review article overview of the role of vanillin on redox

Review ArticleOverview of the Role of Vanillin on Redox Status andCancer Development

Daniel Pereira Bezerra1 Anne Karine Nascimento Soares2

and Damiatildeo Pergentino de Sousa2

1Goncalo Moniz Institute Oswaldo Cruz Foundation (IGM-FIOCRUZ-BA) Salvador BA Brazil2Department of Pharmaceutical Sciences Universidade Federal da Paraıba 58051-970 Joao Pessoa PB Brazil

Correspondence should be addressed to Damiao Pergentino de Sousa damiao desousayahoocombr

Received 17 September 2016 Revised 4 November 2016 Accepted 21 November 2016

Academic Editor Kum Kum Khanna

Copyright copy 2016 Daniel Pereira Bezerra et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Bioactive natural products play critical roles inmodern drug development especially anticancer agents It has been widely reportedthat various pharmacological activities of such compounds are related to their antioxidant properties Vanillin is a natural substancewidely found in many plant species and often used in beverages foods cosmetics and pharmaceutical products Antioxidant andanticancer potential have been described for this compound Considering the importance of vanillin in the area of human healthand food and pharmaceuticals sectors in this review we discuss the role of vanillin on redox status and its potential contributionto the prevention and the treatment of cancer

1 Introduction

Agreat body of in vivo evidence supports the view that oxida-tive stress and the accompanying reactive oxygen species(ROS) are genotoxic and contribute to the development ofcancers Pathological processes mediated by oxidative stressinclude cell membrane leakage mitochondrial dysfunctionglutathione depletion and disturbed redox cell state anddepletion of ATP These processes affect the cells and DNAresulting in tumors inflammatory diseases and various otherhealth problems Oxidative stress is implicated in numerousdiseases and results in shorter life hampered well-being andincreasing public health spending [1] Antioxidant therapiesimplementation requires a better understanding of free radi-cal toxicity its molecular mechanisms and its involvement indisease

Natural bioactive products play critical roles in anticancerdrug development In fact natural molecules with antitumoractivity reveal excellent pharmacotherapeutic potential [2ndash5] Antioxidant activity is commonly found in many of thesemolecules especially the phenolic substances [6 7] Consid-ering the involvement of reactive species as a source of various

types of cancer diets andor drug therapies involving bioac-tive substances with antioxidant activity may well represent apreventive treatment approach to maintain the well-being ofthe patient Some of these natural substances are present invarious pharmaceutical nutritional and cosmetic productsFor example vanillin (Figure 1) a plant secondarymetaboliteand the main constituent of vanilla is a phenolic phenyl-propane C

6-C1carbonic structure derivative It acts as an

important flavor and aromatic component used worldwideVanillin is found in several essential plant oils principallyVanilla planifoliaVanilla tahitensis andVanilla pompona [8]it is often found in processed foods beverages and pharma-ceutical products and also in perfumery [9 10] Vanillin hasantioxidant and antitumor potential [11] and it is reportedthat its activity might be more beneficial for daily health carethan had been previously thought [12] A rich diet in suchradical scavengers could reduce free radical cancer promo-tion [13] Given the data on vanillin and considering itsimportance in its various applications and pharmacologicalproperties we discuss the role of vanillin on redox status andits potential contribution to cancer development and treat-ment

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 9734816 9 pageshttpdxdoiorg10115520169734816

2 Oxidative Medicine and Cellular Longevity

O

OH

OCH3

Figure 1 Chemical structure of vanillin (4-hydroxy-3-methoxy-benzaldehyde)

2 Methodology

Searches were performed in the scientific literature databasesPubMed and Web of Science through June 2016 using thefollowing key words vanillin antitumor anticancer oxidantandor antioxidant

3 Antioxidant and Prooxidant Effects

It is well known that neither O2

∙minus nor H2O2is capable of

interacting with either deoxyribose or the base portions ofDNA this suggests that the secondarily derived ∙OH radicalmay be the primary reactive species Once generated ∙OHmay interact with DNA to produce at least 20 different DNAoxidation products [14] The idea that a major risk factorfor cancer is mitogenesis has also been proposed It haslong been appreciated that dividing cells are at an increasedrisk for developing mutations as compared to quiescentcells [15] Oxidants produced by inflammatory leukocytesmay induce mutagenesis and possibly carcinogenesis bypromoting mitogenesis and by modifying DNA bases [16]There is an increasing interest in oxygen-containing freeradicals in biological systems because of their perceivedroles as causative agents in the etiology of a variety ofchronic disorders Many natural products having antioxidantactivities show protective biochemical functions and suchmetabolites have become subjects of great interest A betterunderstanding of the mechanisms of oxidative biologicalreactions (and their inhibition) should help to understandand treat or prevent various diseases such as cancer

In regard of the antioxidant effect of vanillin somemixedresults have been reported Vanillin had weak superoxideanion scavenging activity (IC

50of 2945 plusmn 247 120583M) and

exhibited no or little antioxidant activity against lipid per-oxidation in mouse liver microsomes (inactive at 3285 120583M)[17] 11-diphenyl-picrylhydrazyl (DPPH) radical scavengingassay (IC

50value higher than 100120583M) [18] 120573-carotene

decolorization assay [19] and linoleic acid and cholesteroloxidation assays [20] On the other hand vanillin at 25mMinhibited protein oxidation and lipid peroxidation induced byphotosensitization with methylene blue plus light in rat livermitochondria [21] It also exhibited hydroxyl radical [22] and221015840-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radi-cal cation (ABTS∙+) (IC

50value of 1625 120583M) [23] scavenging

activities

Furthermore Tai et al [12] assessed the antioxidant effectof vanillin using multiple antioxidant assays Vanillin showedpotent antioxidant activity in the ABTS∙+ scavenging assayin the oxygen radical absorbance capacity (ORAC) assayand in the oxidative hemolysis inhibition assay (OxHLIA)but showed no activity in the DPPH radical and galvinoxylradical scavenging assays Its antioxidant mechanism is viaself-dimerization The dimerization contributed to the highreaction stoichiometry against ABTS∙+ and 221015840-azobis(2-methylpropionamidine) dihydrochloride- (AAPH-) derivedradicals to result in the strong antioxidant effect of vanillin[12] Pretreatment of vanillin (100 nM) also reduced rotenoneinduced mitochondrial dysfunction oxidative stress andapoptosis in SH-SY5Y neuroblastoma cells [24] These datareinforce that vanillin presents interesting antioxidant prop-erties which is dependent on the method used

In in vivo antioxidant assay mice were orally given asingle dose (100mgkg) of vanillin The highest activity inthe plasma ORAC assay was observed at 5min when theconcentrations of vanillin vanillic acid and protocatechuicacid were high [12] Moreover pretreatment with vanillin(150mgkg) presented hepatoprotective effect against carbontetrachloride-induced hepatotoxicity by the inhibition ofprotein and lipid oxidation processes the increase in antiox-idant enzymes activities and the inhibition of inflammationmediators [25] More recently Ben Saad et al [26] demon-strated the protective effects of vanillin against potassiumbromate- (KBrO

