vol 9 pp 1967ndash1976 2004

[90] D W Nebert and D W Russell ldquoClinical importance of thecytochromes P450rdquoTheLancet vol 360 no 9340 pp 1155ndash11622002

[91] X Ding and L S Kaminsky ldquoHuman extrahepatic cytochromesP450 function in xenobiotic metabolism and tissue-selectivechemical toxicity in the respiratory and gastrointestinal tractsrdquo


Annual Review of Pharmacology andToxicology vol 43 pp 149ndash173 2003

[92] DMolina-Ortiz R Camacho-Carranza J F Gonzalez-Zamoraet al ldquoDifferential expression of cytochrome P450 enzymesin normal and tumor tissues from childhood rhabdomyosar-comardquo PLoS ONE vol 9 no 4 Article ID e93261 2014

[93] K M Marks E S Park A Arefolov et al ldquoThe selectivity ofaustocystin D arises from cell-line-specific drug activation bycytochrome P450 enzymesrdquo Journal of Natural Products vol 74no 4 pp 567ndash573 2011

[94] D J Taxman J PMacKeigan C Clements D T Bergstralh andJ P-Y Ting ldquoTranscriptional profiling of targets for combina-tion therapy of lung carcinoma with paclitaxel and mitogen-activated proteinextracellular signal-regulated kinase kinaseinhibitorrdquo Cancer Research vol 63 no 16 pp 5095ndash5104 2003

[95] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010

[96] L M Coussens and Z Werb ldquoInflammation and cancerrdquoNature vol 420 no 6917 pp 860ndash867 2002

[97] M E Tome J B Frye D L Coyle et al ldquoLymphoma cellswith increased anti-oxidant defenses acquire chemoresistancerdquoExperimental and Therapeutic Medicine vol 3 no 5 pp 845ndash852 2012

[98] Z Zhu Z Shen and C Xu ldquoInflammatory pathways aspromising targets to increase chemotherapy response in bladdercancerrdquoMediators of Inflammation vol 2012 Article ID 52869011 pages 2012

[99] S Deaglio K M Dwyer W Gao et al ldquoAdenosine generationcatalyzed by CD39 and CD73 expressed on regulatory T cellsmediates immune suppressionrdquo The Journal of ExperimentalMedicine vol 204 no 6 pp 1257ndash1265 2007

[100] A Clayton S Al-Taei J Webber M D Mason and Z TabildquoCancer exosomes express CD39 and CD73 which suppress Tcells through adenosine productionrdquo Journal of Immunologyvol 187 no 2 pp 676ndash683 2011

[101] A Rimessi E Zecchini R Siviero et al ldquoThe selectiveinhibition of nuclear PKCzeta restores the effectiveness ofchemotherapeutic agents in chemoresistant cellsrdquo Cell Cyclevol 11 no 5 pp 1040ndash1048 2012

[102] F Balkwill K A Charles and A Mantovani ldquoSmoldering andpolarized inflammation in the initiation and promotion ofmalignant diseaserdquo Cancer Cell vol 7 no 3 pp 211ndash217 2005

[103] S Delhalle V Deregowski V Benoit M-P Merville and VBours ldquoNF-120581B-dependent MnSOD expression protects adeno-carcinoma cells fromTNF-120572-induced apoptosisrdquoOncogene vol21 no 24 pp 3917ndash3924 2002

[104] J C Cusack R Liu and A S Baldwin ldquoNF- kappa B andchemoresistance potentiation of cancer drugs via inhibition ofNF- kappa BrdquoDrug ResistanceUpdates vol 2 no 4 pp 271ndash2731999

[105] S Cunı P Perez-Aciego G Perez-Chacon et al ldquoA sustainedactivation of PI3KNF-120581B pathway is critical for the survival ofchronic lymphocytic leukemia B cellsrdquo Leukemia vol 18 no 8pp 1391ndash1400 2004

[106] K Schulze-OsthoffM K A BauerM Vogt and SWesselborgldquoOxidative stress and signal transductionrdquo International Journalfor Vitamin and Nutrition Research vol 67 no 5 pp 336ndash3421997

[107] K A Manu M K Shanmugam L Ramachandran et alldquoIsorhamnetin augments the anti-tumor effect of capeciatbinethrough the negative regulation of NF-120581B signaling cascade ingastric cancerrdquo Cancer Letters vol 363 no 1 pp 28ndash36 2015

[108] M Singh K Bhui R Singh and Y Shukla ldquoTea polyphenolsenhance cisplatin chemosensitivity in cervical cancer cells viainduction of apoptosisrdquo Life Sciences vol 93 no 1 pp 7ndash162013

