REVIEW
Cellula and Molecula Mechanisms o Cance D ug Resis ance
Na u al compounds and s a egies o figh ing agains d ug esis ance in
cance : a special ocus on phenolic compounds and mic oRNAs
Nina Pe o ić,
1,2
I ana Z. Ma ić,
2
and Ta jana S anojko ić
2
1
“VIN
CA”Ins i u e o Nuclea Sciences-Na ional Ins i u e o he Republic o Se bia, Uni e si y o Belg ade, Belg ade, Se bia
and
2
Depa men o Expe imen al Oncology, Ins i u e o Oncology and Radiology o Se bia, Belg ade, Se bia
Abs ac
Bioac i e phy ochemicals, phenolic compounds, e penoids, and alkaloids, exe an ioxida i e, an i-inflamma o y, an igeno oxic,
and an icance e ec s, simul aneously showing minimal o no oxici y on no mal, heal hy cells. Phy ochemicals a ge ing a ious
signaling pa hways and mul iple mechanisms unde lying in insic and acqui ed mul id ug esis ance (MDR) in cance cells make
hem in aluable ools o he de elopmen o no el s a egies o figh ing agains an icance d ug esis ance in di e en ypes o
cance , which is one o he ul ima e goals o mode n oncology esea ch. As MDR is desc ibed o be a simul aneous de elop-
men o esis ance o mul iple d ugs wi h di e en chemical s uc u es, mechanisms o ac ion, and a ge s i is no su p ising ha
mul iple ac o s, such as gene ic and epigene ic changes, as well as noncoding RNAs, including mic oRNAs may significan ly
con ibu e o he de elopmen MDR in cance cells, and i s a ge ing and modula ion o hei exp ession o sensi ize cells o
ea men . This e iew implies ha some na u al compounds, such as cu cumin, es e a ol, kaemp e ol, allicin, and que ce in,
ha e he po en ial o in e ac wi h highly oncogenic and/o p oinflamma o y miRNAs, such as miR-21/155/663/146a, significan ly
influencing he esponse o cance he apy. This a icle aims o poin ou how na u al compounds may be used, accompanied by
miRNAs mimics o miRNA inhibi o s o ea specific ypes o cance and i s sub ypes o o e come mul id ug esis ance. The
main challenge is o de e mine he p ope doses and concen a ions o bo h miRNAs and compounds.
cance d ug esis ance; mic oRNA (miRNA); na u al compounds
INTRODUCTION
Plan kingdom and me abolome a e plen i ul sou ces o
seconda y me aboli es, which exe nume ous heal h-benefi-
cial biological, pha macological, and medicinal p ope ies.
E e y day, he e is mo e and mo e p og ess in he isola ion
and cha ac e iza ion o na u al compounds wi h a p ominen
po en ial in he figh agains mul id ug esis ance (MDR) in
cance . Na u al p oduc s ac on mul iple a ge s and can sig-
nifican ly con ibu e o o e coming esis ance o cance he -
apy. Na u al compounds ha e al eady shown a p ospec i e
ole in he figh agains MDR. Cu en ly, esis ance o chemo-
he apy is one o he bigges p oblems in cance he apy.
MDR is he simul aneous de elopmen o esis ance o mul i-
ple d ugs wi h di e en chemical s uc u es, mechanisms o
ac ion, and a ge s. Recen esea ch has shown ha gene ic
backg ound and epigene ic mechanisms accompanied by he
ansc ip ional and pos ansc ip ional egula ion by non-
coding RNAs, including mic oRNAs (miRNAs), long-noncod-
ing RNAs (lncRNAs), and o he s, may con ibu e o and
induce MDR pheno ype in cance cells (1–4).
Va ious no el na u al p oduc s isola ed om animals,
plan s, and o he o ganisms ha e en iched he chemical
lib a ies and exe ed an icance e ec s. Compa ed wi h
con en ional syn he ic molecules, hey possess unique
cha ac e is ics ha con e ad an ages and disad an ages in
an icance d ug disco e y. Na u al p oduc s ha e shown
po en ial in e e sing MDR in cance cells, which could
acili a e e ec i e cance he apy. Some o he mos e ec-
i e cance ea men s o da e a e na u al p oduc s o com-
pounds de i ed om na u al p oduc s. The fi s na u al
an icance compound was podophyllo oxin isola ed om
Podophyllum pel a um in 1947 (5). F om hen un il oday,
pa ien s use na u al compounds as an essen ial pa o he
complemen a y app oach. Since he popula i y o using
na u al compounds in cance ea men appea s o be g ow-
ing a he han declining, i is necessa y o s udy na u al
compounds so ha we can p ope ly di ec hei u u e appli-
ca ion in cance he apy. On he o he hand, o o e come
he MDR, i is necessa y o use mul iple compounds in com-
bina ion. Na u al compounds a e ideally sui ed o his
applica ion; hey a e ac i e a concen a ions ha can be
N. Pe o ićand I. Z. Ma ićcon ibu ed equally o his wo k.
Co espondence: T. S anojko ić([email p o ec ed]).
