biomolecules
Re iew
An ioxidan s: Posi i e o Nega i e Ac o s?
Baha e Salehi 1,2 , Miquel Ma o ell 3, Jack L. A bise 4,*, An oni Su eda 5,
Na ália Ma ins 6,7,* , Pawan Kuma Mau ya 8, Mehdi Sha i i-Rad 9, P adeep Kuma 10,* and
Ja ad Sha i i-Rad 11,12,*
1Medical E hics and Law Resea ch Cen e , Shahid Behesh i Uni e si y o Medical Sciences,
Teh an 88777539, I an; baha [email p o ec ed]
2S uden Resea ch Commi ee, Shahid Behesh i Uni e si y o Medical Sciences, Teh an 22439789, I an
3Depa men o Nu i ion and Die e ics, Facul y o Pha macy, Uni e si y o Concepcion,
Concepcion 4070386, Chile; [email p o ec ed]
4Depa men o De ma ology, Emo y Uni e si y School o Medicine, A lan a Ve e ans Adminis a ion
Medical Cen e , Winship Cance Ins i u e, A lan a, GA 30322, USA
5
Resea ch G oup on Communi y Nu i ion and Oxida i e S ess (NUCOX) and CIBEROBN (Physiopa hology
o Obesi y and Nu i ion CB12/03/30038), Uni e si y o Balea ic Islands, E-07122 Palma de Mallo ca,
Balea ic Islands, Spain; [email p o ec ed]
6Facul y o Medicine, Uni e si y o Po o, Alameda P o . He nâni Mon ei o, 4200-319 Po o, Po ugal
7Ins i u e o Resea ch and Inno a ion in Heal h (i3S), Uni e si y o Po o, 4200-135 Po o, Po ugal
8Ami y Ins i u e o Bio echnology, Ami y Uni e si y, U a P adesh, Noida 201303, India;
kuma [email p o ec ed]
9Zabol Medicinal Plan s Resea ch Cen e , Zabol Uni e si y o Medical Sciences, Zabol 61615585, I an;
[email p o ec ed]
10 Depa men o Fo es y, No h Eas e n Regional Ins i u e o Science and Technology,
Ni juli 791109, A unachal P adesh, India
11 Phy ochemis y Resea ch Cen e , Shahid Behesh i Uni e si y o Medical Sciences, Teh an 11369, I an
12 Depa men o Chemis y, Richa dson College o he En i onmen al Science Complex,
The Uni e si y o Winnipeg, Winnipeg, MB R3B 2G3, Canada
*Co espondence: ja bise@emo y.edu (J.L.A.); [email p o ec ed] (N.M.); [email p o ec ed] (P.K.);
[email p o ec ed] (J.S.-R.); Tel.: +351-225-512-100 (N.M.); +91-76-2884-1479 (P.K.);
+98-21-8820-0104 (J.S.-R.)
Recei ed: 14 Sep embe 2018; Accep ed: 17 Oc obe 2018; Published: 25 Oc obe 2018


Abs ac :
The e m “an ioxidan ” is one o he mos con using de ini ions in biological/medical
sciences. In chemis y, “an ioxidan ” is simply concei ed “a compound ha emo es eac i e species,
mainly hose oxygen-de i ed”, while in a cell con ex , he concep ual de ini ion o an an ioxidan is
poo ly unde s ood. Indeed, non-clinically ecommended an ioxidan s a e o en consumed in la ge
amoun s by he global popula ion, based on he belie ha cance , in lamma ion and degene a i e
diseases a e igge ed by high oxygen le els (o eac i e oxygen species) and ha h ough blocking
eac i e species p oduc ion, o ganic unbalances/diso de s can be p e en ed and/o e en ea ed.
The popula i y o hese chemicals a ises in pa om he widesp ead public mis us o allopa hic
medicine. In ac , eac i e oxygen species play a dual ole in dealing wi h di e en diso de s,
since hey may con ibu e o disease onse and/o p og ession bu may also play a key ole in disease
p e en ion. Fu he , he abili y o he mos commonly used supplemen s, such as i amins C, E,
selenium, and he bal supplemen s o dec ease pa hologic eac i e oxygen species is no clea ly
es ablished. Hence, he p esen e iew aims o p o ide a nuanced unde s anding o whe e cu en
knowledge is and whe e i should go.
Keywo ds: an ioxidan s; cance ; in lamma ion; na u al p oduc s; eac i e species
Biomolecules 2018,8, 124; doi:10.3390/biom8040124 www.mdpi.com/jou nal/biomolecules
Biomolecules 2018,8, 124 2 o 11
1. In oduc ion
Ae obic cells p oduce eac i e oxygen species (ROS) as a me abolic p ocess byp oduc .
ROS cause mac omolecules-oxida i e damages when body an ioxidan de enses a e o e whelmed.