[109] S J Talbott S Luanpitpong C Stehlik et al ldquoS-nitrosylation ofFLICE inhibitory protein determines its interaction with RIP1and activation of NF-120581Brdquo Cell Cycle vol 13 no 12 pp 1948ndash1957 2014

[110] X Zhou Z Zhang X YangW Chen and P Zhang ldquoInhibitionof cyclin D1 expression by cyclin D1 shRNAs in human oralsquamous cell carcinoma cells is associated with increasedcisplatin chemosensitivityrdquo International Journal of Cancer vol124 no 2 pp 483ndash489 2009

[111] K Husain R A Francois T Yamauchi M Perez S M SebtiandM PMalafa ldquoVitaminE120575-tocotrienol augments the antitu-mor activity of gemcitabine and suppresses constitutive NF-120581Bactivation in pancreatic cancerrdquoMolecular CancerTherapeuticsvol 10 no 12 pp 2363ndash2372 2011

[112] B B Aggarwal A Kumar and A C Bharti ldquoAnticancer poten-tial of curcumin preclinical and clinical studiesrdquo AnticancerResearch vol 23 no 1 pp 363ndash398 2003

[113] Y Hu S Wang X Wu et al ldquoChinese herbal medicine-derivedcompounds for cancer therapy a focus on hepatocellular carci-nomardquo Journal of Ethnopharmacology vol 149 no 3 pp 601ndash612 2013

[114] Y Kwon ldquoCurcumin as a cancer chemotherapy sensitizingagentrdquo Journal of the Korean Society for Applied BiologicalChemistry vol 57 no 2 pp 273ndash280 2014

[115] B B Aggarwal I D Bhatt H Ichikawa et al ldquoCurcumin-biological and medicinal propertiesrdquo in Turmeric the GenusCurcuma P N Ravindran K N Babu and K Sivaraman Edspp 297ndash368 CRC Press New York NY USA 2007

[116] X Xue J-L Yu D-Q Sun et al ldquoCurcumin as a multidrugresistance modulatormdasha quick reviewrdquo Biomedicine amp Preven-tive Nutrition vol 3 no 2 pp 173ndash176 2013

[117] C-L Lin R-F Chen J Y-F Chen et al ldquoProtective effect ofcaffeic acid on paclitaxel induced anti-proliferation and apop-tosis of lung cancer cells involves NF-120581b pathwayrdquo InternationalJournal of Molecular Sciences vol 13 no 5 pp 6236ndash6245 2012

[118] S J Klempner A P Myers and L C Cantley ldquoWhat a tangledwebweweave emerging resistancemechanisms to inhibition ofthe phosphoinositide 3-kinase pathwayrdquo Cancer Discovery vol3 no 12 pp 1345ndash1354 2013

[119] A Bellacosa C C Kumar A D Cristofano and J R TestaldquoActivation of AKT kinases in cancer implications for thera-peutic targetingrdquoAdvances in Cancer Research vol 94 no 1 pp29ndash86 2005

[120] T A Yap L Bjerke P A Clarke and P Workman ldquoDruggingPI3K in cancer refining targets and therapeutic strategiesrdquoCurrent Opinion in Pharmacology vol 23 pp 98ndash107 2015

[121] Z Yu G Xie G Zhou et al ldquoNVP-BEZ235 a novel dualPI3K-mTOR inhibitor displays anti-glioma activity and reduceschemoresistance to temozolomide in human glioma cellsrdquoCancer Letters vol 367 no 1 pp 58ndash68 2015

[122] T Laragione V Bonetto F Casoni et al ldquoRedox regulationof surface protein thiols identification of integrin alpha-4 as amolecular target by using redox proteomicsrdquo Proceedings of the


National Academy of Sciences of the United States of Americavol 100 no 25 pp 14737ndash14741 2003

[123] A Layani-Bazar I Skornick A Berrebi et al ldquoRedox mod-ulation of adjacent thiols in vla-4 by as101 converts myeloidleukemia cells from a drug-resistant to drug-sensitive staterdquoCancer Research vol 74 no 11 pp 3092ndash3103 2014

[124] A-M Gao Z-P Ke J-N Wang J-Y Yang S-Y Chen and HChen ldquoApigenin sensitizes doxorubicin-resistant hepatocellularcarcinoma BEL-7402ADM cells to doxorubicin via inhibitingPI3KAktNrf2 pathwayrdquo Carcinogenesis vol 34 no 8 pp1806ndash1814 2013