3-) induced oxidative stress The treatment

with vanillin (100mgkgday for 15 days) reduced histopatho-logical changes in KBrO

3-induced kidney and decreased

renal oxidative damage by inhibiting ROS generation andreversing antioxidant enzyme activities in kidney [26] Theseeffects may be results of interactions between vanillin andcellular proteins or signaling pathways

In relation of the prooxidant effect of vanillin Castor etal [27] have reported that vanillin can has prooxidant actionwhen its transient free radicals are generated intracellularlyTransient free radicals from vanillin were generated byhorseradish peroxidasehydrogen peroxide-mediated oxida-tion and their prooxidant effects were assessed using cysteineglutathione ovalbumin and the coenzyme NADPH as targetbiomolecules Vanillin at concentration of 10120583M promotedoxidation of glutathione sulfhydryl groups and NADPH atexperimental conditions [27] This prooxidant activity canexplain its cytotoxic action in some tumor cell lines Brieflywe believe that both antioxidant and prooxidant character-istics of vanillin contribute to its benefits and deleteriouseffectsThe antioxidant activity of vanillin seems to be relatedto its antimutagenic and anticarcinogenic activities In con-trast the prooxidant effects of vanillin radicals can be relatedto its anti-invasive antimetastatic antiangiogenic and cyto-toxic activities

The antioxidant activity of phenolic substances has beenreported for several natural substances structurally similar tovanillinThe hydroxyl of the aromatic ring plays an importantrole in the antioxidant activity via the homolytic fragmenta-tion of the O-H bond [28 29] It has been reported that vanil-lin exhibited hydroxyl radical [30] and 221015840-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS∙+)

Oxidative Medicine and Cellular Longevity 3

[23] scavenging activities Its antioxidant activity can beattributed to the presence of hydroxyl group (OH∙) linked toaromatic ringTherefore substances having the phenol func-tional group may also have antioxidant activity as exhibitedby vanillin

4 Antimutagenic Activity

Mutagenic agents are involved in genotoxicity and carcino-genesis processes and as well in the inception and pathogen-esis of several chronic degenerative diseases Antimutagenicagents are the compounds that have protective effects againstmutagenics which include ldquodesmutagensrdquo that cause chem-ical and biochemical mutagen modifications before DNAdamage and ldquobioantimutagensrdquo that reduce the mutationprocess after DNAdamage [31] Vanillin has been classified asa bioantimutagen and is able to inhibit mutagenesis inducedby chemical and physical mutagens in various cell systems

The antimutagenic effect of vanillin was first testedon bacteria [32] Vanillin (at concentration of 150120583gmL[sim986 120583M]) inhibits mutagenesis induced by 4-nitroquinol-ine 1-oxide (4-NQO) furylfuramide (AF-2) captan ormeth-ylglyoxal in Escherichia coli WP2s In studies using repairenzymes in deficient strains it was suggested that vanillinincreased DNA damage repair through the recombinationalrepair pathway [32ndash34] Vanillin was not effective againstmutations provoked by 3-amino-l-methyl-5H-pyrido[43-b]indole (Trp-P-2) or 2-amino-3-methylimidazo[45-f ]quino-line (IQ) in Salmonella typhimuriumTA98 [32] yet it reducedthe frequency of spontaneous mutations in S typhimuriumTA102 and TA104 reducing mutations at GC sites but notAT sites and such antimutagenic effect was dependent onthe presence of the pKM101 plasmid in homologues of TA104[35 36] Vanillin was also effective against spontaneousmutation in the wild-type strain NR9102 of E coli and thiseffect was independent of both the SOS and NER pathwaysMoreover vanillin causes certain types of DNA damagewhich elicit recombinational repair This recombinationalrepair activation permits vanillin-induced damage repair andalso that of other DNA lesions thus reducing the frequencyof spontaneous mutation [37]

The antimutagenic effect of vanillin has also been studiedinDrosophilamelanogaster In the germ cell line ofDmelano-gaster vanillin decreased both spontaneous and mitomycinC- (MMC-) induced ring X-loss but had no effect on themutagenic activity of methyl methanesulfonate (MMS) [38]On the other hand vanillin weakly inhibited mutationsinduced by MMC but increased recombination in MMC-treated lesions in D melanogaster somatic cells [39] Post-treatment with vanillin produced a synergistic effect onrecombination in D melanogaster somatic cells with eitherethyl methanesulfonate (EMS) or bleomycin [40] Howeverthe effects of cotreatment with vanillin led to significantprotection against the general genotoxicity of EMS N-ethyl-N-nitrosourea (ENU) N-methyl-N-nitrosourea (MNU)and bleomycin [41] Using the DNA repair test for Dmelanogaster [42] reported the effects of vanillin on therepair of lethal damage produced by N-ethyl-N-nitrosourea

(ENU) ethyl methanesulfonate (EMS) and MMC Vanillinalso increased the toxicity of MMC and EMS in repair-deficient flies Yet it protected against the lethality of ENU inrepair-defective flies This complex antimutagenic effect hasbeen attributed to vanillin caused inhibitory activity againstoxidative damage and stimulatory action on detoxificationenzymes [41 42]

Contradictory results were also found in studies usingmammalian cells In studies performed in Chinese hamsterovary fibroblast CHO K-1 cells vanillin was able to promotean increase in the frequencies of sister-chromatid exchanges(SCE) in N-ethyl-1198731015840-nitro-N-nitrosguanidine- (ENNG-)MMC- EMS- ENU- and MNU-treated cells but notN-methyl-N-nitrosoguanidine- (MNNG-) or MMS-treatedcellsThe effect was S-phase-dependent inMMC-treated cells[43 44] In contrast the frequency of chromosome aber-rations was significantly decreased in MMC-treated cells inphase G

2 by posttreatment with vanillin [44] In addition

vanillin-treatment in the G1phase suppressed X-ray-induced

breakage-type and exchange-type chromosome aberrationsTreatment with vanillin in phase G

2suppressed ultravio-

let light (UV) and X-ray-induced breakage types but notexchange-type chromosome aberrations [45] In experimentsperformed in Chinese hamster lung fibroblast V79 cellsvanillin reduced the frequencies of 6-thioguanine-resistantmutations induced by UV X-ray and ENU [46] The cyto-toxicity and chromosomal aberrations induced by hydrogenperoxide (H

2O2) were suppressed when V79 cells were

posttreated with vanillin However vanillin increased EMS-induced toxicity [47] Vanillin also reduces methotrexate-X-ray- and UV-induced micronucleated and binucleatedaberrant cells [48 49]

The in vivo antimutagenic effects of vanillin were studiedin X-ray- and MMC-induced micronuclei in mouse bonemarrow cells Posttreatment with vanillin caused decreasesin the frequency of X-ray- and MMC-induced micronucle-ated polychromatic erythrocytes [50 51] Vanillin was alsoinvestigated in themouse spot test usingmale PWand femaleC57BL10 mice Three successive oral administrations ofvanillin at 500mgkg decreased the ENU-induced frequencyof recessive carrier pups [46]

