review article a paradoxical chemoresistance and tumor … · 2019. 7. 31. · review article a...

Review ArticleA Paradoxical Chemoresistance and Tumor SuppressiveRole of Antioxidant in Solid Cancer Cells A Strange Case ofDr Jekyll and Mr Hyde

Jolie Kiemlian Kwee

Coordenacao de Pesquisa Instituto Nacional de Cancer Rua Andre Cavalcante 37 20231-050 Rio de Janeiro RJ Brazil

Correspondence should be addressed to Jolie Kiemlian Kwee jkweeincagovbr

Received 5 December 2013 Revised 16 March 2014 Accepted 17 March 2014 Published 3 April 2014

Academic Editor David Vauzour

Copyright copy 2014 Jolie Kiemlian KweeThis 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

Modulation of intracellular antioxidant concentration is a double-edged sword with both sides exploited for potential therapeuticbenefits While antioxidants may hamper the efficacy of chemotherapy by scavenging reactive oxygen species and free radicalsit is also possible that antioxidants alleviate unwanted chemotherapy-induced toxicity thus allowing for increased chemotherapydoses Under normoxic environment antioxidants neutralize toxic oxidants such as reactive oxygen species (ROS) maintainingthem within narrow boundaries level This redox balance is achieved by various scavenging systems such as enzymatic system(eg superoxide dismutases catalase and peroxiredoxins) nonenzymatic systems (eg glutathione cysteine and thioredoxin)and metal-binding proteins (eg ferritin metallothionein and ceruloplasmin) that sequester prooxidant metals inhibiting theirparticipation in redox reactions On the other hand therapeutic strategies that promote oxidative stress and eventually tumorcells apoptosis have been explored based on availability of chemotherapy agents that inhibit ROS-scavenging systems Thesecontradictory assertions suggest that antioxidant supplementation during chemotherapy treatment can have varied outcomesdepending on the tumor cellular context Therefore understanding the antioxidant-driven molecular pathways might be crucial todesign new therapeutic strategies to fight cancer progression

1 Introduction

Reactive oxygen and nitrogen species (ROSRNS) are oxi-dants natural products formed during cell vital metabolismactivity that orchestrate the transmission of regulatorysignals for proliferation migration defence vasorelax-ation autophagy and apoptosis signals (Figure 1(a)) [1ndash12]Progress in redox biochemistry study has revealed an oxygenadaptation whereby the cell has acquired the capabilityto initiate changes to the local redox environment as ameans of regulating signaling pathways [1ndash4 6ndash11] Thishas changed the way cellular oxidant production is viewedfrom a simplistic model where all oxidant production isinherently damaging to a more complex scenario wherea regulated small increase in oxidant production can beessential for optimal cellular function (Figure 1) [1ndash12] Inthis model ROS and RNS act as second messengers formingan integral part of the signal transduction network [1ndash49 11 12] Reactive nitrogen species are produced by the

endothelium inducing vascular relaxation when vascularsmooth muscle cells were stimulated with vasodilators suchas acetylcholine histamine and bradykinin Nitric oxidesynthase catalyzes a five-electron oxidation of a guanidinenitrogen of L-arginine in the formation of citrulline andnitric oxide [7ndash9 11 12] On the other hand ROS areheterogeneous group diatomic oxygen derived of free andnonfree radicals species with a wide range of reactivity [10ndash12] Their formation begins with the univalent reduction ofoxygen to produce superoxide radical (O

2

∙minus) a free radicalthat gives rise to many highly reactive species such ashydroperoxyl radical (HO

2

∙) hydrogen peroxide (H2O2)

and hydroxyl radical ( ∙OH) (Figure 2) [10ndash12] For examplesuperoxide can dismutate to formhydrogen peroxide (H

2O2)

a membrane-permeable mildly prooxidant molecule whichin turn can lead to formation of several highly oxidizingderivatives such as hydroxyl radicals (Figure 2) Also O

2

∙minus

can react with nitric oxide (NO∙) resulting in peroxynitrite(OONOOminus) a high RNS (Figure 2) [11 12] Mitochondria

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 209845 9 pageshttpdxdoiorg1011552014209845

2 BioMed Research International

Antioxidant

ROSRNS

Signalling Oxidative stress

Normal cells

Apoptosis Migration

Genetic instabilitymalignant transformation

ROSRNS

Tumor metastasis

DefenseProliferation

Physiologicalconditions

Pathophysiologicalconditions

(a) (b)

VasorelaxationAutophagy

Figure 1 Schematic representation of reactive oxygen andnitrogen species (ROSRNS) inductions in physiological (a) andpathophysiological(b) conditions

Antioxidant

Superoxide dismutase

Catalase glutathione (GSH)

L-arginine

ROS

RNS

NADPH NADPcitrulline

NOS

Electron transportchain (ECT)NADPH oxidaseXanthine oxidase

O2

H2O2 H2OO2

NO∙

∙OH

ONOO∙

O2∙

O2∙

Figure 2 Sources of reactive oxygen (ROS) and nitrogen (RNS) species production Enzymatic and nonenzymatic antioxidantscounterbalance it

form the major powerhouse of ROS production they aregenerated in association with the activity of the respiratorychain such as NADH dehydrogenase enzyme complexes inaerobic ATP production [13ndash15] In addition two classicphagocytic ROS-generating enzymes use molecular oxygenas a substrate including the multisubunit NADPH oxidaseand its homologue NOXDuox family and myeloperoxidasein various tissues in response to extracellular influences[16 17] Other sources of ROS production include thecytochromeP450 (CYP450) systemwhich is involvedmainly

in removing or detoxifying toxic substances in the liver[13] and xanthine oxidase which catalyzes the oxidation ofhypoxanthine to xanthine with the formation of H