[125] C De Luca Z Kharaeva and L Korkina ldquoIs there a role forantioxidants in the prevention of infection-associated carcino-genesis and in the treatment of infection-driven tumoursrdquoCurrent Topics in Medicinal Chemistry vol 15 no 2 pp 120ndash135 2015

[126] M G Kelly A B Alvero R Chen et al ldquoTLR-4 signaling pro-motes tumor growth and paclitaxel chemoresistance in ovariancancerrdquo Cancer Research vol 66 no 7 pp 3859ndash3868 2006

[127] S Rajput L D Volk-Draper and S Ran ldquoTLR4 is a noveldeterminant of the response to paclitaxel in breast cancerrdquoMolecular Cancer Therapeutics vol 12 no 8 pp 1676ndash16872013

[128] S Ioannou and M Voulgarelis ldquoToll-like receptors tissueinjury and tumourigenesisrdquo Mediators of Inflammation vol2010 Article ID 581837 9 pages 2010

[129] B Huang J Zhao S Shen et al ldquoListeria monocytogenespromotes tumor growth via tumor cell toll-like receptor 2signalingrdquo Cancer Research vol 67 no 9 pp 4346ndash4352 2007

[130] T Grimmig N Matthes K Hoeland et al ldquoTLR7 and TLR8expression increases tumor cell proliferation and promoteschemoresistance in human pancreatic cancerrdquo InternationalJournal of Oncology vol 47 no 3 pp 857ndash866 2015

[131] M Muccioli L Sprague H Nandigam M Pate and F Benen-cia ldquoToll-like receptors as novel therapeutic targets for ovariancancerrdquo ISRN Oncology vol 2012 Article ID 642141 8 pages2012

[132] D Kim H C Dan S Park et al ldquoAKTPKB signaling mech-anisms in cancer and chemoresistancerdquo Frontiers in Biosciencevol 10 pp 975ndash987 2005

[133] E Tiligada ldquoChemotherapy induction of stress responsesrdquoEndocrine-Related Cancer vol 13 supplement 1 pp S115ndashS1242006

[134] D Kultz ldquoMolecular and evolutionary basis of the cellular stressresponserdquo Annual Review of Physiology vol 67 pp 225ndash2572005

[135] M Landriscina F Maddalena G Laudiero and F EspositoldquoAdaptation to oxidative stress chemoresistance and cell sur-vivalrdquo Antioxidants amp Redox Signaling vol 11 no 11 pp 2701ndash2716 2009

[136] S Singh S Vrishni B K Singh I Rahman and P KakkarldquoNrf2-ARE stress response mechanism a control point inoxidative stress-mediated dysfunctions and chronic inflamma-tory diseasesrdquo Free Radical Research vol 44 no 11 pp 1267ndash1288 2010

[137] K Shen D Cui L Sun Y Lu M Han and J Liu ldquoInhibition ofIGF-IR increases chemosensitivity in human colorectal cancercells throughMRP-2 promoter suppressionrdquo Journal of CellularBiochemistry vol 113 no 6 pp 2086ndash2097 2012

[138] K C Wu J Y Cui and C D Klaassen ldquoEffect of graded nrf2activation on phase-I and -II drug metabolizing enzymes and

transporters in mouse liverrdquo PLoS ONE vol 7 no 7 Article IDe39006 2012

[139] X-J Wang Z Sun N F Villeneuve et al ldquoNrf2 enhancesresistance of cancer cells to chemotherapeutic drugs the darkside of Nrf2rdquo Carcinogenesis vol 29 no 6 pp 1235ndash1243 2008

[140] X TangHWang L Fan et al ldquoLuteolin inhibitsNrf2 leading tonegative regulation of the Nrf2ARE pathway and sensitizationof human lung carcinoma A549 cells to therapeutic drugsrdquo FreeRadical Biology amp Medicine vol 50 no 11 pp 1599ndash1609 2011

[141] D Ren N F Villeneuve T Jiang et al ldquoBrusatol enhancesthe efficacy of chemotherapy by inhibiting the Nrf2-mediateddefense mechanismrdquo Proceedings of the National Academy ofSciences of the United States of America vol 108 no 4 pp 1433ndash1438 2011

[142] M Zhang C Zhang L Zhang et al ldquoNrf2 is a potentialprognostic marker and promotes proliferation and invasion inhuman hepatocellular carcinomardquo BMC Cancer vol 15 article531 2015