The ability of vanillin to inhibit photosensitization-induced single-strand breaks (ssbs) in plasmid pBR322 DNAhas been examined in a cell-free system independent of DNArepairreplication processes Vanillin was found to provideeffective DNA protection against photosensitization-inducedssbs (mainly type II reaction) in the absence of DNA repairreplication machinery or other cellular defenses which canbe in part due to its ability to scavenge O

2[23 52] On the

other hand vanillin was able to inhibit mutations at theCD59locus in human-hamster hybrid AL cells induced by H

2O2

MNNG and MMC but not 137Cs 120574-radiation The effectswere attributed to the ability of vanillin to inhibit the DNArepair process that leads to the death of potential mutants orto enhancement of DNA repair pathways that protect againstmutation but create lethal DNA lesions during the repair pro-cess [53] In addition vanillin is able to block DNA repair bynonhomologous DNA end-joining (NHEJ) and to selectively


inhibit DNA-protein kinase (DNA-PK) activity in experi-ments using human lymphoma GM00558 cells and relatedgene deficient cells Vanillin presented no detectable effectson other steps of the NHEJ process on unrelated proteinkinase or on DNA mismatch repair in cell extracts Vanillinalso potentiated the cytotoxicity of cisplatin but did not affectsensitivity to UV [54]

The antimutagenic potential of vanillin was also assessedusing both spontaneous and IQ-inducedmicronucleus frequ-encies in human hepatocellular carcinomaHepG2 cells Van-illin caused a moderate increase in micronucleus numbersat the high concentration tested (500120583gmL [sim3286120583M])however posttreatment of the cells with vanillin was ableto inhibit IQ-induced micronuclei [55] In addition globalgene expression in vanillin-treated mammalian cells wasassessed against spontaneous mutagenesis in mismatchrepair- (MMR-) deficient human colon cancer HCT116cells At concentrations of 05ndash25mM vanillin decreasedthe spontaneous mutant fraction At concentrations (05ndash25mM) that were antimutagenic in HCT116 cells vanillincaused DNA damage in both mismatch repair-proficient(HCT116 + chr3) and deficient (HCT116) cells A total of 64genes presented the expression changed in vanillin- treated-HCT116 cells (25mM for 4 h) including genes related tooxidative damage stress response DNA damage apoptosisand cell growth demonstrating that DNA damage contribu-tes to vanillinrsquos antimutagenic effect [56] Moreover vanillin(100 120583M) reduced UV-induced cytotoxicity and DNA dam-age in human keratinocyte stem cells It also increased theproduction of proinflammatory cytokines and decreased thephosphorylation of ataxia telangiectasia mutated (ATM)tumor suppressor protein 53 (p53) c-Jun N-terminal kinasestress-activated protein kinase (JNK) serine threonine kinasecheckpoint kinase 2 (Chk2) p38mitogen-activated proteinkinase (p38) S6 ribosomal protein (S6RP) and histone 2Afamily member X (H2AX) suggesting that the ATMp53pathway is involved in the vanillin-induced mutagen protec-tive mechanisms [57]

The protective effect of vanillin against KBrO3induced

liver bone and blood disorders has also been investigated[58 59] Coadministration of vanillin to KBrO

3-treated mice

significantly prevented DNA damage hepatic cell alterationand plasma transaminases increases inhibited hepatic lipidperoxidation and attenuated depletion of enzymatic andnonenzymatic antioxidants and expression levels of proin-flammatory cytokines including tumor necrosis factor-120572interleukin-1120573 interleukin-6 and COX2

Although vanillin has shown comutagenic effects in somemodels its antimutagenic effect (in concentration rangein 120583M) was extensively evaluated and appears to be due to itseffects on cell redox and DNA repair pathways (Figure 2)

5 Anti-Carcinogenic Activity

Since vanillin presents antimutagenic effect in differingmod-els and based on the close relationship between antimuta-genic and anticarcinogenic activities it was expected thatvanillin presents anticarcinogenic effect however few studies

Exogenous andendogenous cell

damage

DNA damage Vanillin

DNA repair

Oxidative stress

Mutagenesisrecombinogenesis

or cell death

Figure 2 Overview of the antimutagenic effect of vanillin

thus performed to investigate its anticarcinogenic effects haveshown only contradictory results

The anticarcinogenic effect of vanillin was first evaluatedin the initiation stage of hepatocarcinogenesis using an ani-malmodel In thismodel the ratswere given a diet containing1 vanillin for 8 days On day 7 the animals received a singledose of the hepatocarcinogen IQ and 12 h afterwards a two-third partial hepatectomy for initiation and 2 weeks there-after they were placed on a promotion regimen comprisingphenobarbital and a single dose of D-galactosamine Within11 weeks antioxidant effect was assessed by comparing valuesfor preneoplastic placental glutathione S-transferase positive(GST-P+) foci Vanillin significantly decreased the numberof GST-P+ focicm2 suggesting inhibitory effects on hepato-carcinogenesis initiation induced by the food carcinogen IQ[60]

Vanillin was also evaluated in a medium termmultiorganrat carcinogenesis model Carcinogen-treated male F344 ratsreceived vanillin in the diet at a dose of 1 Vanillin wasadministered from 1 day before and throughout the carcino-gen exposure period or after completion of the initiation reg-imen All surviving animals were sacrificed at the end of week36 In this model vanillin only weakly inhibited small intes-tine and lung carcinogenesis but significantly increased coloncarcinogenesis in the initiation phase and also enhanced thedevelopment of stomach and renal lesions in the promotionphase [61]

Recently the anticarcinogen or cocarcinogen effects ofvanillin were studied in azoxymethane- (AOM-) inducedaberrant crypt foci- (ACF-) bearing rats AOM-challengedrats were treated with vanillin orally and intraperitoneally atlow (150mgkg) and high (300mgkg) doses and then ACFdensity multiplicity distribution and gene expression wereobserved Vanillin consumed orally had no effect on ACFhowever when administered through intraperitoneal injec-tion at higher concentration vanillin was cocarcinogenicwhich could well increase ACF density and multiplicityThe expression of colorectal cancer biomarkers protoonco-genes (beta-cateninuarr and FOSuarr) recombinational repair(XRCC2uarr) mismatch repair (PMS2uarr) cell cycle arrest (p21uarrand cyclin Bdarr) and tumor suppressor gene (tumor suppressorgene p53uarr) were also affected by vanillin [62 63] The mixedanticarcinogeniccocarcinogenic results found for vanillinsuggest that other carcinogen models must be evaluated tobetter understand the role of vanillin on carcinogenesis


6 Anti-Invasive Antimetastatic andAntiangiogenic Activities

In cancer invasions the key events of metastasis and angio-genesis are considered to be therapeutic targets for cancerprevention and treatment and interestingly vanillin presentsanti-invasive antimetastatic and antiangiogenic activities indiffering models