Submi ed 26 June 2024 / Re ised 17 July 2024 / Accep ed 7 May 2025
h p://www.ajpcell.o g 0363-6143/25 Copy igh ©2025TheAu ho s.Licensedunde C ea i e Commons A ibu ion CC-BY-NC-ND 4.0.
Published by he Ame ican Physiological Socie y.
C183
Am J Physiol Cell Physiol 329: C183–C199, 2025.
Fi s published May 15, 2025; doi:10.1152/ajpcell.00428.2024
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achie ed in he o ganism, and hei mild oxici y allows
hem o be used sa ely (6). Along wi h he g ow h o in e es
in na u al p oduc s, he e has been p og ess in he field o
phy ochemical in es iga ion and isola ion echniques o
elucida e hei s uc u e. O e he yea s, seconda y me abo-
li es we e specially examined. Thousands o seconda y
me aboli es we e isola ed, hei an icance ac i i y was
examined, and leading subs ances ha a e he mos in e -
es ing o new an icance d ugs we e ex ac ed om he
c owded da a (7,8).
Phenolic compounds cons i u e one o he mos nume ous
g oups in he plan kingdom, wi h o e 8,000 iden ified o
da e. The mos abundan ly occu ing phenols in plan s a e
fla onoids, phenolic acids, s ilbenes, and lignans. O e
4,000 fla onoids ha e been iden ified o da e, and in addi-
ion, 6,500 di e en fla onoids ha e been iden ified om
plan sou ces (9,10). The mos amous fla onoids ha ha e
been s udied o da e and whose an icance ac i i y has been
widely in es iga ed a e cu cumin and que ce in (11–14). I
has been shown ha se e al classes o alkaloids can also
e e se MDR, such as ma ine, e and ine, ligus azine,
ne e ine, dau icine, cepha an hine, solanine, and o he s (15–
20). These compounds we e epo ed o inhibi he p oli e a-
ion o a ious cance cells h ough apop osis and cell cycle
a es (21,22). They can also inhibi cance cell mig a ion,
in asion, and adhesion by down egula ing he exp ession o
oncogenes (23–25). On he o he hand, e penes and e pe-
noids, such as ginsenosides, soil bas a d saponin, limonoids,
as well as s e ols, ha e been hea ily exploi ed in a emp s o
iden i y compounds ha would ha e po en an icance
e ec s and help o o e come MDR (26–29). These com-
pounds exe an icance e ec s h ough he induc ion o
apop osis, inhibi ion o p oli e a ion, me as asis, angiogene-
sis, and ac i a ion o immuni y (30,31). Thei use may con-
ibu e o educing oxici y and imp o ing chemosensi i i y
in cance combina ion he apy (26,32). Howe e , na u al
p oduc s show some p oblems, such as poo solubili y, poo
pe meabili y, ins abili y, and insu ficien bioa ailabili y in
biological sys ems. New d ug deli e y s a egies, such as
nano echnology, ha e a emp ed o o e come he p ob-
lems, edisco e ing new benefi s associa ed wi h hese na -
u al p oduc s. Nano echnology could be one o he ways o
imp o e he pha macokine ics and e ec s o na u al p od-
uc s and imp o e hei e ficiency in cance p e en ion and
he apy. Fu he esea ch o imp o e cance he apy due o
manyobs aclesisce ainlyimpe a i e.Theaimo his
e iew was o p o ide a comp ehensi e o e iew o he
abili y o he mos equen ly used na u al compounds,
especially phenolic compounds, o modula e esis ance o
an icance he apies, and hei pe spec i e and impo ance
o de eloping new, mo e e ec i e he apeu ic op ions o
he figh agains cance .