[143] Y J Lee D M Lee and S H Lee ldquoNrf2 expression andapoptosis in quercetin-treated malignant mesothelioma cellsrdquoMolecules and Cells vol 38 no 5 pp 416ndash425 2015

[144] L Zhan H Zhang Q Zhang et al ldquoRegulatory role of KEAP1andNRF2 in PPAR120574 expression and chemoresistance in humannon-small-cell lung carcinoma cellsrdquo Free Radical Biology andMedicine vol 53 no 4 pp 758ndash768 2012

[145] Y Soini M Eskelinen P Juvonen et al ldquoNuclear Nrf2 expres-sion is related to a poor survival in pancreatic adenocarcinomardquoPathology Research and Practice vol 210 no 1 pp 35ndash39 2014

[146] A J Leon-Gonzalez C Auger and V B Schini-Kerth ldquoPro-oxidant activity of polyphenols and its implication on cancerchemoprevention and chemotherapyrdquo Biochemical Pharmacol-ogy vol 98 no 3 pp 371ndash380 2015

[147] D Kandioler-Eckersberger C Ludwig M Rudas et al ldquoTP53mutation and p53 overexpression for prediction of responseto neoadjuvant treatment in breast cancer patientsrdquo ClinicalCancer Research vol 6 no 1 pp 50ndash56 2000

[148] A L Furfaro S Piras M Passalacqua et al ldquoHO-1 up-regulation a key point in high-risk neuroblastoma resistance tobortezomibrdquo Biochimica et Biophysica ActamdashMolecular Basis ofDisease vol 1842 no 4 pp 613ndash622 2014

[149] M Lee D-H Hyun K-A Marshall et al ldquoEffect of overex-pression of Bcl-2 on cellular oxidative damage nitric oxideproduction antioxidant defenses and the proteasomerdquo FreeRadical Biology andMedicine vol 31 no 12 pp 1550ndash1559 2001

[150] D M Hockenbery Z N Oltvai X-M Yin C L Milliman andS J Korsmeyer ldquoBcl-2 functions in an antioxidant pathway toprevent apoptosisrdquo Cell vol 75 no 2 pp 241ndash251 1993

[151] D W Voehringer ldquoBCL-2 and glutathione alterations in cellu-lar redox state that regulate apoptosis sensitivityrdquo Free RadicalBiology and Medicine vol 27 no 9-10 pp 945ndash950 1999

[152] S L Schendel Z Xie M O Montal S Matsuyama M Montaland J C Reed ldquoChannel formation by antiapoptotic proteinBcl-2rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 94 no 10 pp 5113ndash5118 1997

[153] J L Herrmann E Bruckheimer and T J McDonnell ldquoCelldeath signal transduction and Bcl-2 functionrdquo BiochemicalSociety Transactions vol 24 no 4 pp 1059ndash1065 1996

[154] L Chaiswing J M Bourdeau-Heller W Zhong and T DOberley ldquoCharacterization of redox state of two human prostatecarcinoma cell lines with different degrees of aggressivenessrdquoFree Radical Biology and Medicine vol 43 no 2 pp 202ndash2152007


[155] L H Lash D A Putt and A D Jankovich ldquoGlutathione levelsand susceptibility to chemically induced injury in two humanprostate cancer cell linesrdquo Molecules vol 20 no 6 pp 10399ndash10414 2015

[156] J Niestroy A Barbara K Herbst S Rode M van Liempt andP H Roos ldquoSingle and concerted effects of benzo[a]pyrene andflavonoids on the AhR and Nrf2-pathway in the human coloncarcinoma cell line Caco-2rdquo Toxicology in Vitro vol 25 no 3pp 671ndash683 2011

[157] H I Swanson ldquoCytochrome P450 expression in human ker-atinocytes an aryl hydrocarbon receptor perspectiverdquoChemico-Biological Interactions vol 149 no 2-3 pp 69ndash79 2004

[158] A Rannug and E Fritsche ldquoThe aryl hydrocarbon receptor andlightrdquo Biological Chemistry vol 387 no 9 pp 1149ndash1157 2006

[159] DWNebert A L RoeM Z DieterW A Solis Y Yang and TP Dalton ldquoRole of the aromatic hydrocarbon receptor and [Ah]gene battery in the oxidative stress response cell cycle controland apoptosisrdquo Biochemical Pharmacology vol 59 no 1 pp 65ndash85 2000

[160] L Stejskalova Z Dvorak and P Pavek ldquoEndogenous andexogenous ligands of aryl hydrocarbon receptor current stateof artrdquoCurrent DrugMetabolism vol 12 no 2 pp 198ndash212 2011