In vitro studies reveal that vanillin in noncytotoxicconcentrations inhibits invasion and migration of mousemammary adenocarcinoma 4T1 cells and inhibits the enzy-matic activity of their metalloproteinase 9 (MMP-9) matrixsecretions [64] In addition vanillin (also in noncytotoxicconcentrations) reduces invasive capacity suppresses 12-O-tetradecanoylphorbol-13-acetate- (TPA-) induced enzymaticactivity of MMP-9 and decreases the mRNA level of MMP-9induced in HepG2 cells which occurs via downregulation ofthe NF-120581B signaling pathway [65] In the range of noncyto-toxic concentrations vanillin also exhibits inhibitory effectson hepatocyte growth factor- (HGF-) induced migration ofhuman lung A549 carcinoma cells this due to inhibitoryactivity of phosphatidylinositol 3-kinase (PI3K) The effecthas no correlation with the antioxidant activity of vanillin[66]

The in vivo antitumor antimetastatic and antiangiogeniceffects of vanillin have also been investigated The effect ofvanillin on the growth andmetastasis of 4T1 cells was assessedin BALBcmice In thismodel the 4T1 cells were injected intothe mammary fat pad in female mice Vanillin (100mgkg)was orally administrated 6 times per week for one monthstarting on the first day after tumor implantation Vanillin-treated animals showed significantly reduced numbers ofmetastasized lung colonies as compared to the controlswithout any inhibitory effect on primary tumor growth [64]The in vivo antiangiogenic activity of vanillin was determinedthrough inhibition of minor blood vessel formation (in chickchorioallantoic membrane CAM assay) between day 3 andday 4 of chick embryo development After exposure tovanillin for 24 h inhibition of the minor blood vessel forma-tion in day 4 eggs in the areas under the agarose pellets wasobserved at dosage in the range 100ndash500 nmolpellet egg [66]Despite the promising results found for the anti-invasiveantimetastatic and antiangiogenic activities of vanillin thedata are limited Further studies must be performed innew models to better characterize the effects and molecularpathways of vanillin

7 Cytotoxic Activity

Vanillin in high concentrations (mM range) has been des-cribed as a cytotoxic agent against many cell lines includingmouse fibroblast 3T3 cells [67 68] human ovarian carcinomaA2780-SC1 cells [54] human colorectal carcinoma HT-29cells [68] HepG2 cells [69] human cervical carcinoma HeLacells [70] and human colorectal carcinoma SW480 cells [71]However only a few studies investigated vanillinrsquos cytotoxicmechanism of action

The vanillin-treatment gene expression profile was eval-uated [69] in HepG2 cells Genes downregulated by vanillin

were grouped into three gene ontological categories regula-tion of cellular process cell cycle and death Further mostof the downregulated geneswere associatedwith cancer prog-ression Analysis of Fos-related transcription factor activa-tor protein 1 (AP-1) showed that vanillin inhibits AP-1 acti-vity while diminishing the phosphorylation of extracellu-lar signal-regulated protein kinase (ERK) thus indicatingvanillin-regulatedAP-1 activity via the ERKpathway In otherresults [68] vanillin was able to induce both cytolytic andcytostatic effects in HT-29 cells It also led to cell deaththrough apoptosis pathways Cell cycle analysis showed thatvanillin induces G

0G1

arrest at lower concentrations(200120583gmL [sim1315 120583M]) while leading to G

2M arrest at

higher concentrations (1000 120583gmL [sim6573120583M]) In addi-tion pretreatment of HeLa cells with vanillin enhancedtumor necrosis factor-related apoptosis-inducing ligand(TRAIL) induced cell death through inhibition of NF-120581Bactivation [70] As cited above the cytotoxic effect of vanillinis yet poorly reported but based on the fact that it presentscytotoxicity only in high concentrations its potential as acytotoxic agent is low The therapeutic potential of vanillinseems to be linked to its chemopreventive anti-invasive anti-metastatic and antiangiogenic actions (Table 1)

8 Conclusion

The studies presented in this review reveal vanillinrsquos antioxi-dant activity its antitumor action and its therapeutic poten-tial in cancer treatment and prevention Consequently theuse of vegetables rich in this natural product might well beuseful in inhibiting the free radicals responsible for tumordevelopment The data reported in this review are in accor-dance with the scientific understanding that a better qualityof life and increased longevity may be obtained via healthyfood with the beneficial action of natural bioactive products

Abbreviations

4-NQO 4-Nitroquinoline 1-oxideAAPH 221015840-Azobis(2-methylpropionamidine)

dihydrochlorideABTS∙+ 221015840-Azinobis(3-ethylbenzothiazoline-6-sulfonic

acid) radical cationACF Aberrant crypt fociAF-2 FurylfuramideAOM AzoxymethaneAP-1 Activator protein 1ATM Ataxia telangiectasia mutatedChk2 Serine threonine kinase checkpoint kinase 2DNA-PK DNA-protein kinaseDPPH 11-Diphenyl-picrylhydrazylEMS Ethyl methanesulfonateENNG 119873-Ethyl-1198731015840-nitro-119873-nitrosguanidineENU 119873-Ethyl-119873-nitrosoureaERK Extracellular signal-regulated protein kinase


Table 1 Summary of the main molecular targets of vanillin

Biological process Molecular target

Cell proliferation and cell cycleAktdarr AP-1darr ATMdarr aurora kinase Bdarr calcyclindarr Chk2darr CTGF cyclin A2darr cyclin Bdarr cyclin

D1darr ERKdarr H2AXdarr INSIG1darr I120581B-120572 darr JNKdarr JUNDdarr MAP2K2darr MARK4darr MMP-9darr NF-120581Bdarrp38darr p65darr PCNAdarr PI3Kdarr polo-like kinase 1darr S6RPdarr survivindarr TGFB1I1darr 120573-cateninuarr FOSuarr

DNA damage oxidative and stressresponses

CLK2uarr DDIT4uarr GCLCuarr GCLMuarr HMOX1uarr HSPA1Buarr PMS2uarr SLC7A11uarr TRIM16uarr UGP2uarrXRCC2uarr DNA-PKdarr DNMT3Bdarr DUSP6darr FGFR2darr FZD2darr NHEJdarr PPP1R10darr SLC35D2darr