Jones ede ined oxida i e s ess as a dis up ion o edox signaling and con ol [
1
]. Howe e , a ce ain
amoun o oxida i e damage akes place e en unde no mal condi ions, besides o be obse ed,
a ise in damage a e wi h aging and disease p ocesses, since an ioxidan and epai mechanisms
e iciency dec eases [
2
]. On he o he hand, oxida i e/ni osa i e s ess (O and NS) has also been
ma kedly implica ed in he pa hophysiology o many diso de s [
2
]. B ie ly, O and NS a e de ined as
an imbalance be ween ROS p oduc ion and ROS neu alizing/coun e ac ing o ganic abili y, h ough
an ioxidan and de oxi ying mechanisms. Reac i e oxygen and ni ogen species (ROS/RNS), such as
he supe oxide adical (O
2
−.
), hyd ogen pe oxide (H
2
O
2
), he hyd oxyl adical (
.
OH), ni ic oxide
(NO) and pe oxyni i e (ONOO
−
) a e na u ally p oduced by all ae obic o ganisms and exis in cells in
homeos asis wi h an ioxidan molecules and enzymes.
An ioxidan s a e compounds ha inhibi oxida ion. Oxida ion is a chemical eac ion ha can
p oduce ee adicals, he eby leading o chain eac ions ha can damage he cells o o ganisms.
An ioxidan s, such as hiols o asco bic acid ( i amin C) end hese chain eac ions. To balance he
oxida i e s a e, plan s and animals main ain complex sys ems o o e lapping an ioxidan s, such as
glu a hione and enzymes (e.g., ca alase and supe oxide dismu ase), p oduced in e nally, o he
die a y an ioxidan s i amins C and E [3]. An ioxidan de enses induc ion o endogenous ROS/RNS
le els educ ion is a apid and clea oxida i e s ess indica o . Indeed, ROS/RNS p oduc ion and
accumula ion is a common denomina o in many diso de s and en i onmen al insul s, a he same
ime ha can cause se ious cell damage leading o physiological dys unc ion and cell dea h in almos
all ae obes [
4
]. An ioxidan he apy has long been in es iga ed as a means o educing he ex en o
inju y esul ing om an ischemic s oke wi h a ying deg ees o success [5].
Enzyma ic and non-enzyma ic an ioxidan sys ems in he body, including supe oxide
dismu ase (SOD), ca alase (CAT), glu a hione pe oxidase (GPX), lipid-soluble i amin E, ca o enes,
and wa e -soluble i amin C, egula e he balance be ween ROS and an ioxidan s. On he o he hand,
die a y an ioxidan s, mos ly ob ained om ui and ege able consump ion, has also been associa ed
wi h a g ea balance be ween ee adicals and an ioxidan s a us, which helps o minimize oxida i e
s ess and educe he isk o cance , ca dio ascula diseases and aging [
6
]. Indeed, die a y an ioxidan s
comp ise a widesp ead g oup o colo ed molecules esponsible o mul iple bioac i e e ec s, b oadly
co esponding o di e en colo s o dis inc biomolecules classes. Full consump ion ad an ages and
heal h bene i s can also be eached h ough hei mixing since hey ac syne gis ically. Fo example,
some an ioxidan s display a mo e impo an ole in p e en ing ce ain diseases, such as cance ,
while o he ones wo k be e igh ing degene a i e diseases. In ac , housands o an ioxidan s a e
p esen in die a y pa e ns and ha some o hem may ha e s onge an ioxidan e ec s. Cance s induce
oxida i e s ess by changing wi h p og ession and he esul ing an ioxidan s a us di e s om pa ien
o pa ien . In “ea ly” lung cance s, seconda y eac i e oxygen species (SOSs) a e compa able o in e io
o ha o heal hy people. The ole o i amins a ies wi h gende , ype o cance and me as asis [7].
2. An ioxidan : Func ional De ini ion
An ioxidan s en e ed in public’s nu i ional ocabula y in he 1990s, a a ime when esea che s
we e slowly disco e ing how oxygen- igge ed ee adical eac ions in he body play a key ole
in aging-associa ed ch onic diseases [
8
]. Cu en ly, an an ioxidan is de ined as any subs ance
able o elimina e ROS and de i a i es (RNS, o eac i e sul u species, RSS), di ec ly o indi ec ly,
ac ing as an an ioxidan de ense egula o , o eac i e species p oduc ion inhibi o [
9
]. ROS a e a
molecules g oup p oduced o e cellula me abolism, due o mi ochond ial oxidases ac ion o by o he
cellula compa men s, being his p oduc ion aised wi h mi ochond ial damage. RNS and RSS esul ,
espec i ely, om he eac ion be ween ROS and ni ic oxide and hiols [
9
]. ROS/RNS can cause cell
damages by co alen joining wi h o he molecules and by s imula ing abno mal cell g ow h, o e en
Biomolecules 2018,8, 124 3 o 11
senescence induc ion, which may lead o pe sis en cells popula ion ha p oduce in lamma o y
cy okines a la ge amoun s. Acco ding o he common belie , so-called an ioxidan s may block
eac i e species p oduc ion-dele e ious e ec s and, he e o e, block aging, in lamma ion and cance .