[161] E S Shen and J P Whitlock Jr ldquoProtein-DNA interactions at adioxin-responsive enhancer mutational analysis of the DNA-binding site for the liganded Ah receptorrdquo The Journal ofBiological Chemistry vol 267 no 10 pp 6815ndash6819 1992

[162] S Kalthoff U Ehmer N Freiberg M P Manns and C PStrassburg ldquoIntercation between oxidative stress sensor Nrf2and xenobiotic-activated aryl hydrocarbon receptor in theregulation of the human phase II detoxifying UDP-glucurono-syltransferase 1A10rdquo The Journal of Biological Chemistry vol285 no 9 pp 5993ndash6002 2010

[163] R L Yeager S A Reisman LMAleksunes andCD KlaassenldquoIntroducing the lsquoTCDD-inducible AhR-Nrf2 gene batteryrsquordquoToxicological Sciences vol 111 no 2 pp 238ndash246 2009

[164] H I Swanson and C A Bradfield ldquoThe AH-receptor geneticsstructure and functionrdquo Pharmacogenetics vol 3 no 5 pp 213ndash230 1993

[165] T Haarmann-Stemmann H Bothe and J Abel ldquoGrowthfactors cytokines and their receptors as downstream targets ofarylhydrocarbon receptor (AhR) signaling pathwaysrdquo Biochem-ical Pharmacology vol 77 no 4 pp 508ndash520 2009

[166] Q Ma ldquoInfluence of light on aryl hydrocarbon receptor sig-naling and consequences in drug metabolism physiology anddiseaserdquo Expert Opinion on Drug Metabolism and Toxicologyvol 7 no 10 pp 1267ndash1293 2011

[167] A Puga CMa and J LMarlowe ldquoThe aryl hydrocarbon recep-tor cross-talks with multiple signal transduction pathwaysrdquoBiochemical Pharmacology vol 77 no 4 pp 713ndash722 2009

[168] C M Klinge K Kaur and H I Swanson ldquoThe aryl hydrocar-bon receptor interacts with estrogen receptor alpha and orphanreceptors COUP-TFI and ERR1205721rdquo Archives of Biochemistry andBiophysics vol 373 no 1 pp 163ndash174 2000

[169] F Ohtake K-I Takeyama T Matsumoto et al ldquoModulationof estrogen receptor signaling by association with the activateddioxin receptorrdquo Nature vol 423 no 6939 pp 545ndash550 2003

[170] E Guyot A Chevallier R Barouki and X Coumoul ldquoTheAhR twist ligand-dependent AhR signaling and pharmaco-toxicological implicationsrdquo Drug Discovery Today vol 18 no9-10 pp 479ndash486 2013

[171] M A Callero andA I Loaiza-Perez ldquoThe role of aryl hydrocar-bon receptor and crosstalkwith estrogen receptor in response ofbreast cancer cells to the novel antitumor agents benzothiazolesand aminoflavonerdquo International Journal of Breast Cancer vol2011 Article ID 923250 9 pages 2011

[172] H Eguchi T Ikuta T Tachibana Y Yoneda and K Kawajiri ldquoAnuclear localization signal of human aryl hydrocarbon receptornuclear translocatorhypoxia-inducible factor 1120573 is a novelbipartite type recognized by the two components of nuclearpore-targeting complexrdquo The Journal of Biological Chemistryvol 272 no 28 pp 17640ndash17647 1997

[173] Y Kanno Y Miyama Y Takane T Nakahama and Y InouyeldquoIdentification of intracellular localization signals and of mech-anisms underlining the nucleocytoplasmic shuttling of humanaryl hydrocarbon receptor repressorrdquo Biochemical and Biophys-ical Research Communications vol 364 no 4 pp 1026ndash10312007

[174] P S Wong W Li C F Vogel and C F Matsumura ldquoCharac-terization of MCF mammary epithelial cells overexpressing theArylhydrocarbon receptor (AhR)rdquo BMC Cancer vol 9 article234 pp 234ndash10 2009

[175] G D Goode B R Ballard H C Manning M L Freeman YKang and S E Eltom ldquoKnockdown of aberrantly upregulatedaryl hydrocarbon receptor reduces tumor growth and metas-tasis of MDA-MB-231 human breast cancer cell linerdquo Interna-tional Journal of Cancer vol 133 no 12 pp 2769ndash2780 2013