CHEMOSENSITIZING EFFECTS OF PHENOLIC
COMPOUNDS
The plan phenolic compounds a e seconda y me aboli es
well known as mul i a ge an icance bioac i e phy ochemi-
cals, which may sensi ize cance cells o chemo he apy
d ugs o biologically a ge ed he apies (Fig. 1).
RESVERATROL
Res e a ol is a plan polyphenol ound in g apes, ed and
whi e wines, be ies, peanu s, and soy (33), well- ecognized
o i s cance -chemop e en i e and cance - he apeu ic
e ec s, including chemosensi iza ion and adiosensi iza ion
e ec s (34,35). The inhibi o y e ec o es e a ol on P-gp
and MRP1 anspo e e flux unc ion in he Caco-2 colo-
ec al adenoca cinoma cells and P-gp o e exp essing CEM/
ADR5000 doxo ubicin- esis an leukemia cells had been
demons a ed in addi ion o inc eased esis an cells sensi-
i i y o doxo ubicin (36). Res e a ol inhibi ed he ac i i y
o me abolic enzymes cy och ome P450 3A4 (CYP3A4) and
glu a hione S- ans e ase (GST), induced apop osis in esis -
an cance cells, and dec eased exp ession le els o genes-
coding ABC anspo e s MDR-1,MRP1, and b eas cance
esis ance p o ein (BCRP), in addi ion o CYP3A4,GST, and
Figu e 1. O e iew o he mechanisms o
he mos p ominen an icance phenolic
compounds in o e coming mul id ug esis -
ance in cance .
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hei egula o y gene-coding ecep o hPXR in Caco-2 cells,
confi ming i s supp essi e e ec s on di e en mechanisms o
cance MDR (36). Inc eased sensi i i y o MDR cance cell
lines o es e a ol, ABCB5-o e exp essing HEK-293/ABCB5
cells (emb yonic kidney), and mu a ion-ac i a ed epide mal
g ow h ac o ecep o (EGFR) o e exp essing U87.MGDEGFR
glioblas oma cells, which may be explained by es e a ol-
caused si uin 1 (SIRT1) o e exp ession, had been epo ed
(37). An icance d ug-sensi izing e ec s o es e a ol in
b eas cance ha e been well documen ed in i o and in i o
s udies (38–41). Yang e al. (38) showed a syne gis ic e ec o
es e a ol and cispla in on su i al, mig a ion, and in asion
o iple-nega i e b eas adenoca cinoma MDA-MB-231 cells
h ough PI3K/AKT, Smad, NF-κB, JNK, and ERK; i inc eased
he e ec o cispla in in MDA-MB-231 xenog a s and educed
ad e se e ec s. Res e a ol was e ec i e in o e coming he
esis ance o HER-2 o e exp essing SK-BR-3 b eas cance
cells o doce axel h ough down egula ion o he HER-2-Ak
signaling axis ac i a ed by doce axel (39). The sensi iza ion
e ec o es e a ol o b eas cance cells o poly (ADP- ibose)
polyme ase (PARP) inhibi o alazopa ib media ed by inhibi-
ion o Ak pa hway and au ophagy flux, leading o impai -
men o double-s and b eak epai , has been also epo ed.
The combina ion o es e a ol and alazopa ib in b eas can-
ce cells led o cell cycle p og ession dys egula ion, p38-
MAPK-media ed apop osis, induc ion o DNA damage, abno -
mal mi o ic p og ession, educed au ophagosome o ma ion,
and pos poned/inhibi ed au ophagy flux (40). The es e a ol
e ficacy was confi med in he in i o p eclinical SCID mouse
b eas cance xenog a model (40). The incuba ion wi h
es e a ol enhanced he e ec s o doxo ubicin in b eas can-
ce MCF-7 and MDA-MB-231 cells (41). T ea men wi h doxo u-
bicin and es e a ol o b eas cance cells induced apop osis
(Bax:Bcl-2 and caspase-9), down egula ed inflamma ion-asso-
cia ed p o eins (NF-κB, COX-2), au ophagy-associa ed p o eins
(LC3, Beclin-1), and edox egula o (N 2) (41).