2O2[18]

The imbalance of this cellular redox state is characteristic ofmany diseases where abnormal oxidant production causesextensive tissue damage (Figure 1(b)) [3 6 19] Antioxidanthas been defined as any substance that significantly delaysor prevents oxidative damage of an oxidizable substrate(Figure 2) Due to their high reactivity the ROS productionlevels are tightly controlled by antioxidants to avoid oxidative

BioMed Research International 3

Cycling hypoxia

Reoxygenation

Hypoxia

[ROS]

[ROS] [Antioxidant]

[O2]

HIF-1120572-HIF-1120573HIF-2120572

[O2]

Figure 3 Schematic representation of cycling hypoxia effects onROS production through activities modulations of HIF-1120572 andHIF-2120572

stress and eventually oxidative damage which is frequentlylinked to genetic instability tumor promotion andmetastasis(Figure 1) [20] On the other hand the primary mecha-nism of many chemotherapy drugs and ionizing radiationwidely used against cancer cells is the formation of ROS[11 21] At this point questions arise whether reduction ofoxidative stress in tumor cell environment with antioxidanttreatment would be beneficial or not [22] Moreover itshould be stressed that the antioxidants cannot distinguishbetween the radicals that play a beneficial role and those thatcause carcinogenesis Understanding the biological redoxsystem for the development of more effective and less toxicchemotherapy ROS induction strategies for cancer cells isdeserved [21 22] Therefore the modulation of intracellularantioxidant concentration is a double-edged sword with bothsides exploited for potential therapeutic benefits

2 ROS and Hypoxia in Solid Tumors

Solid tumors are known to have a poor microvascular net-work and high interstitial fluid pressure resulting in hypoxicenvironment conferring chemo and radiotherapy resistance[22] There are three major forms of hypoxia that varies withthe duration acute chronic and intermittent Acute hypoxiaoccurs when tumor vessels become temporarily hypoxic fora period of seconds or a few hours Chronic hypoxia is aprogressive and severe reduction in oxygen (hours to days)[22] Intermittent hypoxia also referred to as cycling hypoxiais characterized by cyclic periods of hypoxia and reoxygena-tion and plays the main role in resistance of solid tumortreatments (Figure 3) [23ndash26] Hypoxic microenvironmentsare characterized by extreme heterogeneities in tumor cellsoxygenation that arise as a result of the increased oxygendiffusion distance due to tumor expansion and poorly devel-

oped vascular networks [22 27] Gradients in oxygen arefrequently found surrounding perfused vessels ranging fromnormal values near the blood vessel to complete anoxia adja-cent to necrosis [27 28] The balanced proportion of hypoxiccells in cancer is driven by the tolerance of individual cells tothese different types of hypoxia and varies remarkably amongdifferent tumors with otherwise similar clinical features [29]These differences are important because the fraction of viablehypoxic cells is a major determinant of prognosis as hypoxiccells are highly resistant to chemotherapy and radiationtherapy (Figure 3) Reducing cellular tolerance to hypoxiais therefore a strategy to reduce the proportion of hypoxiccells in tumors to improve current cancer therapy [27ndash33]Tumor cells can adapt to hypoxic conditions by employinga variety of survival tools which result in the promotion ofcancer cell growth and metastasis [22 32] This adaptationis mainly mediated by hypoxia-inducible factor-1 (HIF-1)(Figure 3) HIF-1 is a heterodimeric transcription factor con-sisting of an oxygen-regulated subunit (HIF-1120572) and a stablenuclear factor HIF-1120573 aryl hydrocarbon receptor nucleartranslocator (ARNT) Under normoxic conditions HIF-1120572is hydroxylated by prolyl hydroxylase (PHD) at proline 402and proline 564 and the hydroxylated HIF-1120572 recruits vonHippel-Lindau (pVHL) an E3 ubiquitin protein ligase andis rapidly degraded by the proteasome after being targetedfor ubiquitination (Figure 3) Under hypoxic conditionscytosolic HIF-1120572 is stabilized by inhibition of the oxygen- andPHD-dependent enzymatic hydroxylation of proline residuesand subsequently translocated to the nucleus where it bindsHIF-1120573 [30 34 35] The complex binds to the hypoxia-response element in its targets which results in the trans-activation of numerous genes encoding proteins necessaryfor the blood supply energy production growthsurvivalinvasionmetastasis and chemoradioresistance (Figure 4)[30 35] An association of HIF-1120572 overexpression with cellproliferation and poor prognosis has been observed in manykinds of human cancers [30 34 35] It is well known thathypoxic conditions increase intracellular ROS levels [14] andrecent studies provide important insights into the molecularmechanisms bywhich cycling hypoxia increases the oxidativestress [24]This constant generation of ROS through intensivecycling hypoxia stabilizes HIF-1120572 by preventing its degrada-tion and induces HIF-2120572 degradation (Figure 3) Since HIF-1120572 regulates genes encoding prooxidant enzymes and HIF-2120572 is a potent regulator of the genes encoding antioxidantenzymes it was proposed that both HIFs contribute in partto the oxidative stress caused by cycling hypoxia [36ndash39]Ironically the main mechanism of ionizing irradiation andmany anticancer drugs to induce apoptosis is through ROSwhich activate HIF-1120572 [11 30]

3 ROS and Chemotherapeutic Drugs

Despite great improvements in screening strategies and adju-vant therapies current treatments still rely heavily on con-ventional chemotherapy for most cancers Additionally mostof these conventional chemotherapies agents such as taxanesanthracyclines and platinum coordination complexes induceROS [11 40ndash42] and are somehow cardiotoxic [43 44]