[176] G Goode S Pratap and S E Eltom ldquoDepletion of the arylhydrocarbon receptor in MDA-MB-231 human breast cancercells altered the expression of genes in key regulatory pathwaysof cancerrdquo PLoS ONE vol 9 no 6 Article ID e100103 2014

[177] L Partanen J Staaf M Tanner V J Tuominen A Borg and JIsola ldquoAmplification and overexpression of theABCC3 (MRP3)gene in primary breast cancerrdquoGenes Chromosomes andCancervol 51 no 9 pp 832ndash840 2012

[178] C OrsquoBrien G Cavet A Pandita et al ldquoFunctional genomicsidentifies ABCC3 as a mediator of taxane resistance in HER2-amplified breast cancerrdquo Cancer Research vol 68 no 13 pp5380ndash5389 2008

[179] D Caccamo E Cesareo S Mariani et al ldquoXenobioticsensor- andmetabolism-related gene variants in environmentalsensitivity-related illnesses a survey on the Italian populationrdquoOxidative Medicine and Cellular Longevity vol 2013 Article ID831969 9 pages 2013

[180] S Helmig J U Seelinger J Dohrel and J Schneider ldquoRNAexpressions of AHR ARNT andCYP1B1 are influenced byAHRArg554Lys polymorphismrdquoMolecularGenetics andMetabolismvol 104 no 1-2 pp 180ndash184 2011

[181] P B Busbee M Rouse M Nagarkatti and P S NagarkattildquoUse of natural AhR ligands as potential therapeutic modalitiesagainst inflammatory disordersrdquo Nutrition Reviews vol 71 no6 pp 353ndash369 2013

[182] V Kostyuk A Potapovich A Stancato et al ldquoPhoto-oxidationproducts of skin surface squalene mediate metabolic andinflammatory responses to solar UV in human keratinocytesrdquoPLoS ONE vol 7 no 8 Article ID e44472 2012

[183] S Pastore D Lulli P Fidanza et al ldquoPlant polyphenols regulatechemokine expression and tissue repair in human keratinocytesthrough interaction with cytoplasmic and nuclear componentsof epidermal growth factor receptor systemrdquo Antioxidants andRedox Signaling vol 16 no 4 pp 314ndash328 2012

[184] A I Potapovich D Lulli P Fidanza et al ldquoPlant polyphe-nols differentially modulate inflammatory responses of human


keratinocytes by interfering with activation of transcriptionfactors NF120581B and AhR and EGFR-ERK pathwayrdquo Toxicologyand Applied Pharmacology vol 255 no 2 pp 138ndash149 2011

[185] J-F Savoure M Antenos M Quesne J Xu E Milgrom and RF Casper ldquo7-ketocholesterol is an endogenous modulator forthe arylhydrocarbon receptorrdquo Journal of Biological Chemistryvol 276 no 5 pp 3054ndash3059 2001

[186] A Wilhelmsson M L Whitelaw J-A Gustafsson and LPoellinger ldquoAgonistic and antagonistic effects of 120572-naph-thoflavone on dioxin receptor function role of the basicregion helix-loop-helix dioxin receptor partner factor arntrdquoTheJournal of Biological Chemistry vol 269 no 29 pp 19028ndash190331994

[187] S-H Kim E C Henry D-K Kim et al ldquoNovel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2378-TCDD-inducedtoxicity by antagonizing the aryl hydrocarbon receptorrdquoMolec-ular Pharmacology vol 69 no 6 pp 1871ndash1878 2006

[188] J-E Lee and S Safe ldquo31015840 41015840-dimethoxyflavone as an arylhydrocarbon receptor antagonist in human breast cancer cellsrdquoToxicological Sciences vol 58 no 2 pp 235ndash242 2000

[189] I A Murray C A Flaveny B C DiNatale et al ldquoAntag-onism of aryl hydrocarbon receptor signaling by 62101584041015840-trimethoxyflavonerdquo Journal of Pharmacology and ExperimentalTherapeutics vol 332 no 1 pp 135ndash144 2010

[190] Y-F Lu M Santostefano B D M CunninghamM DThread-gill and S Safe ldquoIdentification of 31015840-methoxy-41015840-nitroflavone asa pure aryl hydrocarbon (Ah) receptor antagonist and evidencefor more than one form of the nuclear Ah receptor in MCF-7 human breast cancer cellsrdquo Archives of Biochemistry andBiophysics vol 316 no 1 pp 470ndash477 1995

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


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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OphthalmologyJournal of