The e ficacy o es e a ol, which can c oss he blood-b ain
ba ie , has been documen ed in glioblas oma, showing
po en ial as a adiosensi ize and chemosensi ize (42). The
ea men o doxo ubicin- esis an U87MG/DOX glioblas oma
cells e e sed hei sensi i i y o doxo ubicin by up egula ing
phospha ase and ensin homolog (PTEN) and down egula ing
PI-3K, Ak , and memb ane anspo e P-gp le els (43). The
ecen esea ch also demons a ed he abili y o es e a ol o
inc ease he e ec o emozolomide (TMZ) agains A172 and
LN428 glioblas oma cells, o e ec i ely inhibi cell p oli e a-
ion, mig a ion, and induce apop osis (44). T ea men wi h
es e a ol and emozolomide e e sed he sensi i i y o
LN428 glioblas oma cells o emozolomide, which could be
a ibu ed o he down egula ion o O
6
-me hylguanine-DNA
me hyl ans e ase (MGMT) and signal ansduce and ac i a-
o o ansc ip ion 3 (STAT3) (44). Res e a ol has been ecog-
nized as a sensi ize o panc ea ic cance cells o gemci abine
(45). I inhibi ed lipid syn hesis by down egula ion o s e ol
egula o y elemen -binding p o ein 1 (SREBP1) and e e sed
he gemci abine-induced s emness o panc ea ic cance in
i o and in i o (45). Res e a ol has been p o en o be e ec-
i e in o e coming MDR esis ance in human nonsmall cell
and small cell lung cance cells (46,47). In MDR human cell
lines, SPC-A-1/CDDP es e a ol inhibi ed cell p oli e a ion,
induced apop osis, and inc eased chemosensi i i y o cispla in,
pacli axel, and gefi inib (46). The an icance e ficacy o es e a-
ol was confi med in nude mice implan ed wi h SPC-A-1/
CDDP lung cance cells. Mo eo e , es e a ol enhanced he
sensi i i y o H69AR small-cell lung cance cells esis an o
doxo ubicin by inhibi ing inflamma o y media o s, STAT3/
VEGF pa hway, and P-gp ac i i y (47). Colo ec al cance may
be also e ec i ely chemosensi ized by es e a ol by a ec ing
mul iple egula o y signaling pa hways implica ed in chemo-
he apy d ug esis ance and plas ici y (48). The s udy by Chung
e al. (49) showed ha ea men wi h es e a ol e e sed he
sensi i i y o esis an colo ec al cance HCT116 and DLD1 cells
o 5-fluo ou acil (5FU). When used in combina ion, es e a ol
and 5-fluo ou acil inc eased apop osis o colo ec al cance
cells, inhibi ed STAT3 and Ak signaling pa hways, inhibi ed
epi helial-mesenchymal ansi ion (EMT), and educed elo-
me ase ac i i y (49).
APIGENIN
The fla onoid ha possesses he po en ial o be used as a
pa o combina ion he apy wi h an icance d ugs o a i-
ous malignan diseases is fla one apigenin, ound in many
ege ables and ui s, such as g apes and apples, chamomile
ea, ed wine, and medicinal he bs (50). Recen ly published
esea ch showed he abili y o apigenin o inc ease he sensi-
i i y o b eas adenoca cinoma MCF-7 cells esis an o dox-
o ubicin by educing he exp ession le els o anspo e
mul id ug esis ance-associa ed p o ein (MDR1) (P-gp) in
esis an MCF-7 cells and inhibi ion o phospho yla ion and
ac i a ion o JAK2 and STAT3 (51). The down egula ion o
MRP1, MRP3, MRP5, and BCRP caused by apigenin in MCF-7
cells esis an o doxo ubicin has been also epo ed (52).
Apigenin p o ed i s e ficacy as a chemosensi izing compound
agains h ee-dimensional (3-D) sphe oids o MDA-MB-231
b eas cance cells ea ed wi h apigenin and doxo ubicin,
induced inc eased DNA damage le els, and ac i a ed apop osis
h ough caspase-3 and caspase-9 (53). Sudhaka an e al. (53)
epo ed ha apigenin-induced sensi iza ion o b eas cance
sphe oids o doxo ubicin is pa ially media ed h ough RNA-
binding p o ein: he e ogeneous ibonuclea p o ein A2/B1
(hnRNPA2). Apigenin educed gene exp ession le els o doxo -
ubicin e flux anspo e s (ABCB1,ABCC1,ABCC4,andABCG2),
egula ed by hnRNPA2-dependen and independen mecha-
nisms (53). Apigenin inc eased cispla in-induced apop osis in
lung cance A549 and NCI-H1299 cells (54). T ea men wi h api-
genin and cispla in o A549 cells igge ed p53-dependen
apop osis media ed by ac i a ion o he E k/MAPK signaling
pa hway (54). Fu he mo e, apigenin used wi h gefi inib had
p o ed e ficacy agains EGFR mu an - esis an nonsmall cell
lung cance NCI-H1975 cells, which could be a ibu ed o sup-
p essi e e ec s on c-Myc, HIF-1a, and EGFR, inhibi ion o
AMPK pa hway and au ophagy flux, dec eased glucose up ake,
impai ed me abolism leading o apop osis (55). The s udy by Li
e al. (56) demons a ed he abili y o apigenin o inc ease he
sensi i i y o hypoxia-induced d ug- esis an li e cance o
pacli axel in i o and in i o h ough AKT/p-AKT pa hway,
HSP90, and HIF-1a. Chemosensi iza ion p ope ies o apigenin
agains hepa ocellula cance ea ed wi h so a enib in in i o
(HepG2 and Huh7 cells) and in i o se ings (mice hepa ocellu-
la ca cinoma model) had been epo ed (57).