Normoxia Hypoxia

Prolyl hydroxylase

HO

HO

Ubiquitination

pVHL

DegradationChemoradioresistance

InvasionmetastasisGrowthsurvival

Energy productionROS enhancement

Blood supply

[ROS]

Genes activation

Normoxia Hypoxia

ResistanceSensitive

HIF-1120572 HIF-1120573 HIF-1120572-HIF-1120573

O2

[O2]

HIF-1120572

[O2][O2]

Figure 4 Role of ROS in hypoxia and normoxia

Hence the efficacy of these prooxidant chemotherapeuticagents is dose-dependent which is limited by toxicity tonontumor tissues as a result of its poor tumor selectivityModulation of ROS levels by antioxidants may be effectivein protecting nontumor tissues especially the heart fromoxidative damage but they may also reduce the efficacy ofthese anticancer drugs [43] Nevertheless the mechanism bywhich these chemotherapeutic agents inducers exhibit antitu-mor effects is likely multifactorial Consequently to improvesurvival length and preserve quality of life the challengeis to develop approaches aimed at increasing chemotherapytoxicity to tumor tissue while not affecting nontumor tissues[43 44]Therefore the degree to which ROS contribute to theantineoplastic effects of these chemotherapeutic drugs shouldbe evaluated

4 Antioxidants Playing Hyde and Jekyll

41 Exogenous Antioxidant In order to maintain an appro-priate level of ROS and regulate their action the bodyrsquosnatural defense against oxidative stress consists of sev-eral antioxidative systems Therefore mammalian cells havedeveloped many enzymatic and nonenzymatic antioxidativesystems [20 45 46] as well as transfer proteins that sequesterprooxidant metals inhibiting their participation in redoxreactions (Table 1) [47] Components of the endogenousantioxidant defense system work together and in concertwith dietary antioxidants (Table 2) [20 21 46] to prevent andreduce oxidative stress In addition the antioxidant activityof many of these enzymes and compounds is reliant uponminerals derived from the diet such as selenium coppermanganese and zinc (Table 2) [48] Much debate has focusedon the use of antioxidant supplements by patients undergoingchemotherapy due to concerns that the antioxidants mayinterfere with the mechanism of action of the therapeutic

Table 1 Endogenous antioxidants

Endogenous antioxidants Examples

EnzymesSuperoxide dismutaseCatalasePeroxiredoxins

GSH enzyme-linked systemGlutathione peroxidaseGlutathione S-transferaseGlutathione reductase

NonenzymesGlutathioneCysteineThioredoxin

Metal-binding proteinsFerritinMetallothioneinCeruloplasmin

Table 2 Exogenous antioxidants

Example of exogenous antioxidantsVitamin C 997888rarr Ascorbateascorbic acidVitamin E 997888rarr Tocopherols tocotrienolsCarotenoids 997888rarr 120572-carotene 120573-carotene lycopene

Polyphenols 997888rarr Flavonols flavanols anthocyaninsisoflavones phenolic acid

Trace elements 997888rarr Selenium copper manganese zinc

agent and subsequently decrease its efficacy [21 49] Onthe other hand others argue that antioxidant supplementsare beneficial to patients undergoing chemotherapy becausethey enhance the efficacy of the chemotherapy as wellas alleviate toxic side effects allowing patients to toleratechemotherapy for the full course of treatment and lessenthe need for dose reduction [20 43] Despite convincing


evidence from preclinical experiments clinical trials thattested dietary antioxidant nutrients and micronutrients ascancer chemoprevention agents have been unsuccessful oreven resulted in harm [49 50] The lack of success in clinicaltrials and the discrepancies with preclinical experiments canbe explained by factors such as (i) lack of biological rationalefor selecting the specific agents of interest (ii) limited numberof agents tested to date and (iii) insufficient duration ofthe interventions and follow-up Moreover this high level ofheterogeneity within epidemiological data may support theexistence of other factors that couldmodulate the relationshipbetween antioxidant and cancer development explainingcontrasted results across different populations [21 49]

42 Endogenous Antioxidants Modulation of endogenousantioxidants is among other strategies to balance the intra-cellular redox levels Among the various ROS metabolicallygenerated H

2O2 the nonradical two-electron reduction

product of oxygen emerged as central hub in redox signalingand oxidative stress Processes such as proliferation differen-tiation inflammation and apoptosis use H

2O2as signaling

compound Metabolic sinks of this low-molecular-weightinclude the peroxidatic reaction carried out by catalase andnumerous peroxidases [51] However due to the high affinityof H2O2for thiol residues the new and expanding family

of thiol-specific antioxidant enzymes peroxiredoxins hasreceived considerable attention Indeed under physiologicalconditions eukaryotic peroxiredoxins are responsible for thereduction of 90 of intracellular H

2O2 On the other hand

peroxiredoxins can be easily inactivated by H2O2 disabling

peroxidase activity and therefore limiting their ability toact as antioxidant particularly in an oxidative environmentlike inflammation and intermittent hypoxia [52] Notablyenhancement of GSH levels was described in hypoxic intra-cellular environment [53 54] Glutathione (GSH) is consid-ered to be themajor thiol-disulfide redox buffer of the cell Onaverage the GSH intracellular concentration is 05ndash10mM[55] This is far higher than most redox active compoundsmaking GSH an important intracellular antioxidant andredox potential regulator that plays a vital role in drugdetoxification and cellular protection from damage by freeradicals peroxides and toxins [56] Given the range ofcritical cellular functions involving GSH it has long beenconsidered that the modulation of intracellular GSH levelswould be of great clinical benefits Enhancement of GSHlevels for cytoprotection is available by the administration ofits precursor N-Acetyl cysteine since direct administrationof reduced GSH has physical and chemical limitations [5657] Contrastingly these cytoprotective effects of GSH andits associated enzymes in many types of cancer lead toan increased tumor cell survival and chemotherapy drugresistance [58]