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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


reported that MDR relies not exclusively on transportingsystems for drug uptake and efflux but also on intracellulardrug metabolism and DNA damage [4] Transporting andmetabolic systems definingMDR are expressed in the major-ity of normal cells are essential for nutrients uptake andmetabolites efflux and play a vital role in protecting cellsagainst xenobiotics Hence harsh inhibition of a functionallyessential mechanism results in general intoxication

To gain protection against foreign invasions andmaintainhomeostasis the human organism employs several types ofphysical chemical and biological defence systems For exam-ple skin and other lining epitheliamechanically prevent inva-sion of relatively large organic and inorganic particles Theimmune system has been evolved to fight cellular invadersand high-molecular-weight compounds of biological origin

The chemical defence system consisting of biosensoringtransmitting and responsive elements has been evolvedstarting from primitive eukaryotes and lower plants [5] toprotectmulticellular organisms against environmental chem-ical insults (xenobiotics) and to maintain homeostasis ofendogenous low-molecular-weightmetabolites (endobiotics)[6] Being exposed to xenobiotic (drug) stress an organism ischallenged to rapid and appropriate adaptation by activatingconstitutive and expressing inducible systems thus attenuat-ing negative biological consequences For this purpose anarray of gene families and molecular pathways have beendeveloped during evolution to prevent cellular access todetoxify and eliminate toxins and to repair chemical damageThe active efflux proteins for example P-glycoproteins (P-gp) [7] multidrug resistance (MDR) proteins [8] and multi-xenobiotic resistance (MXR) proteins [9] directly eliminateslightly lipophilic organic xenobiotics from cells serving asthe first line of chemical defence Escaping the first-lineguardians once in the cytoplasm toxic nucleophilic com-pounds undergo biotransformation by the oxidative phaseI enzymes (cytochrome P450 (CYP) flavoprotein monooxy-genase hemeoxygenase amine oxidases xanthine oxi-dase and others) to become electrophilic The electrophileis subjected to reductive or conjugative modification byphase II enzymes (glutathione-S-transferases (GSTs) UDP-glucuronosyltransferases (UGTs) catechol-O-methyl trans-ferases (COMT) N-acetyl transferases (NATs) and manyothers)

Reactive oxygen species (ROS) generated as by-productsof phase I reactions are rapidly reduced to nontoxic ldquophysi-ologicalrdquo levels by antioxidant enzymes (superoxide dismu-tases (SODs) catalase (CAT) glutathione peroxidases (GPx)peroxiredoxins (PRx) and nonenzymatic antioxidants suchas reduced glutathione (GSH) uric acid ascorbic acid andceruloplasmin among others) All these constitutive protec-tive systems are sufficient to cope with low levels of xenobi-otics or endobioticsThe inducible chemical defence relies onthe array of stress responsive genes In this case chemicalstressors like anticancer chemotherapeutics should first berecognised by specific sensors which in turn transmit alarmsignals to activate or express de novo transporting biotrans-forming and detoxifying enzymes

The primary member of mammalian proteins-sensors oforganic chemicals is the aryl hydrocarbon receptor (AhR)

activated by planar aromatic hydrocarbons of natural orsynthetic origin [10ndash12] A second group of chemical sensorscomprises nuclear receptors such as pregnane X constitutiveandrostane peroxisome proliferators-activated liver-X andfarnesoid-X receptors recognising a wide variety of xeno-and endobiotics [12ndash14] Nuclear factor erythroid-derived2-related factors (Nrf1 and Nrf2) and related caprsquonrsquocollar-(CNC-) basic leucine zipper proteins belong to anotherfamily of sensors activated by oxidants and electrophiles[15 16] Activation of such recognition elements after ligandbinding may result in alterations of ion channel conductivitykinase machinery and cytoplasmic and nuclear transcriptionfactors inducing cell response (signal transduction)

Signal transduction is oftenmediated by redox substances(superoxide anion radical hydrogen peroxide lipid perox-ides aldehydes and others) [17ndash21] At moderate concentra-tions they are signals to start gene transcription via activationof transcription factors (nuclear factor 120581B (NF-120581B) activatorprotein 1 (AP-1) and antioxidant response element- (ARE-)binding proteins) or initiating the protein kinase cascade [516 19]The latter pathway leads to the interactionwith specificARE of DNA motifs on promoters of antioxidant defenceenzymes such as GST Mn-superoxide dismutase (MnSOD)and glutamyl-cysteine ligase among others [15]