Thei unc ion can be classi ied in o dis inc de ense lines, acco ding o hei mechanisms o ac ion:
(a) p e en a i e agen s ha supp ess new adicals o ma ion (which includes enzymes, such as SOD,
CAT and GPX, p o eins ha bind me als, like e i in and ce uloplasmin, and mine als such as selenium
(Se), coppe (Cu), and zinc (Zn)); (b) adical sca enging agen s ha inhibi chain ini ia ion and/o
p opaga ion, which includes glu a hione, albumin, i amins C and E, ca o enoids, and la onoids;
(c) epai and de no o enzymes ha epai and econs i u e cell memb anes, which includes lipases,
p o eases, DNA epai enzymes, ans e ases, and me hionine-sul oxide educ ases; and (d) adap a ion
agen s ha gene a e app op ia e an ioxidan enzymes and ans e hem o essen ial si e o ac ion [
9
,
10
].
Redox balance is essen ial in heal hy cellula mic oen i onmen main enance.
3. An ioxidan Role in Redox Imbalance P e en ion: Gaps o Knowledge
Redox imbalance is caused by a balance al e a ion be ween ROS and i s de i a i es and o he
cell an ioxidan de ense sys em e iciency [
10
]. Cells and issues a e con inuously being exposed
o eac i e species de i ed om me abolism o ex e nal ac o s, like smoking, pollu ion, pes icides,
mic obes, alle gens, and ul a iole and gamma adia ion, which gene a e ee adicals, all o hem
associa ed wi h bo h aging and o he diseases [
11
]. In addi ion, eac i e species p oduc ion can
o e come body abili y o elimina e o o con ain hem. The an ioxidan s ield has been hampe ed
by he ollowing gaps o knowledge: (1) Wha a e he co ec an ioxidan s doses? The e is ample
e idence ha mo e is no be e and may be wo se [
12
]. Vi ually, all so-called an ioxidan s do no
demons a e a classic dose- esponse bu may ha e opposi e e ec s wi h changing doses. (2) How
a e an ioxidan s abso bed? Li le is known on an ioxidan s gu mic obial me abolism, as well as
whe he an ioxidan s a ec gu mic o lo a in a p o- o an i-in lamma o y way. I is also poo ly
unde s ood whe he an ioxidan s a e abso bed unchanged o me abolized o comple ely di e en
compounds. One example is ellagic acid, a poo ly soluble compound ha is me abolized in o mo e
soluble me aboli es, ha can media e i s an i-in lamma o y ac i i y [
13
,
14
]. (3) An ioxidan s na u ally
occu ing may be abso bed as complexes o wo o mo e compounds and complexes may ha e e y
di e en biological ac i i ies han isola ed compounds alone. (4) E en wi h ideal abso p ion and
pene a ion in o umo s, umo s may espond wi h compensa o y pa hways. Fo example, ROS
inhibi ion may lead o compensa o y mi ogen-ac i a ed p o ein (MAP) kinase ac i a ion, ha could
mani es as mo e apid umo g ow h, despi e he ac ha hese umo s migh be de icien in nuclea
ac o kappa B (NF-κB) ac i a ion and mo e suscep ible o chemo he apy o adia ion [15] (Figu e 1).
4. Ad e se E ec s o An ioxidan s
The mos popula “an ioxidan s” o ms include i amins, such as i amin A ( e inol, e inoic
acid), i amin C (L-asco bic acid, asco bic acid, asco ba e), i amin E (
α
- ocophe ol),
β
-ca o ene,
mine als, like Se, and na u ally-occu ing polyphenols, each one has a di e en e ec on body cells.
Vi amins and
β
-ca o ene ha e conjuga ed double bonds and key unc ional g oups esponsible o hei
an ioxidan ole and quali y as pigmen s in se e al oods, like ui s and ege ables. Below, we b ie ly
summa ize he ad e se e ec s o hese popula an ioxidan s, o en consumed as supplemen s a much
highe doses han hose ound in oods u s. While hei ad e se e ec s a e known in he medical
communi y, hey a e no well-known among he popula ion, who belie e ha na u al p oduc s canno
be oxic. Cze nichow in es iga ed he e ec o an ioxidan supplemen a ion o 7.5 yea s on me abolic
synd ome (Me S) incidence and e en he epidemiologic associa ion be ween baseline se um an ioxidan
concen a ions and Me S p ospec i e isk [
16
]. No bene icial e ec s o an ioxidan supplemen a ion
we e obse ed in a gene ally well-nou ished popula ion. Baseline se um an ioxidan concen a ions o
β
-ca o ene and i amin C, howe e , we e nega i ely associa ed wi h Me S isk. Baseline se um zinc
concen a ions we e posi i ely associa ed wi h he isk o de eloping Me S [16]. Pa k [17] ound ha
Biomolecules 2018,8, 124 4 o 11
he e was no associa ion be ween die a y in akes o i amins A, C, and E and colon cance isk in his
pooled analysis o hi een p ospec i e coho s udies. Howe e , o al i amins A, C, and E in akes we e
each one in e sely associa ed wi h colon cance isk. Mul i i amin use, pa icula ly in combina ion
wi h a single i amin A, C and/o E supplemen s use, was in e sely associa ed wi h colon cance
isk. A low die a y in ake o an ioxidan i amins and mine als aises he incidence o ca dio ascula
diseases and cance [17]. A e 7.5 yea s, low-dose an ioxidan supplemen a ion lowe ed o al cance
incidence and all-cause mo ali y in men bu no in women. In ac , supplemen a ion may be e ec i e
in men only because o hei low basal s a us o ce ain an ioxidan s, especially o β-ca o ene [18].