UNG2darrApoptosis p21uarr p53uarrInvasion and metastasis MMP-9darr PI3KdarrAkt protein kinase B AP-1 activator protein 1 ATM ataxia telangiectasia mutated Chk2 serine threonine kinase checkpoint kinase 2 CLK2 CDC-likekinase 2 CTGF connective tissue growth factor DDIT4 damage-inducible transcript 4 DNA-PK DNA-protein kinase DNMT3B DNA (cytosine-5-)-methyltransferase 3 beta DUSP6 dual specificity phosphatase 6 ERK extracellular signal-regulated protein kinase FGFR2 fibroblast growth factor receptor2 FZD2 frizzled homolog 2 (Drosophila) GCLC glutamate-cysteine ligase catalytic subunit GCLM glutamate-cysteine ligase modifier subunit H2AXhistone 2A family member X HMOX1 heme oxygenase (decycling) 1 HSPA1B heat shock 70 kDa protein 1B INSIG1 insulin induced gene 1 I120581B-120572 nuclearfactor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha JNK c-jun N-terminal kinasestress-activated protein kinase JUND jun D proto-oncogene MAP2K2 mitogen-activated protein kinase kinase 2 MARK4 MAPmicrotubule affinity-regulating kinase 4 MMP-9 matrix metalloproteinase9 NF-120581B factor nuclear kappa B NHEJ non-homologous DNA end-joining p21 cyclin-dependent kinase inhibitor 1 p38 p38mitogen-activated proteinkinase p53 tumor suppressor protein 53 p65 transcription factor p65 PCNA proliferating cell nuclear antigen PI3K phosphatidylinositol 3-kinase PMS2mismatch repair endonuclease PPP1R10 protein phosphatase 1 regulatory subunit 10 S6RP S6 ribosomal protein SLC35D2 solute carrier family 35 memberD2 SLC7A11 solute carrier family 7 TGFB1I1 transforming growth factor beta 1 induced transcript 1 TRIM16 tripartite motif-containing 16 UGP2 UDP-glucose pyrophosphorylase 2 UNG2 uracil-DNA glycosylase 2 XRCC2 DNA repair protein

GST-P+ Preneoplastic glutathioneS-transferase placental form-positive

H2AX Histone 2A family member XH2O2 Hydrogen peroxide

HGF Hepatocyte growth factorIQ 2-Amino-3-methylimidazo[45-

f ]quinolineJNK c-Jun N-terminal

kinasestress-activated protein kinaseMMC Mitomycin CMMP-9 Matrix metalloproteinase 9MMS Methyl methanesulfonateMNNG 119873-Methyl-119873-nitrosoguanidineMNU 119873-Methyl-119873-nitrosoureaNF-120581B Factor nuclear kappa BNHEJ Nonhomologous DNA end-joiningORAC Oxygen radical absorbance capacityOxHLIA Oxidative hemolysis inhibition assayp38 p38mitogen-activated protein kinasep53 Tumor suppressor protein 53potassium bromate KBrO

3

PI3K Phosphatidylinositol 3-kinaseS6RP S6 ribosomal proteinSCE Sister-chromatid exchangesssbs Single-strand breaksTPA 12-O-Tetradecanoylphorbol-13-acetateTRAIL Tumor necrosis factor-related

apoptosis-inducing ligandTrp-P-2 3-Amino-l-methyl-5119867-pyrido[43-

119887]indoleUV Ultraviolet light

Competing Interests

The authors declare no conflict of interests

Acknowledgments

The authors are grateful to the Conselho Nacional de Desen-volvimento Cientıfico e Tecnologico (CNPq) and the Coor-denacao de Aperfeicoamento de Pessoal de Nıvel Superior(CAPES) by financial support

References

[1] G Waris and H Ahsan ldquoReactive oxygen species role in thedevelopment of cancer and various chronic conditionsrdquo Journalof Carcinogenesis vol 5 article 14 2006

[2] M V Sobral A L Xavier T C Lima and D P De Sousa ldquoAnti-tumor activity of monoterpenes found in essential oilsrdquo TheScientific World Journal vol 2014 Article ID 953451 35 pages2014

[3] A A Carvalho L N Andrade E B V de Sousa and D P deSousa ldquoAntitumor phenylpropanoids found in essential oilsrdquoBioMed Research International vol 2015 Article ID 392674 21pages 2015

[4] L N Andrade T C Lima R G Amaral et al ldquoEvaluation of thecytotoxicity of structurally correlated p-menthane derivativesrdquoMolecules vol 20 no 7 pp 13264ndash13280 2015

[5] D P de Sousa Bioactive Essential Oils and Cancer SpringerInternational New York NY USA 1st edition 2015

[6] V Georgiev A Ananga and V Tsolova ldquoRecent advances anduses of grape flavonoids as nutraceuticalsrdquo Nutrients vol 6 no1 pp 391ndash415 2014

[7] C Kandaswami L T Lee P P Lee et al ldquoThe antitumor acti-vities of flavonoidsrdquo In Vivo vol 19 pp 895ndash909 2005

[8] H Priefert J Rabenhorst and A Steinbuchel ldquoBiotechnolog-ical production of vanillinrdquo Applied Microbiology and Biotech-nology vol 56 no 3-4 pp 296ndash314 2001

[9] G S Clark ldquoVanillin perfumerdquoFlavour vol 15 pp 45ndash54 1990


[10] N A Zamzuri and S Abd-Aziz ldquoBiovanillin from agro wastesas an alternative food flavourrdquo Journal of the Science of Food andAgriculture vol 93 no 3 pp 429ndash438 2013

[11] L S Pedroso GM Favero L E A De Camargo RMMainar-des and N M Khalil ldquoEffect of the o-methyl catechols apocy-nin curcumin and vanillin on the cytotoxicity activity of tamox-ifenrdquo Journal of Enzyme Inhibition andMedicinal Chemistry vol28 no 4 pp 734ndash740 2013

[12] A Tai T Sawano F Yazama and H Ito ldquoEvaluation of anti-oxidant activity of vanillin by usingmultiple antioxidant assaysrdquoBiochimica et Biophysica ActamdashGeneral Subjects vol 1810 no 2pp 170ndash177 2011

[13] T Sawa M Nakao T Akaike K Ono and H Maeda ldquoAlkyl-peroxyl radical-scavenging activity of various flavonoids andother phenolic compounds implications for the anti-tumor-promoter effect of vegetablesrdquo Journal of Agricultural and FoodChemistry vol 47 no 2 pp 397ndash402 1999

[14] B N Ames andM K Shigenaga ldquoDNAdamage by endogenousoxidants and mitogenesis as causes of aging and cancerrdquo inMolecular Biology of Free Radical Scavengers System J GScandalios Ed pp 1ndash22 Cold Spring Harbor Laboratory PressPlain-View NY USA 1993

[15] B N Ames and L S Gold ldquoChemical carcinogenesis too manyrodent carcinogensrdquo Proceedings of the National Academy ofSciences of the United States of America vol 87 no 19 pp 7772ndash7776 1990

[16] S AhmadOxidative Stress and Antioxidant Defenses in BiologyChapman amp Hall New York NY USA 1995

[17] Z Yan-Chun and Z Rong-Liang ldquoPhenolic compounds andan analog as superoxide anion scavengers and anti oxidantsrdquoBiochemical Pharmacology vol 42 no 6 pp 1177ndash1179 1991

[18] M Deters H Knochenwefel D Lindhorst et al ldquoDifferent cur-cuminoids inhibit T-lymphocyte proliferation independentlyof their radical scavenging activitiesrdquo Pharmaceutical Researchvol 25 no 8 pp 1822ndash1827 2008