Inherited or acquired alterations at any key point of thechemical defence system might lead to chronic intoxicationand numerous human pathologies (chronic inflammationdegeneration carcinogenesis multiple chemical sensitivitysyndrome etc) in the inherited or acquired MDR respec-tively (Figure 1) Usually the course of anticancer chemo-therapy induces the overexpression of drug transportersMDRMXRP-gp [3 4] activation of sensoring receptorselectrophileoxidant sensors transcription factors and over-expressionactivation of detoxifyingantioxidant enzymes [1]Collectively it causes rapid metabolism and eliminationof both the anticancer drugs and cytotoxic by-productstargeting tumour cells Since the chemical defence system isubiquitous for all human organs and tissues and central toorganism functions the attempts for its pharmacological sup-pression in order to diminish MDR potentially bear the riskof a multitude of undesired side effects Upon the pharma-cological interaction with components of universal chemicaldefence system the ldquogood guyrdquo evolved on purpose to protectmulticellular organisms from low-molecular-weight chemi-cals could become a ldquobad guyrdquo blocking desired therapeuticaleffects of anticancer drugs (MDR)

On the grounds of our current knowledge redox regu-lation of multiple molecular pathways essential for humanchemical defence system can be implicated differentially innormal host and in tumour cells Owing to the fact that redoxbalance in tumour cells is greatly altered as compared tothat of normal host cells [22 23] selective redox inhibitorstargeting tumour-associated chemical defence as a cause ofMDR should be developed Regarding potential health effectsof redox modulators on tumours they are mainly attributedto cancer chemoprevention direct anticancer action (forcomprehensive review see [23]) cancer sensitisation to con-ventional chemotherapeutics preferentially through MDRsuppressionreversal cancer sensitisation to radio- and


P-gp



Prx)

MXRMDR

Metaboliteexcretion

XB


Prx)

ROS

ROS

(a)

Anticancer drug

AhR




PI3-K

NR

Nrf2 ARE

P-gp MDR MXR



ROS

=

(NF-120581B AP-1)

(b)



Redox

Radiotherapy



a drug)

Redox

Chemotherapy

MDR suppression

Directantitumour


toxicity

Sensitisation to

radiotherapy

Redox adjuvants

Redox

Photodynamictherapy


Cancer therapies























2O2and







GPx

LOOH

CAT

NADPHNADPH

NADPHNADPH

GSH

GSSG

LOOH

HOOH

GR

TrxR

HOOHHOOH

NADP+

NADP+

H2O

Prxred

Prxox

TrxredTrxox




























4 Conclusions



Abbreviations









References
















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















P-gp



Prx)

MXRMDR

Metaboliteexcretion

XB


Prx)

ROS

ROS

(a)

Anticancer drug

AhR




PI3-K

NR

Nrf2 ARE

P-gp MDR MXR



ROS

=

(NF-120581B AP-1)

(b)



Redox

Radiotherapy



a drug)

Redox

Chemotherapy

MDR suppression

Directantitumour


toxicity

Sensitisation to

radiotherapy

Redox adjuvants

Redox

Photodynamictherapy


Cancer therapies























2O2and







GPx

LOOH

CAT

NADPHNADPH

NADPHNADPH

GSH

GSSG

LOOH

HOOH

GR

TrxR

HOOHHOOH

NADP+

NADP+

H2O

Prxred

Prxox

TrxredTrxox




























4 Conclusions



Abbreviations









References
















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Redox

Radiotherapy



a drug)

Redox

Chemotherapy

MDR suppression

Directantitumour


toxicity

Sensitisation to

radiotherapy

Redox adjuvants

Redox

Photodynamictherapy


Cancer therapies























2O2and







GPx

LOOH

CAT

NADPHNADPH

NADPHNADPH

GSH

GSSG

LOOH

HOOH

GR

TrxR

HOOHHOOH

NADP+

NADP+

H2O

Prxred

Prxox

TrxredTrxox




























4 Conclusions



Abbreviations









References
















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























2O2and







GPx

LOOH

CAT

NADPHNADPH

NADPHNADPH

GSH

GSSG

LOOH

HOOH

GR

TrxR

HOOHHOOH

NADP+

NADP+

H2O

Prxred

Prxox

TrxredTrxox




























4 Conclusions



Abbreviations









References
















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















GPx

LOOH

CAT

NADPHNADPH

NADPHNADPH

GSH

GSSG

LOOH

HOOH

GR

TrxR

HOOHHOOH

NADP+

NADP+

H2O

Prxred

Prxox

TrxredTrxox




























4 Conclusions



Abbreviations









References
















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































4 Conclusions



Abbreviations









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
















Review Article Redox Control of Multidrug Resistance and Its...

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