Biomolecules 2018, 8, x FOR PEER REVIEW 4 o 11
in akes o i amins A, C, and E and colon cance isk in his pooled analysis o hi een p ospec i e
coho s udies. Howe e , o al i amins A, C, and E in akes we e each one in e sely associa ed wi h
colon cance isk. Mul i i amin use, pa icula ly in combina ion wi h a single i amin A, C and/o E
supplemen s use, was in e sely associa ed wi h colon cance isk. A low die a y in ake o
an ioxidan i amins and mine als aises he incidence o ca dio ascula diseases and cance [17].
A e 7.5 yea s, low-dose an ioxidan supplemen a ion lowe ed o al cance incidence and all-cause
mo ali y in men bu no in women. In ac , supplemen a ion may be e ec i e in men only because
o hei low basal s a us o ce ain an ioxidan s, especially o β-ca o ene [18].
Figu e 1. O e iew o eac i e oxygen signaling. Supe oxide, which can a ise om NADPH oxidases
ac ion o mi ochond ial leak, oxida i ely inac i a e p53, PTEN, and IkB, leading o Ak and NF-κB
ac i a ion. Reac i e oxygen inhibi ion wi h NADPH oxidase inhibi o s can e e se his pheno ype.
Glu a hione o ma ion h ough N 2 ac i a ion can lead o eac i e oxygen educ ion and, hus,
possibly an NF-κB dec ease bu also may eac wi h chemo he apy and adia ion gene a ed species,
hus, p o ec ing umo cells.
Resea che s epo ed he exis ence o inc eased e a ogenici y isk o bi h de ec s among
babies bo n om women who ook mo e han 10,000 IU i amin A pe day in he o m o
supplemen s [19]. Indeed, excessi e die a y i amin A in ake has been associa ed wi h bi h de ec s
in humans in se e al s udies epo ed in pas yea s [20–22]. A con olled clinical ial ound ha
people who ook 25,000 IU o i amin A pe day o a median o 3.8 yea s had 11% inc ease in
iglyce ides, 3% inc ease in o al choles e ol and 1% dec ease in high-densi y lipop o ein (HDL)
choles e ol, unlike hose who did no ake i amin A [23]. In a ecen case epo , a 4-yea -old boy
p esen ed se e al bone pains due o i amin A oxici y (600,000 IU e e y day o mo e han 3
mon hs) [2]. In ac , i has been epo ed ha excessi e i amin A in ake can accele a e bone loss
and isk o hip ac u e, possibly due o i amin A-induced os eoclas s s imula ion, besides i
inhibi s new bone o ma ion, inc easing os eopo osis isk [24].
On he o he hand, i amin C can be me abolized o oxala e and migh inc ease kidney oxala e
exc e ion. Se e al s udies sugges ha i amin C supplemen s may inc ease u ina y oxala e
Figu e 1.
O e iew o eac i e oxygen signaling. Supe oxide, which can a ise om NADPH oxidases
ac ion o mi ochond ial leak, oxida i ely inac i a e p53, PTEN, and IkB, leading o Ak and NF-
κ
B
ac i a ion. Reac i e oxygen inhibi ion wi h NADPH oxidase inhibi o s can e e se his pheno ype.
Glu a hione o ma ion h ough N 2 ac i a ion can lead o eac i e oxygen educ ion and, hus, possibly
an NF-
κ
B dec ease bu also may eac wi h chemo he apy and adia ion gene a ed species, hus,
p o ec ing umo cells.
Resea che s epo ed he exis ence o inc eased e a ogenici y isk o bi h de ec s among babies
bo n om women who ook mo e han 10,000 IU i amin A pe day in he o m o supplemen s [
19
].
Indeed, excessi e die a y i amin A in ake has been associa ed wi h bi h de ec s in humans in se e al
s udies epo ed in pas yea s [
20
–
22
]. A con olled clinical ial ound ha people who ook 25,000 IU
o i amin A pe day o a median o 3.8 yea s had 11% inc ease in iglyce ides, 3% inc ease in o al
choles e ol and 1% dec ease in high-densi y lipop o ein (HDL) choles e ol, unlike hose who did no
ake i amin A [
23
]. In a ecen case epo , a 4-yea -old boy p esen ed se e al bone pains due o
i amin A oxici y (600,000 IU e e y day o mo e han 3 mon hs) [
2
]. In ac , i has been epo ed ha
excessi e i amin A in ake can accele a e bone loss and isk o hip ac u e, possibly due o i amin
A-induced os eoclas s s imula ion, besides i inhibi s new bone o ma ion, inc easing os eopo osis
isk [24].