[19] B N Shyamala M Madhava Naidu G Sulochanamma and PSrinivas ldquoStudies on the antioxidant activities of natural vanillaextract and its constituent compounds through in vitromodelsrdquoJournal of Agricultural and Food Chemistry vol 55 no 19 pp7738ndash7743 2007

[20] A Rosa M Deiana G Corona et al ldquoProtective effect ofcapsinoid on lipid peroxidation in rat tissues induced by Fe-NTArdquo Free Radical Research vol 39 no 11 pp 1155ndash1162 2005

[21] J P Kamat A Ghosh and T P A Devasagayam ldquoVanillin as anantioxidant in rat liver mitochondria inhibition of protein oxi-dation and lipid peroxidation induced by photosensitizationrdquoMolecular and Cellular Biochemistry vol 209 no 1-2 pp 47ndash532000

[22] RHarish S Divakar A Srivastava andT Shivanandappa ldquoIso-lation of antioxidant compounds from themethanolic extract ofthe roots of Decalepis hamiltonii (Wight and Arn)rdquo Journal ofAgricultural and Food Chemistry vol 53 no 20 pp 7709ndash77142005

[23] D K Maurya S Adhikari C K K Nair and T P ADevasagayam ldquoDNA protective properties of vanillin against120574-radiation under different conditions possible mechanismsrdquoMutation Research vol 634 no 1-2 pp 69ndash80 2007

[24] C Dhanalakshmi T Manivasagam J Nataraj A JThenmozhiand M M Essa ldquoNeurosupportive role of vanillin a naturalphenolic compound on rotenone induced neurotoxicity in SH-SY5Y neuroblastoma cellsrdquo Evidence-Based Complementary

and Alternative Medicine vol 2015 Article ID 626028 11 pages2015

[25] MMakni Y Chtourou H Fetoui E M Garoui T Boudawaraand N Zeghal ldquoEvaluation of the antioxidant anti-inflamma-tory and hepatoprotective properties of vanillin in carbon tetra-chloride-treated ratsrdquo European Journal of Pharmacology vol668 no 1-2 pp 133ndash139 2011

[26] H Ben Saad D Driss S Ellouz Chaabouni et al ldquoVanillinmiti-gates potassium bromate-induced molecular biochemical andhistopathological changes in the kidney of adult micerdquo Che-mico-Biological Interactions vol 252 pp 102ndash113 2016

[27] L R G Castor K A Locatelli and V F Ximenes ldquoPro-oxidantactivity of apocynin radicalrdquo Free Radical Biology andMedicinevol 48 no 12 pp 1636ndash1643 2010

[28] K C Machado G L S Oliveira E B V de Sousa et al ldquoSpect-roscopic studies on the in vitro antioxidant capacity of isopentylferulaterdquo Chemico-Biological Interactions vol 225 pp 47ndash532015

[29] B Dimitrios ldquoSources of natural phenolic antioxidantsrdquo Trendsin Food Science and Technology vol 17 no 9 pp 505ndash512 2006


[31] T Kada and K Shimoi ldquoDesmutagens and bio-antimutagensmdashtheir modes of actionrdquo BioEssays vol 7 no 3 pp 113ndash116 1987

[32] T Ohta M Watanabe K Watanabe Y Shirasu and T KadaldquoInhibitory effects of flavourings on mutagenesis induced bychemicals in bacteriardquo Food and Chemical Toxicology vol 24no 1 pp 51ndash54 1986

[33] T Ohta M Watanabe Y Shirasu and T Inoue ldquoPost-replica-tion repair and recombination in uvrAumuC strains of Escheri-chia coli are enhanced by vanillin an antimutagenic comp-oundrdquoMutation Research vol 201 no 1 pp 107ndash112 1988

[34] K Takahashi M Sekiguchi and Y Kawazoe ldquoEffects of vanillinand o-vanillin on induction of DNA-repair networks modula-tion of mutagenesis in Escherichia colirdquo Mutation ResearchFundamental and Molecular Mechanisms of Mutagenesis vol230 no 2 pp 127ndash134 1990

[35] D T Shaughnessy RW Setzer and DM DeMarini ldquoThe anti-mutagenic effect of vanillin and cinnamaldehyde on spontan-eous mutation in Salmonella TA104 is due to a reduction inmutations at GC but not AT sitesrdquo Mutation ResearchFunda-mental andMolecular Mechanisms of Mutagenesis vol 480-481pp 55ndash69 2001

[36] S De Flora C Bennicelli A Rovida L Scatolini and ACamoirano ldquoInhibition of the lsquospontaneousrsquo mutagenicity inSalmonella typhimuriumTA102 andTA104rdquoMutationResearchFundamental and Molecular Mechanisms of Mutagenesis vol307 no 1 pp 157ndash167 1994

[37] D T Shaughnessy R M Schaaper D M Umbach and D MDeMarini ldquoInhibition of spontaneous mutagenesis by vanillinand cinnamaldehyde in Escherichia coli dependence on recom-binational repairrdquo Mutation Research vol 602 no 1-2 pp 54ndash64 2006

[38] H H R de Andrade J H Santos M C Gimmler-Luz M J FCorrea M Lehmann and M L Reguly ldquoSuppressing effect ofvanillin on chromosome aberrations that occur spontaneouslyor are induced by mitomycin C in the germ cell line of Droso-phila melanogasterrdquoMutation Research vol 279 no 4 pp 281ndash287 1992


[39] J H Santos U Graf M L Reguly and H H Rodrigues DeAndrade ldquoThe synergistic effects of vanillin on recombinationpredominate over its antimutagenic action in relation toMMC-induced lesions in somatic cells of Drosophila melanogasterrdquoMutation ResearchGenetic Toxicology and Environmental Mut-agenesis vol 444 no 2 pp 355ndash365 1999

[40] M Sinigaglia M L Reguly and H H Rodrigues De AndradeldquoEffect of vanillin on toxicant-induced mutation and mitoticrecombination in proliferating somatic cells of Drosophilamelanogasterrdquo Environmental and Molecular Mutagenesis vol44 no 5 pp 394ndash400 2004

[41] M Sinigaglia M Lehmann P Baumgardt et al ldquoVanillin as amodulator agent in SMART test inhibition in the steps thatprecede N-methyl-N-nitrosourea- N-ethyl-N-nitrosourea-ethylmethanesulphonate- and bleomycin-genotoxicityrdquo Muta-tion ResearchGenetic Toxicology and Environmental Mutagene-sis vol 607 no 2 pp 225ndash230 2006

[42] M P Furlanetto M Sinigaglia V S Do Amaral R R Dihl andH H R De Andrade ldquoEffect of vanillin on toxicant-inducedlethality in the Drosophila melanogaster DNA repair testrdquoEnvironmental andMolecularMutagenesis vol 48 no 1 pp 67ndash70 2007

[43] Y F Sasaki H Imanishi T Ohta andY Shirasu ldquoEffects of anti-mutagenic flavourings on SCEs induced by chemical mutagensin cultured Chinese hamster cellsrdquo Mutation ResearchGeneticToxicology vol 189 no 3 pp 313ndash318 1987