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LUTEOLIN
Fla one lu eolin is a fla onoid p esen in medicinal plan s,
ui s,and ege ables,suchasapples,o anges,lemons,g apes,
ca o s, cele y, onion, spinach, o egano, and hyme, which is
also well-known o i s mul iple mechanisms o an icance
e ec s (58,59). Lu eolin inhibi ed g ow h, induced cell cycle
a es , and igge ed apop osis in MDR P-gp-exp essing NCI-
ADR/RES and BCRP-exp essing MCF-7/Mi oR cance cell lines,
while a he same ime no inhibi ing unc ions o he d ug
anspo e s (60). The an ip oli e a i e and p oapop o ic ac i -
i ies o lu eolin we e ela ed o he gene a ion o eac i e oxygen
species (ROS), DNA agmen a ion, ac i a ion o he ATR/Chk2/
p53 signaling pa hway, inhibi ion o NF-κB signaling pa hway,
ac i a ion o p38 pa hway, and deple ion o an iapop o ic p o-
eins c-IAP1, claspin, su i in, and XIAP (60). This fla one
showed p omising p ope ies o o e come MDR o mul iple
myeloma cells o bo ezomib in i o and in i o by inhibi ion
o TGF-b/Smad2/Smad3 pa hway and h ough he au ophagy
pa hway ALK5 le els, as well as educing he amoun s o
ALDH1 þcells (61). The syne gis ic ac i i y o lu eolin and low-
dose pacli axel has been epo ed agains esophageal cance
cells and xenog a models (62). Combined ea men wi h
lu eolin and pacli axel supp essed cell g ow h, cell mig a ion,
induced apop osis, and EMT; hese e ec s we e a ibu ed o
he ac i a ion o ROS/JNK signaling pa hway (62). Lu eolin
showed chemosensi izing e ec s agains amoxi en- esis an
MCF-7 b eas cance cells by supp essing he exp ession o
cyclin E2 and cell p og ession om G1 o S phase (63).
Fu he mo e, lu eolin inc eased he e ec s o pacli axel on
b eas MDA-MB-231 cells and lowe ed he exp ession o p o-
eins associa ed wi h b eas cance s emness media ed h ough
down egula ing N 2, HO-1, Si 3, C ip o-1, ABCG2, CD44,
Oc 4, and ALDH1 (64). A s udy by Wang e al. (65) epo edsen-
si iza ion o cispla in- esis an o a ian cance CAOV3/DDP
cells by lu eolin, e iden as enhancemen o an ip oli e a i e,
p oapop o ic, and an i-in asi e e ec s ha we e confi med in
i o. Lu eolin inc eased he an icance e ec s o cispla in in
hepa ocellula ca cinoma HepG2 and colo ec al ca cinoma
HCT116 cells wi h wild- ype p53, which we e a ibu ed o
inc easing JNK ac i a ion, p53 phospho yla ion, and educed
p o ein ubiqui ina ion and p o easomal deg ada ion; his
e ec was also shown in i o (66).
QUERCETIN AND RUTIN
Fla anol que ce in ound in many ui s, ege ables, and
medicinal plan s, possesses an icance and cance -chemo-
sensi izing p ope ies. This fla anol has been shown o
inc ease he sensi i i y o panc ea ic cance cells o dauno u-
bicin, gemci abine, sul o aphane, doxo ubicin, b omodo-
main, and ex a e minal domain inhibi o s, and he umo
nec osis ac o (TNF)- ela ed apop osis inducing ligand
(TRAIL), media ed by e ec s on egula ion o oxida i e and
inflamma o y signaling pa hways, as e iewed by Hu e al.