Biomolecules 2018,8, 124 5 o 11
On he o he hand, i amin C can be me abolized o oxala e and migh inc ease kidney
oxala e exc e ion. Se e al s udies sugges ha i amin C supplemen s may inc ease u ina y oxala e
concen a ions, doubling he isk o calcium oxala e kidney s ones [
25
–
27
]. A s udy de ined ha high
i amin C in ake om supplemen s is associa ed wi h a ise in ca dio ascula disease mo ali y in
pos menopausal women wi h diabe es bu his has ne e been con i med [
28
]. Theo e ically, i amin C
may cause oo much i on abso p ion bu his is likely o be signi ican only in pe sons who ha e high
i on s o es o in pa ien s wi h i on o e load, such as he edi a y hemoch oma osis, whe e an inc easing
i on oxici y isk may exis [
29
]. Pa lo ou [
30
] e alua ed ee oxygen adicals (FORT) and ee oxygen
adicals de ense (FORD) le els in pa ien s wi h newly diagnosed ype 2 DM pa ien s. The au ho s
ound ha FORT le els we e inc eased in diabe ic pa ien s compa ed o con ols; howe e , FORD
le els we e lowe in diabe ic pa ien s compa ed o con ols.
A s udy epo ed ha die a y i amin E supplemen a ion signi ican ly inc eases p os a e cance
isk among heal hy men [
31
]. A me a-analysis ende s mo e e idence o i amin E ad e se e ec s
on s oke sub ypes. Indeed, he s udy de ined a 22% inc eased hemo hagic s oke isk and a 10%
dec eased ischemic s oke isk wi h i amin E supplemen a ion, al hough he absolu e e ec s a e
mino [
32
]. S ill, a s udy unde lined ha 22–30 mg/day o i amin E in human p egnancy may be
associa ed wi h bi h weigh dec ease [33].
Scien is s ha e epo ed ha
β
-ca o ene supplemen a ion (and no he in ake o ege ables ich
in
β
-ca o ene) has ac ually inc eased he isk o dea h om lung cance o hea disease in smoke s,
a he han educing cance incidence [
34
–
37
]. In ac , we belie e ha o he an ioxidan side e ec s may
no be epo ed and o he ones will be disco e ed in he u u e. None heless, he s udies pe o med
so a ha e se e ely impai ed he epu a ion o an ioxidan s in gene al. Howe e , in an ideal wo ld,
we could go back o his s udy, h ough examining issues p e- and pos - ea men , and de e mine
whe he in e en ions had a signaling e ec in he umo s. Based on p e ious s udies o ebselen,
an o ganoselenium compound wi h b oad an ioxidan p ope ies [
38
], i is likely ha ROS educ ion
in umo s, o ins ance in Bu ki s lymphoma, esul s in MAP kinase signaling ac i a ion and an
inc eased umo g ow h a e [
15
]. In addi ion, mo e apidly g owing umo s may be mo e suscep ible
o subsequen chemo he apy and adia ion. Thus, he cu en s a e o a ai s sugges s ha he mos
common an ioxidan s a e, a bes , ine ec i e and po en ially ha m ul.
5. A e An ioxidan s Bene i s Mo e Appa en Than Real?
Pa o he p oblem ega ding an ioxidan s is ying o impose an an ioxidan chemical de ini ion
on a biochemical sys em. Ancien man used ca bon as an an ioxidan o educe i on o e o i on, h ough
emo ing oxygen in i on o e wi h ca bon and d i ing o oxygen as ca bon dioxide. This de ini ion,
while applicable o me al e ining, does no conside he complexi y o biological sys ems. Fo example,
nuclea ac o e y h oid 2-like 2 (N 2) ansc ip ion is one o he mos s udied an ioxidan sys ems
in biology, being no mally N 2 complexed wi h Kelch-like ECH-associa ed p o ein 1 (Keap 1). So,
cells ea ed wi h N 2 induce s leads o N 2 nuclea ansloca ion [
39
,
40
]. Many N 2 induce s bind
o N 2 h ough a Michael addi ion, oxidizing N 2 sul hyd yl g oups. Thus, many N 2 induce s
a e oxidan s and, he e o e, an an ioxidan esponse is an oxidan esponse [
41
–
43
]. Fu he mo e,
educed glu a hione, he main small an ioxidan molecule in mammalian cells, is a p oduc o se e al
N 2downs eam a ge genes, coun e balancing mi ochond ial ROS p oduc ion [
44
]. None heless,
he e is an open ques ion whe he he an ioxidan e ec o glu a hione syn hesis exe s an ioxidan
ac i i y beyond co ec ing o iginal oxida i e s esso o ins ead exe s mul iple unc ions, beyond
educing in acellula milieu main enance [
44
]. Finally, in glu a hione, ee sul hyd yl g oups
(-SH g oups) could exe an ioxidan e ec s bu , a he same ime, bind o chemo he apy eac i e
in e media es and block e ec i e umo cells killing [
45
–
47
]. This ac may explain why glu a hione
induc ion/supplemen a ion has no been an as e ec i e s a egy agains cance as o iginally implied.