[44] Y Sasaki H Imanishi T Ohta and Y Shirasu ldquoEffects ofvanillin on sister-chromatid exchanges and chromosome aber-rations induced by mitomycin C in cultured Chinese hamsterovary cellsrdquoMutation Research Letters vol 191 no 3-4 pp 193ndash200 1987

[45] Y Sasaki H Imanishi M Watanabe T Ohta and Y ShirasuldquoSuppressing effect of antimutagenic flavorings on chromosomeaberrations induced by UV-light or X-rays in cultured Chinesehamster cellsrdquoMutation Research vol 229 no 1 pp 1ndash10 1990

[46] H Imanishi Y Sasaki K Matsumoto et al ldquoSuppression of6-TG-resistant mutations in V79 cells and recessive spot forma-tions in mice by vanillinrdquo Mutation Research Letters vol 243no 2 pp 151ndash158 1990

[47] K Tamai H Tezuka and Y Kuroda ldquoDifferent modificationsby vanillin in cytotoxicity and genetic changes induced byEMS and H

2O2in cultured Chinese hamster cellsrdquo Mutation

Research vol 268 no 2 pp 231ndash237 1992[48] C Keshava N Keshava W Z Whong J Nath and T M Ong

ldquoInhibition of methotrexate-induced chromosomal damage byvanillin and chlorophyllin in V79 cellsrdquo Teratogenesis Carcino-genesis and Mutagenesis vol 17 pp 313ndash326 1997-1998

[49] C Keshava N Keshava T-M Ong and J Nath ldquoProtectiveeffect of vanillin on radiation-induced micronuclei and chro-mosomal aberrations in V79 cellsrdquoMutation Research vol 397no 2 pp 149ndash159 1998

[50] T Inouye Y F Sasaki H Imanishi M Watanabe T Ohta andY Shirasu ldquoSuppression of mitomycin C-induced micronucleiin mouse bone marrow cells by post-treatment with vanillinrdquoMutation Research vol 202 no 1 pp 93ndash95 1988

[51] Y Sasaki T Ohta H Imanishi et al ldquoSuppressing effects ofvanillin cinnamaldehyde and anisaldehyde on chromosomeaberrations induced by X-rays in micerdquo Mutation ResearchLetters vol 243 no 4 pp 299ndash302 1990

[52] S S Kumar A Ghosh T P A Devasagayam and P S ChauhanldquoEffect of vanillin on methylene blue plus light-induced single-strand breaks in plasmid pBR322DNArdquoMutation Research vol469 no 2 pp 207ndash214 2000

[53] D L Gustafson H R Franz A M Ueno C J Smith D JDoolittle and C AWaldren ldquoVanillin (3-methoxy-4-hydroxy-benzaldehyde) inhibits mutation induced by hydrogen perox-ide N-methyl-N-nitrosoguanidine and mitomycin C but not137Cs-120574-radiation at the CD59 locus in human-hamster hybridA119871cellsrdquoMutagenesis vol 15 no 3 pp 207ndash213 2000

[54] S Durant and P Karran ldquoVanillinsmdasha novel family of DNA-PKinhibitorsrdquoNucleic Acids Research vol 31 no 19 pp 5501ndash55122003

[55] R Sanyal F Darroudi W Parzefall M Nagao and S Knas-muller ldquoInhibition of the genotoxic effects of heterocyclicamines in human derived hepatoma cells by dietary bioantimu-tagensrdquoMutagenesis vol 12 no 4 pp 297ndash303 1997

[56] A A King D T Shaughnessy KMure et al ldquoAntimutagenicityof cinnamaldehyde and vanillin in human cells global geneexpression and possible role of DNA damage and repairrdquoMutation ResearchFundamental and Molecular Mechanisms ofMutagenesis vol 616 no 1-2 pp 60ndash69 2007

[57] J Lee J Y Cho S Y Lee K-W Lee J Lee and J-Y SongldquoVanillin protects human keratinocyte stem cells against Ultra-violet B irradiationrdquo Food and Chemical Toxicology vol 63 pp30ndash37 2014

[58] H Ben Saad I Ben Amara N Krayem et al ldquoAmeliorativeeffects of vanillin on potassium bromate induces bone andblood disorders in vivordquo Cellular andMolecular Biology vol 61pp 12ndash22 2015

[59] H Ben Saad D Driss I Ben Amara et al ldquoAltered hepaticmRNA expression of immune response-associated DNA dam-age in mice liver induced by potassium bromate protective roleof vanillinrdquo Environmental Toxicology vol 31 no 12 pp 1796ndash1807 2016

[60] H Tsuda N Uehara Y Iwahori et al ldquoChemopreventive effectsof120573-carotene120572-tocopherol and five naturally occurring antiox-idants on initiation of hepatocarcinogenesis by 2-amino-3-methylimidazo[45-f ]quinoline in the ratrdquo Japanese Journal ofCancer Research vol 85 no 12 pp 1214ndash1219 1994

[61] K Akagi M Hirose T Hoshiya Y Mizoguchi N Ito and TShirai ldquoModulating effects of ellagic acid vanillin and quercetinin a rat medium term multi-organ carcinogenesis modelrdquoCancer Letters vol 94 no 1 pp 113ndash121 1995

[62] K L Ho P P Chong L S Yazan andM Ismail ldquoVanillin differ-entially affects azoxymethane-injected rat colon carcinogenesisand gene expressionrdquo Journal of Medicinal Food vol 15 no 12pp 1096ndash1102 2012

[63] S Kapoor ldquoMultiorgan anticarcinogenic effects of vanillinrdquoJournal of Medicinal Food vol 16 no 9 pp 777ndash777 2013

[64] K Lirdprapamongkol H Sakurai N Kawasaki et al ldquoVanillinsuppresses in vitro invasion and in vivo metastasis of mousebreast cancer cellsrdquo European Journal of Pharmaceutical Sci-ences vol 25 no 1 pp 57ndash65 2005

[65] J-A Liang S-L Wu H-Y Lo C-Y Hsiang and T-YHo ldquoVanillin inhibits matrix metalloproteinase-9 expressionthrough down-regulation of nuclear factor-120581B signaling path-way in human hepatocellular carcinoma cellsrdquoMolecular Phar-macology vol 75 no 1 pp 151ndash157 2009

[66] K Lirdprapamongkol J-P Kramb T Suthiphongchai et alldquoVanillin suppresses metastatic potential of human cancer cells


through PI3K inhibition and decreases angiogenesis in vivordquoJournal of Agricultural and Food Chemistry vol 57 no 8 pp3055ndash3063 2009

[67] H Babich E Borenfreund andA Stern ldquoComparative cytotox-icities of selected minor dietary non-nutrients with chemopre-ventive propertiesrdquo Cancer Letters vol 73 no 2-3 pp 127ndash1331993

[68] K Ho L S Yazan N Ismail and M Ismail ldquoApoptosis and cellcycle arrest of human colorectal cancer cell line HT-29 inducedby vanillinrdquo Cancer Epidemiology vol 33 no 2 pp 155ndash1602009