421 Glutathione and Chemoresistance Preclinical studiesof chemosensitization through antioxidant modulation havebeen reported in different tumor cells [44 58ndash60] Howeverchemoresistance is a complex system with multiple and het-erogeneous mechanisms of action which are orchestrated notonly by the tumormicroenvironments but also by the biology

of the tumor [61 62] Althoughmost of the chemotherapeuticdrugs are prooxidants not all the cancer cell death inductionpathways areROS-dependent [43]Nevertheless chemoresis-tance is not caused by a single factor but rather contributedby combinations of many drug-resistant factors such as (1)reduced intracellular drug accumulation which may resultfrom changes in drug transportation (increased efflux anddecreased influx of anticancer drugs) andor enhancementof detoxification activity (2) increased DNA repair involvingincreased nucleotide excision repair interstrand crosslinkrepair or loss mismatch repair (3) changes in the apoptoticcell death pathways and (4) intracellular elevated antioxidantlevels [63] Among the antioxidants involved in the mainte-nance of intracellular redox balance a main role is playedby glutathione (GSH) [57] GSH and its related enzymesparticipate not only in the antioxidant defense systems butalso in some drug-resistance metabolic processes such asdetoxification and efflux of xenobiotics and blockage of theapoptosis tumor cell death pathway [58] GSH is a majorcontributing factor to drug resistance by interacting withchemotherapeutic drugs such as cisplatin and trisenox [6465] In fact there are clinical evidences supporting a roleof the GSH system in overcoming drug resistance andortoxicity in solid tumors (eg lung cancers and bladder)treatments outcome [60 63]Therefore much effort has beendirected at depleting cellular GSH levels in order to sensitizetumor cells to the cytotoxic effects of anticancer drugs Theuse of buthionine sulfoximine (BSO) an inhibitor of GSHsynthesis [66] was performed in clinical trials [67ndash70] How-ever the approach was limited by BSO availability and lack ofselectivity of this drug for tumor versus normal cells [56] Butit is notable that GSH plays an important role in drug resis-tance and its depletion demonstrated to be effective in thesensitization of different types of cancer patients to cytotoxicchemotherapy [67ndash70] Another alternative in progress is thedevelopment and optimization of GSH analogues that inhibitthe enzyme glutathione-S-transferase (GST) responsible forthe detoxification overcoming therefore chemoresistance[56 71] Among the GSH analogues developed one (TLK286) which is in clinical trial phase 3 settings for non-small-cell lung and ovarian cancer appears to sensitize these tumorsto cytotoxic chemotherapies [56] However the lack of tumorspecificity is still a potential problem

43 Antioxidant and Possible Clinical Benefits Altogetherit should be recognized that understanding the redox bio-chemistry differences between normal and cancer cells isessential for the design and development of strategies toovercome oxidative damage or prooxidant chemoresistance[61 62] Even within a specific cancer type the malignantcell populations are heterogeneous and intracellular oxidativelevels may change as the disease progress [61] Consequentlystudying intra- and intertumor heterogeneous distribution ofantioxidants levels may be an important factor to overcometumor progression Additionally it is known that alterationsin cellular redox metabolism play a crucial role in the acti-vation or loss of tumor suppressor proteins activities such asbreast cancer susceptibility gene breast cancer 1 (BRCA1) andphosphatase and tensin homolog deleted on chromosome 10


PTEN(active)

PTEN(inactive)

ROS

Hypoxia

AntioxidantGSH

BRCA1

PI3KTumor progression therapy resistance

metastasis

Tumor cell proliferation

Figure 5 Possible clinical benefits of antioxidant in tumor progression

(PTEN) [3 72ndash78] The BRCA1 is an oncosuppressor genewith a relatively broad cellular role such as DNA repair(including nucleotide excision repair NER and double-strand break repair DSBR) transcriptional regulation andchromatin remodeling [79ndash83] Notably BRCA1 has also anantioxidant role in response to oxidative stress in whichROS cause DNA damage due to oxidation [73ndash75] Lossor mutation of the BRCA1 gene was firstly described to beassociated with increased risk of breast and ovarian cancers[80 82ndash86]Moreover BRCA1 expression has been correlatedwith cancer aggressiveness and chemotherapy sensitivity inother solid tumors such as prostate [87ndash89] non-small-celllung cancer [90ndash94] and pancreas [95 96] The superfamilyof protein tyrosine phosphatase (PTP) enzymes functionsin a coordinated pattern with protein tyrosine kinases tocontrol the cellular regulatory signal processes such as cellgrowth proliferation and differentiation [97ndash100] PTEN aclass 2 VH1-like (poxvirus vaccinia) DUSP (dual specificityphosphatase) [100] and likewise a member of phosphataseprotein family is modulated by ROS [98 101] The oxidationof the active site Cys byROS abrogates PTENcatalytic activityand thereby switching on the phosphatidylinositol-3-kinase(PI3K) proliferation pathway [72 75ndash77 100 101] The tumorsuppressor PTEN is one of themost frequentlymutated genesin human cancer and is generally associated with advancedcancers andmetastases [72] A recent study reveals that PTENloss activity is the most important alteration for cellularmalignant transformation in mammary epithelial cells [102]A recent study reveals that PTEN loss activity is a commonevent in breast cancers caused by BRCA1 deficiency [103]due to ROS enhancement Recently the modulation of othertumor suppressor genes was described to be ROS-dependent[78 104 105] Therefore the use of antioxidant might protectthe biomarkers ROS-dependent tumorigenesis like BRCA1and PTEN (Figure 5)