Tumo s wi h mu an p53 demons a e high N 2 ac i a ion le els and his could p o ec umo cells
agains eac i e adduc induced DNA damage [48].

Biomolecules 2018,8, 124 6 o 11
In a ecen s udy, N 2 was ound o be induced by oncogenic Ras and N 2 loss was ound o be
p o ec i e in ansgenic models o ca cinogenesis. In his s udy, endogenous oncogenic Ras was ound
o dec ease ROS h ough N 2induc ion, while exogenous oncogenic Ras o e exp ession inc eases ROS
le els. Indeed, N 2 loss dec eased p eneoplas ic panc ea ic cells exp ession and ea u es o senescence
we e obse ed in N 2 de icien umo cells [
49
]. Thus, hese s udies sugges ha ROS may play a
physiologic ole in p e en ing p eneoplas ic cells p opaga ion wi h Ras d i e mu a ions (Figu e 2).
Biomolecules 2018, 8, x FOR PEER REVIEW 6 o 11
ound o dec ease ROS h ough N 2induc ion, while exogenous oncogenic Ras o e exp ession
inc eases ROS le els. Indeed, N 2 loss dec eased p eneoplas ic panc ea ic cells exp ession and
ea u es o senescence we e obse ed in N 2 de icien umo cells [49]. Thus, hese s udies sugges
ha ROS may play a physiologic ole in p e en ing p eneoplas ic cells p opaga ion wi h Ras d i e
mu a ions (Figu e 2).
Figu e 2. Po en ial ou comes o an ioxidan s a di e ing umo igenesis s ages. The p esence o a
d i e mu a ion in a p ima y cell leads o eac i e oxygen-media ed endoplasmic e iculum (ER)
s ess. No mally, his could lead o senescence, in which P16ink4a and FOXO4 senescence ma ke s
a e ele a ed, as well as NF-κB ac i a ion. This leads o a pe sis en senescen pheno ype which
canno e-en e he cell cycle. On he o he hand, ER s ess elie wi h an an ioxidan , o umo
supp esso (i.e., p16ink4a) loss leads o clonal cells expansion wi h d i e mu a ions. This may lead
o ca cinogenesis. In ad anced umo s, NF-κB migh be ac i a ed by ROS and a ROS blockade may
lead o NF-κB ac i a ion dec ease and chemo he apy and adia ion sensi i i ies inc ease.
T ea men wi h an ioxidan N-ace yl cys eine elie ed he block, which is consis en wi h: (a)
Cells wi h oncogenic d i e mu a ions exhibi endoplasmic e iculum s ess, which migh be in pa
media ed by high ROS le els, and he e o e high ROS le els elie may allow p eneoplas ic cells
p oli e a ion and ankly malignan cells con e sion and (b) o he obse a ions ha an ioxidan s
pa adoxically p omo e cance [9,12,48,50–52].
ROS ha e dis inc umo -p omo ing e ec s, which include DNA me hyl ans e ase 1 (DNMT)
induc ion [53,54], oxida i ely umo supp esso s p53 inac i a ion, kB (IkB), phospha ase and ensin
homolog (PTEN) inhibi ion [55]. This leads o p o umo igenic NF-κB and Ak ac i a ion and,
he e o e, ea men wi h a supe oxide p oduc ion inhibi o (NADPH oxidase inhibi o ) leads o
p53 eac i a ion, and NF-κB and Ak inac i a ion. This would be bene icial as NF-κB and Ak
inhibi ion p imes o inc ease chemo he apy and adia ion suscep ibili y h ough he
down egula ion o a ge genes, such as mul id ug esis ance p o ein 1 (Md 1) and DNA epai
genes. On he o he hand, sul u supplemen a ion in e ms o inc easing educed glu a hione, o
N 2 induc ion, could ha e dele e ious e ec s on chemo he apy and adia ion by p o ec ing umo
DNA.
As i has been exposed, supplemen al an ioxidan adminis a ion du ing chemo he apy and
adia ion he apy is cu en ly con o e sial [9,10,12,56,57]. So a , i has been di icul o de e mine
which an ioxidan s may exe a bene icial impac on cance ea men ou comes o which may
con ibu e o ea men ad e se e ec s’ amelio a ion [9,57]. Fo his eason, du ing chemo he apy
Figu e 2.
Po en ial ou comes o an ioxidan s a di e ing umo igenesis s ages. The p esence o a
d i e mu a ion in a p ima y cell leads o eac i e oxygen-media ed endoplasmic e iculum (ER) s ess.