[69] W-Y Cheng C-Y Hsiang D-T Bau et al ldquoMicroarrayanalysis of vanillin-regulated gene expression profile in humanhepatocarcinoma cellsrdquo Pharmacological Research vol 56 no6 pp 474ndash482 2007

[70] K Lirdprapamongkol H Sakurai S Suzuki et al ldquoVanillinenhances TRAIL-induced apoptosis in cancer cells throughinhibition of NF-kappaB activationrdquo In Vivo vol 24 no 4 pp501ndash506 2010

[71] J Deb H Dibra S Shan et al ldquoActivity of aspirin analoguesand vanillin in a human colorectal cancer cell linerdquo OncologyReports vol 26 no 3 pp 557ndash565 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


O

OH

OCH3

Figure 1 Chemical structure of vanillin (4-hydroxy-3-methoxy-benzaldehyde)

2 Methodology

Searches were performed in the scientific literature databasesPubMed and Web of Science through June 2016 using thefollowing key words vanillin antitumor anticancer oxidantandor antioxidant

3 Antioxidant and Prooxidant Effects

It is well known that neither O2

∙minus nor H2O2is capable of

interacting with either deoxyribose or the base portions ofDNA this suggests that the secondarily derived ∙OH radicalmay be the primary reactive species Once generated ∙OHmay interact with DNA to produce at least 20 different DNAoxidation products [14] The idea that a major risk factorfor cancer is mitogenesis has also been proposed It haslong been appreciated that dividing cells are at an increasedrisk for developing mutations as compared to quiescentcells [15] Oxidants produced by inflammatory leukocytesmay induce mutagenesis and possibly carcinogenesis bypromoting mitogenesis and by modifying DNA bases [16]There is an increasing interest in oxygen-containing freeradicals in biological systems because of their perceivedroles as causative agents in the etiology of a variety ofchronic disorders Many natural products having antioxidantactivities show protective biochemical functions and suchmetabolites have become subjects of great interest A betterunderstanding of the mechanisms of oxidative biologicalreactions (and their inhibition) should help to understandand treat or prevent various diseases such as cancer

In regard of the antioxidant effect of vanillin somemixedresults have been reported Vanillin had weak superoxideanion scavenging activity (IC

50of 2945 plusmn 247 120583M) and

exhibited no or little antioxidant activity against lipid per-oxidation in mouse liver microsomes (inactive at 3285 120583M)[17] 11-diphenyl-picrylhydrazyl (DPPH) radical scavengingassay (IC

50value higher than 100120583M) [18] 120573-carotene

decolorization assay [19] and linoleic acid and cholesteroloxidation assays [20] On the other hand vanillin at 25mMinhibited protein oxidation and lipid peroxidation induced byphotosensitization with methylene blue plus light in rat livermitochondria [21] It also exhibited hydroxyl radical [22] and221015840-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radi-cal cation (ABTS∙+) (IC

50value of 1625 120583M) [23] scavenging

activities

Furthermore Tai et al [12] assessed the antioxidant effectof vanillin using multiple antioxidant assays Vanillin showedpotent antioxidant activity in the ABTS∙+ scavenging assayin the oxygen radical absorbance capacity (ORAC) assayand in the oxidative hemolysis inhibition assay (OxHLIA)but showed no activity in the DPPH radical and galvinoxylradical scavenging assays Its antioxidant mechanism is viaself-dimerization The dimerization contributed to the highreaction stoichiometry against ABTS∙+ and 221015840-azobis(2-methylpropionamidine) dihydrochloride- (AAPH-) derivedradicals to result in the strong antioxidant effect of vanillin[12] Pretreatment of vanillin (100 nM) also reduced rotenoneinduced mitochondrial dysfunction oxidative stress andapoptosis in SH-SY5Y neuroblastoma cells [24] These datareinforce that vanillin presents interesting antioxidant prop-erties which is dependent on the method used

In in vivo antioxidant assay mice were orally given asingle dose (100mgkg) of vanillin The highest activity inthe plasma ORAC assay was observed at 5min when theconcentrations of vanillin vanillic acid and protocatechuicacid were high [12] Moreover pretreatment with vanillin(150mgkg) presented hepatoprotective effect against carbontetrachloride-induced hepatotoxicity by the inhibition ofprotein and lipid oxidation processes the increase in antiox-idant enzymes activities and the inhibition of inflammationmediators [25] More recently Ben Saad et al [26] demon-strated the protective effects of vanillin against potassiumbromate- (KBrO

3-) induced oxidative stress The treatment

with vanillin (100mgkgday for 15 days) reduced histopatho-logical changes in KBrO

3-induced kidney and decreased

renal oxidative damage by inhibiting ROS generation andreversing antioxidant enzyme activities in kidney [26] Theseeffects may be results of interactions between vanillin andcellular proteins or signaling pathways

In relation of the prooxidant effect of vanillin Castor etal [27] have reported that vanillin can has prooxidant actionwhen its transient free radicals are generated intracellularlyTransient free radicals from vanillin were generated byhorseradish peroxidasehydrogen peroxide-mediated oxida-tion and their prooxidant effects were assessed using cysteineglutathione ovalbumin and the coenzyme NADPH as targetbiomolecules Vanillin at concentration of 10120583M promotedoxidation of glutathione sulfhydryl groups and NADPH atexperimental conditions [27] This prooxidant activity canexplain its cytotoxic action in some tumor cell lines Brieflywe believe that both antioxidant and prooxidant character-istics of vanillin contribute to its benefits and deleteriouseffectsThe antioxidant activity of vanillin seems to be relatedto its antimutagenic and anticarcinogenic activities In con-trast the prooxidant effects of vanillin radicals can be relatedto its anti-invasive antimetastatic antiangiogenic and cyto-toxic activities

The antioxidant activity of phenolic substances has beenreported for several natural substances structurally similar tovanillinThe hydroxyl of the aromatic ring plays an importantrole in the antioxidant activity via the homolytic fragmenta-tion of the O-H bond [28 29] It has been reported that vanil-lin exhibited hydroxyl radical [30] and 221015840-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS∙+)


















2[23 52] On the


2O2







3-treated mice






damage

DNA damage Vanillin

DNA repair

Oxidative stress


or cell death















0G1


2M arrest at


8 Conclusion


Abbreviations

















3




Competing Interests


Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































2[23 52] On the


2O2







3-treated mice






damage

DNA damage Vanillin

DNA repair

Oxidative stress


or cell death















0G1


2M arrest at


8 Conclusion


Abbreviations

















3




Competing Interests


Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















3-treated mice






damage

DNA damage Vanillin

DNA repair

Oxidative stress


or cell death















0G1


2M arrest at


8 Conclusion


Abbreviations

















3




Competing Interests


Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























0G1


2M arrest at


8 Conclusion


Abbreviations

















3




Competing Interests


Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























3




Competing Interests


Acknowledgments


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 overview of the role of vanillin on redox

Documents