5 Conclusions

Enhancing the capacity of antioxidant in order to protectcells from redox-related changes or environmental toxinsrepresents a persistent aim in the search for cytoprotectivestrategies against cancer On the contrary the strategy of

depleting antioxidant is aimed at sensitizing cancer cellsto chemotherapy the so-called chemosensitization In thiscontext it has been reported that antioxidant may be adetermining factor for the sensitivity of some tumors tovarious chemotherapeutic agents In particular GSH andGSH enzyme-linked system are a relevant parameter forchemotherapy response and it may be utilized as a usefulbiomarker for selecting tumors potentially responsive tochemotherapeutic regimentsThe involvement of antioxidantin the carcinogenesis and in the drug resistance of tumorcell is clear but further studies aimed at understandingthe antioxidant-driven molecular pathways and the biologyof the tumor cells are crucial to design new therapeuticstrategies to fight cancer progression and overcome chemore-sistance

Conflict of Interests

The author declares that there is no conflict of interests regar-ding the publication of this paper

Acknowledgments

Theauthorwould like to express the deepest gratitude toA CS Ferreira B M Bomfim L F R Silva and R A Fernandeswho believed in their project from the start and in particularto D F Baptista to whom this paper is dedicated This workwas supported by grants from Fundacao do Cancer (FAF)

References

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[5] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012

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[8] J S Stamler D J Singel and J Loscalzo ldquoBiochemistry of nitricoxide and its redox-activated formsrdquo Science vol 258 no 5090pp 1898ndash1902 1992

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[15] C L Quinlan I V Perevoshchikova M Hey-Mogensen et alldquoSites of reactive oxygen species generation by mitochondriaoxidizing different substratesrdquo Redox Biology vol 1 no 1 pp304ndash312 2013

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[17] R P Brandes N Weissmann and K Schroder ldquoNox familyNADPH oxidases in mechano-transduction mechanisms andconsequencesrdquo Antioxidants and Redox Signaling vol 20 no 6pp 887ndash898 2014

[18] N Cantu-Medellin and E E Kelley ldquoXanthine oxidoreductase-catalyzed reactive species generation a process in critical needof reevaluationrdquo Redox Biology vol 1 no 1 pp 353ndash358 2013

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[25] Y Liu X Song X Wang et al ldquoEffect of chronic intermittenthypoxia on biological behavior and hypoxia-associated geneexpression in lung cancer cellsrdquo Journal of Cellular Biochemistryvol 111 no 3 pp 554ndash563 2010

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[36] J Nanduri NWang G Yuan et al ldquoIntermittent hypoxia degr-ades HIF-2120572 via calpains resulting in oxidative stress implica-tions for recurrent apnea-induced morbiditiesrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 4 pp 1199ndash1204 2009

[37] B Keith R S Johnson and M C Simon ldquoHIF1 120572 and HIF2120572 sibling rivalry in hypoxic tumour growth and progressionrdquoNature Reviews Cancer vol 12 no 1 pp 9ndash22 2012

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antioxidant capacityrdquo Cancer Research vol 65 no 18 pp 8455ndash8460 2005

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[42] A Brozovic A Ambriovic-Ristov andM Osmak ldquoThe relatio-nship between cisplatin-Induced reactive oxygen species glu-tathione and BCL-2 and resistance to cisplatinrdquo Critical Rev-iews in Toxicology vol 40 no 4 pp 347ndash359 2010

[43] D T Vincent Y F IbrahimM G Espey et al ldquoThe role of anti-oxidant in the era of cardio-oncologyrdquo Cancer Chemotherapyand Pharmacology vol 72 no 6 pp 1157ndash1168 2013

[44] C Glorieux N Dejeans B Sid R Beck P B Calderon and JVerrax ldquoCatalase overexpression inmammary cancer cells leadsto a less aggressive phenotype and an altered response to che-motherapyrdquoBiochemical Pharmacology vol 82 no 10 pp 1384ndash1390 2011

[45] E M Hanschmann J R Godoy C Berndt et al ldquoThioredox-ins glutaredoxins and peroxiredoxinsmdashmolecular mechani-sms and health significance from cofactors to antioxidants toredox signalingrdquo Antioxidants and Redox Signaling vol 19 no13 pp 1539ndash1605 2013

[46] D D Rio A R Mateos J P E Spencer et al ldquoDietary (poly)phenolics in human health structures bioavailability andevidence of protective effects against chronic diseasesrdquo Antiox-idants and Redox Signaling vol 18 no 14 pp 1818ndash1892 2013

[47] M Zalewska J Trefon and H Milnorowicz ldquoThe role of meta-llothionein interactions with other proteinsrdquo Proteomics 2014

[48] I Romero-Canelon and P J Sadler ldquoNext-generation metalanticancer complexes multitargeting via redox modulationrdquoInorganic Chemistry vol 52 no 21 pp 12276ndash12291 2013

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

[50] G Bjelakovic D Nikolova and C Gluud ldquoAntioxidant supple-ments and mortalityrdquo Current Opinion in Clinical Nutrition andMetabolic Care vol 17 no 1 pp 40ndash44 2014