No mally, his could lead o senescence, in which P16ink4a and FOXO4 senescence ma ke s a e ele a ed,
as well as NF-
κ
B ac i a ion. This leads o a pe sis en senescen pheno ype which canno e-en e he
cell cycle. On he o he hand, ER s ess elie wi h an an ioxidan , o umo supp esso (i.e., p16ink4a)
loss leads o clonal cells expansion wi h d i e mu a ions. This may lead o ca cinogenesis. In ad anced
umo s, NF-
κ
B migh be ac i a ed by ROS and a ROS blockade may lead o NF-
κ
B ac i a ion dec ease
and chemo he apy and adia ion sensi i i ies inc ease.
T ea men wi h an ioxidan N-ace yl cys eine elie ed he block, which is consis en wi h: (a) Cells
wi h oncogenic d i e mu a ions exhibi endoplasmic e iculum s ess, which migh be in pa media ed
by high ROS le els, and he e o e high ROS le els elie may allow p eneoplas ic cells p oli e a ion
and ankly malignan cells con e sion and (b) o he obse a ions ha an ioxidan s pa adoxically
p omo e cance [9,12,48,50–52].
ROS ha e dis inc umo -p omo ing e ec s, which include DNA me hyl ans e ase 1 (DNMT)
induc ion [
53
,
54
], oxida i ely umo supp esso s p53 inac i a ion, kB (IkB), phospha ase and ensin
homolog (PTEN) inhibi ion [
55
]. This leads o p o umo igenic NF-
κ
B and Ak ac i a ion and, he e o e,
ea men wi h a supe oxide p oduc ion inhibi o (NADPH oxidase inhibi o ) leads o p53 eac i a ion,
and NF-
κ
B and Ak inac i a ion. This would be bene icial as NF-
κ
B and Ak inhibi ion p imes
o inc ease chemo he apy and adia ion suscep ibili y h ough he down egula ion o a ge genes,
such as mul id ug esis ance p o ein 1 (Md 1) and DNA epai genes. On he o he hand, sul u
supplemen a ion in e ms o inc easing educed glu a hione, o N 2 induc ion, could ha e dele e ious
e ec s on chemo he apy and adia ion by p o ec ing umo DNA.
As i has been exposed, supplemen al an ioxidan adminis a ion du ing chemo he apy and
adia ion he apy is cu en ly con o e sial [
9
,
10
,
12
,
56
,
57
]. So a , i has been di icul o de e mine
Biomolecules 2018,8, 124 7 o 11
which an ioxidan s may exe a bene icial impac on cance ea men ou comes o which may
con ibu e o ea men ad e se e ec s’ amelio a ion [
9
,
57
]. Fo his eason, du ing chemo he apy and
adia ion he apy, an an ioxidan p esc ip ion is con using and consequen ly, his should conside he
ype o cance , backg ound and s a e o pa ien , an i umo he apy, d ugs mechanism o ac ion and
d ugs used in ea men , as also he an ioxidan ype and dosage [9,57].
6. Redox Imbalance Posi i e and An ioxidan E ec Nega i e
I is now well-es ablished ha eac i e species and a basal edox imbalance le el a e essen ial o
cell su i al [58]. Concomi an ly, i is also well-known ha while se e e edox imbalance o en leads
o widesp ead oxida i e and ni osa i e damage and cell dea h, a mode a e edox imbalance le el,
induced by wide s esso s a ie y, can yield g ea bene icial e ec s on adap i e cellula esponses,
such inc eased endogenous an ioxidan de ense sys ems le els [12,58].
Ho mesis was de ined as a cellula adap i e esponse o s esso s ha esul s in a biphasic
dose- esponse ela ionship, such ha low-dose s imula ion esul s in a bene icial adap a ion,
whe eas a high-dose esul s in a oxic e ec [
59
]. In his con ex , low ROS doses, p oduced du ing
exe cise aining, a e equi ed o he exe cise-induced aining esponse in skele al muscle. Thus,
ROS a e equi ed o exe cise adap i e esponse and a e essen ial o enhance spo s pe o mance [
59
].
In his sense,
low cell s esso doses, such as chemicals, oxins, adia ion and mode a e exe cise esul s
in an adap i e esponse, inc ease he an ioxidan capaci y o cells. In ac , exe cise i sel can be
conside ed an an ioxidan , since aining inc eases classical an ioxidan enzymes exp ession, like SOD
and GPX, while, in gene al, an ioxidan supplemen s may no be a good s a egy when aining because
hey elimina e ROS p oduc ion ha ac s o s imula e endogenous an ioxidan enzymes [
60
]. Mo eo e ,
mi ochond iogenesis is egula ed by many edox-sensi i e enzymes, in ol ing MAP kinases, NF-
κ
B,
p53, hea shock ac o , pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-alpha (PGC-1
α
),
and o he s in ol ed in modula ing muscle adap a ion o muscle [60].
On he o he hand, i is belie ed ha an ioxidan s can p e en cance de elopmen a ec ing
he cell cycle, in lamma ion, umo p oli e a ion and in asi eness, apop osis and de ox mechanisms.
So, he an i umo e ec s o se e al an ioxidan s (i.e., ca echins, iso la ones, lignans, la anones,
es e a ol, ellagic acid, que ce in, and cu cumin) ha e been ex ensi ely s udied [
9
]. Howe e ,
an ioxidan supplemen a ion may block endogenous an ioxidan s aise and o he cell adap a ion
mechanisms, such as be e ene ge ic me abolism. Indeed, a basal edox imbalance le el is c ucial o
cell adap a ion. The ques ion is wha eac i e species concen a ion ange is bene icial and wha is
ha m ul? In his con ex , he co ela ion be ween ciga e e smoke and lung-cance is well-es ablished
bu will he e be a bene icial low-dose? (Ha dly an e hics commi ee would app o e his kind o
expe imen al s udy).
7. Wha An ioxidan s Can Do o Imp o e Heal h o Wha They Canno Do?
Despi e billions o dolla s spen on an ioxidan supplemen s yea ly, he modi ica ion o a ch onic
disease cou se emains elusi e. Nume ous agen s ha e demons a ed chemop e en i e e ec s in
mu ine models bu hese ha e no ye been ansla ed o human diseases. Cu en ly, we ha e enough
clinical e idence ha an ioxidan s a ailable as supplemen s ha e a bes li le alue in p e en ing
o modi ying a ch onic disease cou se. Inhe en di e ences in oden s e sus human’s biology,
high-dose ea men in oden s and non-deli e y o human issues a e p obably behind he cu en
ailu e eco d. Howe e , he e is oom o op imism bu i can only come om a sophis ica ed
unde s anding o ch onic disease biology. In he case o cance , cu en ly a ailable an ioxidan s
could be ha m ul in p e en ing physiologic senescence in pa ien s who ha e d i e mu a ions lesions
p edominance. Physiologic senescence p e en ion could expand mu a ed cells popula ion ha can
unde go ca cinogenesis. Howe e , in ad anced umo s, ROS down egula ion agen s inducing NF-
κ
B
could be use ul in chemo he apy and adia ion combina ion o igge umo cell apop osis.
Biomolecules 2018,8, 124 8 o 11
The e is nuance in his as well, as an agen ha inc eases sul hyd yl’s, ei he h ough exogenous
sul hyd yl supply o N 2 induc ion, could p o ec umo DNA and inac i a e chemo he apeu ic
agen s. Wha is needed is a “sma an ioxidan ”, i.e., one ha could cause a edox imbalance in umo
cells bu no in no mal issues. A po en ial ca ego y o compounds is si uin 3 ac i a o s. Indeed, si uin
3 is a majo mi ochond ial NAD
+
-dependen deace ylase ha plays a c i ical ole in mi ochond ial
p o eins ac i a ion, is in ol ed in ene gy me abolism, and changes in i s exp ession a e associa ed
wi h excessi e ROS p oduc ion [
61
]. The e is e idence ha some polyphenolic compounds ound in
na u e could ac as “sma an ioxidan ” ia si uin 3 ac i a ion [
62
–
64
]. Such an agen could po en ially
dec ease NF-
κ
B a he same ime as no inducing N 2. This would ip he balance and could be use ul
in bo h oxida i e p ecu so lesions des uc ion wi h d i e mu a ions as well as sensi izing ad anced
cance o chemo he apy and adia ion.
8. Conclusions and Upcoming Pe spec i es
In conclusion, o minimize ch onic edox imbalance damages, i is bes o ollow a balanced and
a ied die , including in i s composi ion many g ains, legumes, ui s and ege ables o di e en colo s.
In addi ion, heal hy li es yle habi s should be included, such as exe cise aining on a egula basis
o a oid obesi y, no smoking and educing alcoholic be e ages in ake. The in ake o an ioxidan
supplemen s would only make sense in a case o de ici s, ying o no malize hei le els, bu no as a
usual in ake. In addi ion, an ioxidan s he apeu ic use ulness agains cance s ill has many open on s
ha should be in es iga ed in he u u e.
Au ho Con ibu ions:
Au ho s B.S., M.M., J.L.A., A.S., N.M., P.K.M., M.S.-R., P.K. and J.S.-R. con ibu ed equally
in he w i ing o his wo k. J.L.A., N.M., P.K., and J.S.-R. c i ically e iewed he manusc ip . All he au ho s ead
and app o ed he inal manusc ip .
Funding: The APC was unded by N.M.
Acknowledgmen s:
An oni Su eda acknowledges he suppo o Ins i u e o Heal h Ca los III (P ojec CIBEROBN
CB12/03/30038). Na ália Ma ins hank o Po uguese Founda ion o Science and Technology (FCT–Po ugal)
o he S a egic p ojec e . UID/BIM/04293/2013 and “NORTE2020-P og ama Ope acional Regional do No e”
(NORTE-01-0145-FEDER-000012).
Con lic s o In e es : The au ho s decla e no con lic o in e es .
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