[51] H Sies ldquoRole of metabolic H2O2generation redox signaling

and oxidative stressrdquoThe Journal Biological Chemistry 2014[52] R A Poynton andM BHampton ldquoPeroxiredoxins as biomark-

ers of oxidative stressrdquo Biochimica et Biophysica Acta vol 1840no 2 pp 906ndash912 2014

[53] J J Merino C Roncero M J Oset-Gasque et al ldquoAntioxidantand protectivemechanisms against hypoxia and hypoglycaemiain cortical neurons in vitrordquo International Journal of MolecularSciences vol 15 no 2 pp 2475ndash2493 2014

[54] V V Khramtsov and R J Gillies ldquoJanus-faced tumor microen-vironment and redoxrdquo Antioxidant and Redox Signaling 2014

[55] V I Lushchak ldquoGlutathione homeostasis and fuctions poten-tial targets for medical interventionsrdquo Journal of Amino Acidsvol 2012 Article ID 736837 26 pages 2012

[56] J HWu and G Batist ldquoGlutathione and glutathione analoguestherapeutic potentialsrdquo Biochimica et Biophysica Acta vol 1830no 5 pp 3350ndash3353 2013

[57] DM Townsend K D Tew andH Tapiero ldquoThe importance ofglutathione in human diseaserdquo Biomedicine and Pharmacother-apy vol 57 no 3 pp 145ndash155 2003

[58] N Traverso R Ricciarelli M Nitti et al ldquoRole of glutathione incancer progression and chemoresistancerdquo Oxidative Medicine

and Cellular Longevity vol 2013 Article ID 972913 10 pages2013

[59] J K KweeDG Luque A CD S Ferreira et al ldquoModulation ofreactive oxygen species by antioxidants in chronic myeloid leu-kemia cells enhances imatinib sensitivity through survivin dow-nregulationrdquo Anti-Cancer Drugs vol 19 no 10 pp 975ndash9812008

[60] P Yang J O Ebbert Z Sun and R M Weinshilboum ldquoRole ofthe glutathionemetabolic pathway in lung cancer treatment andprognosis a reviewrdquo Journal of Clinical Oncology vol 24 no 11pp 1761ndash1769 2006

[61] D Hanahan and R AWeinberg ldquoHallmarks of cancer the nextgenerationrdquo Cell vol 144 no 5 pp 646ndash674 2011

[62] T Fiaschi and P Chiarugi ldquoOxidative stress tumor microen-vironment and metabolic reprogramming a diabolic liaisonrdquoInternational Journal of Cell Biology vol 2012 Article ID762825 8 pages 2012

[63] X Hu and Y Xuan ldquoBypassing cancer drug resistance by acti-vating multiple death pathwaysmdasha proposal from the study ofcircumventing cancer drug resistance by induction of necrop-tosisrdquo Cancer Letters vol 259 no 2 pp 127ndash137 2008

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

[65] P-S Ong S-Y Chan and P C Ho ldquoDifferential augmenta-tive effects of buthionine sulfoximine and ascorbic acid inAs2O3-induced ovarian cancer cell death Oxidative stress-

independent and -dependent cytotoxic potentiationrdquo Interna-tional Journal of Oncology vol 38 no 6 pp 1731ndash1739 2011

[66] M Jozefczak T Remans J Vangronsveld andACuypers ldquoGlu-tathione is a key player in metal-induced oxidative stress defe-nsesrdquo International Journal of Molecular Sciences vol 13 no 3pp 3145ndash3175 2012

[67] H H Bailey R T Mulcahy K D Tutsch et al ldquoPhase I clinicaltrial of intravenous L-buthionine sulfoximine and melphalanan attempt at modulation of glutathionerdquo Journal of ClinicalOncology vol 12 no 1 pp 194ndash205 1994

[68] P J OrsquoDwyer T C Hamilton F P LaCreta et al ldquoPhase I trialof buthionine sulfoximine in combination with melphalan inpatients with cancerrdquo Journal of Clinical Oncology vol 14 no 1pp 249ndash256 1996

[69] H H Bailey G Ripple K D Tutsch et al ldquoPhase I study ofcontinuous-infusion L-SR-buthionine sulfoximine with intra-venous melphalanrdquo Journal of the National Cancer Institute vol89 no 23 pp 1789ndash1796 1997

[70] HH Bailey ldquoL-SR-buthionine sulfoximine historical develop-ment and clinical issuesrdquo Chemico-Biological Interactions vol111-112 pp 239ndash254 1998

[71] D Hamilton and G Batist ldquoGlutathione analogues in cancertreatmentrdquo Current Oncology Reports vol 6 no 2 pp 116ndash1222004

[72] L Salmena A Carracedo and P P Pandolfi ldquoTenets of PTENtumor suppressionrdquo Cell vol 133 no 3 pp 403ndash414 2008

[73] T Saha J K Rih and E M Rosen ldquoBRCA1 down-regulatescellular levels of reactive oxygen speciesrdquoThe FEBS Letters vol583 no 9 pp 1535ndash1543 2009

[74] Z Huang L Zuo Z Zhang et al ldquo331015840-Diindolylmethanedecreases VCAM-1 expression and alleviates experimental col-itis via a BRCA1-dependent antioxidant pathwayrdquo Free RadicalBiology and Medicine vol 50 no 2 pp 228ndash236 2011


[75] B Vurusaner G Poli and H Basaga ldquoTumor suppressor genesand ROS complex networks of interactionsrdquo Free Radical Bio-logy and Medicine vol 52 no 1 pp 7ndash18 2012

[76] H Luo Y Yang J Duan et al ldquoPTEN-regulated AKTFoxO3aBim signaling contributes to reactive oxygen species-mediatedapoptosis in selenite-treated colorectal cancer cellsrdquo Cell Deathand Disease vol 4 article e481 2013

[77] F G Meng and Z Y Zhang ldquoRedox regulation of protein tyr-osine phosphatase activity by hydroxyl radicalrdquo Biochimica etBiophysica Acta vol 1834 no 1 pp 464ndash469 2013

[78] S J Kim H J Jung and C J Lim ldquoReactive oxygen species-dependent down-regulation of tumor suppressor genes PTENUSP28 DRAM TIGAR and CYLD under oxidative stressrdquoBiochemical Genetics vol 51 no 11-12 pp 901ndash915 2013

[79] A Tutt and A Ashworth ldquoThe relationship between the roles ofBRCA genes in DNA repair and cancer predispositionrdquo Trendsin Molecular Medicine vol 8 no 12 pp 571ndash576 2002

[80] N Turner A Tutt and A Ashworth ldquoHallmarks of rsquoBRCAnessrsquoin sporadic cancersrdquo Nature Reviews Cancer vol 4 no 10 pp814ndash819 2004

[81] R Roy J Chun and S N Powell ldquoBRCA1 and BRCA2 differentroles in a common pathway of genome protectionrdquo NatureReviews Cancer vol 12 no 1 pp 68ndash78 2012

[82] M L Li and R A Greenberg ldquoLinks between genome integrityand BRCA1 tumor suppressionrdquo Trends in Biochemical Sciencesvol 37 no 10 pp 418ndash424 2012

[83] W D Foulkes and A Y Shuen ldquoIn brief BRCA1 and BRCA2rdquoJournal of Pathology vol 230 no 4 pp 347ndash349 2013

[84] Y Miki J Swensen D Shattuck-Eidens et al ldquoA strong can-didate for the breast and ovarian cancer susceptibility geneBRCA1rdquo Science vol 266 no 5182 pp 66ndash71 1994

[85] P A Futreal Q Liu D Shattuck-Eidens et al ldquoBRCA1 muta-tions in primary breast and ovarian carcinomasrdquo Science vol266 no 5182 pp 120ndash122 1994

[86] N J Birkbak B Kochupurakkai J M G Izarzugaza et alldquoTumor mutation burden forecasts outcome in ovarian cancerwith BRCA1 or BRCA2 mutationsrdquo PLos ONE vol 08 no 11Article ID e80023 2013

[87] S Fan J-A Wang R-Q Yuan et al ldquoBRCA1 as a potentialhuman prostate tumor suppressor modulation of proliferationdamage responses and expression of cell regulatory proteinsrdquoOncogene vol 16 no 23 pp 3069ndash3082 1998

[88] E Castro C Goh D Olmos et al ldquoGermline BRCAmutationsare associated with higher risk of nodal involvement distantmetastasis and poor survival outcomes in prostate cancerrdquoJournal of Clinical Oncology vol 31 no 14 pp 1748ndash1757 2013

[89] P de Luca C P Moiola F Zalazar et al ldquoBRCA1 and p53regulate critical prostate cancer pathwaysrdquo Prostate Cancer andProstatic Diseases vol 16 no 3 pp 233ndash238 2013

[90] A Passaro A Palazzo P Trenta et al ldquoMolecular and clinicalanalysis of predictive biomarkers in non-small-cell lung cancerrdquoCurrent Medicinal Chemistry vol 19 no 22 pp 3689ndash37002012

[91] M Pesta V Kulda O Fiala et al ldquoPrognostic significance ofERCC1 RRM1 and BRCA1 in surgically-treated patients withnon-small cell lung cancerrdquo Anticancer Research vol 32 no 11pp 5003ndash5010 2012

[92] H Harada K Miyamoto Y Yamashita et al ldquoMethylation ofbreast cancer susceptibility gene 1 (BRCA1) predicts recurrencein patients with curatively resected stage I non-small cell lungcancerrdquo Cancer vol 119 no 4 pp 792ndash798 2013

[93] M Tiseo P Bordi B Bortesi et al ldquoERCC1BRCA1 expressionand gene polymorphisms as prognostic and predictive factorsin advanced NSCLC treated with or without cisplatinrdquo BritishJournal of Cancer vol 108 no 8 pp 1695ndash1703 2013

[94] M Sung and P Giannakakou ldquoBRCA1 regulates microtubuledynamics and taxane-induced apoptotic cell signalingrdquo Onco-gene vol 33 no 11 pp 1418ndash1428 2014

[95] J E Axilbund and E A Wiley ldquoGenetic testing by cancer sitepancreasrdquo Cancer Journal vol 18 no 4 pp 350ndash354 2012

[96] T Wang S C Wentz N L Ausborn et al ldquoPattern of breastcancer susceptibility gene 1 expression is a potential prognosticbiomarker in resectable pancreatic ductal adenocarcinomardquoPancreas vol 42 no 6 pp 977ndash982 2013

[97] E B Fauman and M A Saper ldquoStructure and function of theprotein tyrosine phosphatasesrdquo Trends in Biochemical Sciencesvol 21 no 11 pp 413ndash417 1996

[98] NK Tonks ldquoProtein tyrosine phosphatases fromgenes to fun-ction to diseaserdquo Nature Reviews Molecular Cell Biology vol 7no 11 pp 833ndash846 2006

[99] T Hunter ldquoTyrosine phosphorylation thirty years and count-ingrdquo Current Opinion in Cell Biology vol 21 no 2 pp 140ndash1462009

[100] L Tautz D A Critton and S Grotegut ldquoProtein tyrosine pho-sphatases structure function and implication in human dis-easerdquoMethods inMolecular Biology vol 1053 pp 179ndash221 2013

[101] N K Tonks ldquoRedox redux revisiting PTPs and the control ofcell signalingrdquo Cell vol 121 no 5 pp 667ndash670 2005

[102] M M Pires B D Hopkins L H Saal et al ldquoAlterations ofEGFR p53 and PTEN that mimic changes found in basal-like breast cancer promote transformation of humanmammaryepithelial cellsrdquo Cancer Biology and Therapy vol 14 no 3 pp246ndash253 2013

[103] L H Saal S K Gruvberger-Saal C Persson et al ldquoRecurrentgross mutations of the PTEN tumor suppressor gene in breastcancers with deficient DSB repairrdquo Nature Genetics vol 40 no1 pp 102ndash107 2008

[104] K Bensaad A Tsuruta M A Selak et al ldquoTIGAR a p53-ind-ucible regulator of glycolysis and apoptosisrdquo Cell vol 126 no 1pp 107ndash120 2006

[105] K Bensaad E C Cheung and K H Vousden ldquoModulation ofintracellular ROS levels by TIGAR controls autophagyrdquo TheEMBO Journal vol 28 no 19 pp 3015ndash3026 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Antioxidant

ROSRNS

Signalling Oxidative stress

Normal cells

Apoptosis Migration

Genetic instabilitymalignant transformation

ROSRNS

Tumor metastasis

DefenseProliferation

Physiologicalconditions

Pathophysiologicalconditions

(a) (b)

VasorelaxationAutophagy

Figure 1 Schematic representation of reactive oxygen andnitrogen species (ROSRNS) inductions in physiological (a) andpathophysiological(b) conditions

Antioxidant

Superoxide dismutase

Catalase glutathione (GSH)

L-arginine

ROS

RNS

NADPH NADPcitrulline

NOS

Electron transportchain (ECT)NADPH oxidaseXanthine oxidase

O2

H2O2 H2OO2

NO∙

∙OH

ONOO∙

O2∙

O2∙

Figure 2 Sources of reactive oxygen (ROS) and nitrogen (RNS) species production Enzymatic and nonenzymatic antioxidantscounterbalance it

form the major powerhouse of ROS production they aregenerated in association with the activity of the respiratorychain such as NADH dehydrogenase enzyme complexes inaerobic ATP production [13ndash15] In addition two classicphagocytic ROS-generating enzymes use molecular oxygenas a substrate including the multisubunit NADPH oxidaseand its homologue NOXDuox family and myeloperoxidasein various tissues in response to extracellular influences[16 17] Other sources of ROS production include thecytochromeP450 (CYP450) systemwhich is involvedmainly

in removing or detoxifying toxic substances in the liver[13] and xanthine oxidase which catalyzes the oxidation ofhypoxanthine to xanthine with the formation of H

2O2[18]

The imbalance of this cellular redox state is characteristic ofmany diseases where abnormal oxidant production causesextensive tissue damage (Figure 1(b)) [3 6 19] Antioxidanthas been defined as any substance that significantly delaysor prevents oxidative damage of an oxidizable substrate(Figure 2) Due to their high reactivity the ROS productionlevels are tightly controlled by antioxidants to avoid oxidative


Cycling hypoxia

Reoxygenation

Hypoxia

[ROS]

[ROS] [Antioxidant]

[O2]

HIF-1120572-HIF-1120573HIF-2120572

[O2]









Normoxia Hypoxia

Prolyl hydroxylase

HO

HO

Ubiquitination

pVHL




Blood supply

[ROS]

Genes activation

Normoxia Hypoxia

ResistanceSensitive

HIF-1120572 HIF-1120573 HIF-1120572-HIF-1120573

O2

[O2]

HIF-1120572

[O2][O2]





















2O2as signaling










PTEN(active)

PTEN(inactive)

ROS

Hypoxia

AntioxidantGSH

BRCA1


metastasis




5 Conclusions





Acknowledgments


References

























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Cycling hypoxia

Reoxygenation

Hypoxia

[ROS]

[ROS] [Antioxidant]

[O2]

HIF-1120572-HIF-1120573HIF-2120572

[O2]









Normoxia Hypoxia

Prolyl hydroxylase

HO

HO

Ubiquitination

pVHL




Blood supply

[ROS]

Genes activation

Normoxia Hypoxia

ResistanceSensitive

HIF-1120572 HIF-1120573 HIF-1120572-HIF-1120573

O2

[O2]

HIF-1120572

[O2][O2]





















2O2as signaling










PTEN(active)

PTEN(inactive)

ROS

Hypoxia

AntioxidantGSH

BRCA1


metastasis




5 Conclusions





Acknowledgments


References

























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Normoxia Hypoxia

Prolyl hydroxylase

HO

HO

Ubiquitination

pVHL




Blood supply

[ROS]

Genes activation

Normoxia Hypoxia

ResistanceSensitive

HIF-1120572 HIF-1120573 HIF-1120572-HIF-1120573

O2

[O2]

HIF-1120572

[O2][O2]





















2O2as signaling










PTEN(active)

PTEN(inactive)

ROS

Hypoxia

AntioxidantGSH

BRCA1


metastasis




5 Conclusions





Acknowledgments


References

























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






2O2as signaling










PTEN(active)

PTEN(inactive)

ROS

Hypoxia

AntioxidantGSH

BRCA1


metastasis




5 Conclusions





Acknowledgments


References

























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


PTEN(active)

PTEN(inactive)

ROS

Hypoxia

AntioxidantGSH

BRCA1


metastasis




5 Conclusions





Acknowledgments


References

























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





















































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article a paradoxical chemoresistance and tumor … · 2019. 7. 31. · review article a...

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