(67). Que ce in demons a ed he po en ial o o e come MDR
in esis an gas ic adenoca cinoma AGS-cy 61 cells and
inc eased sensi i i y o 5-fluo ou acil and doxo ubicin by
dec easing CYR61, MRP1, and NF-κB p65 le els, induc ion o
apop osis, inhibi ion o cell mig a ion, and down egula ed
epi helial-mesenchymal ansi ion- ela ed p o eins (68).
Zhou e al. (69) epo ed he abili y o que ce in o o e come
he P-gp-media ed MDR in colon cance SW620/Ad300 cells
and imp o e he sensi i i y o doxo ubicin media ed by inhibi-
ion o P-gp anspo ac i i y, inhibi ion o he exp ession o
he glu amine anspo e solu e ca ie amily 1, membe 5
(SLC1A5), and blocking D-glu ama e and D-glu amine me abo-
lism. In addi ion, que ce in exe ed syne gis ic e ec s wi h
5-fluo ou acil in d ug- esis an colon cance HCT-116 cells
ela ed o inhibi ion o he N 2/HO-1 pa hway (70). Que ce in
had also been shown o be e ec i e in he e e sal o sensi i i y
o doxo ubicin- esis an MCF-7 b eas cance cells o doxo ubi-
cin, pacli axel, and inc is ine, which was explained by down-
egula ing P-gp exp ession and elimina ing b eas cance s em
cells wi h CD44
þ
/CD24
/
low
pheno ype h ough inhibi ion o
YB-1 p o ein nuclea ansloca ion (71). The chemosensi izing
e ec s o que ce in on p os a e cance cells o doce axel ha e
been demons a ed in i o and in i o (72,73). This e ec was
media ed by inhibi ion o P-gp exp ession, supp ession o he
mesenchymal and s em-like cell cha ac e is ics, and inhibi-
ion o ac i a ion o PI3K/Ak signaling pa hways in LNCaP/R
and PC-3/R p os a e cance cells (72). Sha ma e al. (73)disco -
e ed ha p e ea men o p os a e cance cells o 24 h wi h
que ce in and ea men o ano he 24 h wi h low doses o
doce axel was he mos e ec i e in o e coming d ug esis -
ance in PC-3 and DU 145 p os a e cance cells. A que ce in glu-
coside u in is also a p omising an icance fla onoid, which
may be used in combina ion wi h chemo he apy d ugs (74).
Ru in inc eased he cy o oxici y o cyclophosphamide and
me ho exa e on b eas adenoca cinoma MDA-MB-231 cells,
inhibi ed he ac i i y o P-gp and b eas cance esis ance p o-
ein (BCRP), and e e sed MDR o b eas cance cells (75).
KAEMPFEROL
Ano he fla onol compound, kaemp e ol, occu ing in ui s
and ege ables, migh be use ul o o e coming MDR and
enhancing he e ec s o an icance he apies. Kaemp e ol
inc eased he sensi i i y o 5-fluo ou acil- esis an colo ec al
cance HCT8-R cells o his d ug and dec eased glucose up ake
and gene a ion o lac ic acid by inhibi ing py u a e kinase M2
(76). The chemosensi izing e ec o kaemp e ol was also dem-
ons a ed in 5-fluo ou acil- esis an colo ec al adenoca ci-
noma LS-174T cells ela ed o inhibi ion o ROS gene a ion and
modula ion o JAK/STAT3, MAPK, PI3K/AKT, and NF-κB sig-
naling pa hways (77). Kaemp e ol dec eased he exp ession le -
els o MDR genes ABCB1 and ABCC1 in acu e p omyelocy ic
leukemia HL-60 cells, up egula ed apop o ic genes, and down-
egula ed su i al genes (PI3K,AKT,andBcl-2)(78). This
fla onol sensi ized o a y adenoca cinoma OVCAR-3 cells o
cispla in by down egula ion o ABCC6 anspo e and c-myc
p o ooncogene (79). A ecen ly published s udy showed ha
kaemp e ol alone o in combina ion wi h e apamil supp essed
he exp ession o componen s o b eas cance s emness and
chemoe asion pa hways esponsible o chemo esis ance phe-
no ype (SOX2, OCT4, NANOG, MDR1, and CD44) in MDA-MB-
231 and p ima y b eas cance s em cells (80).
FLAVANOLS
The chemosensi izing e ec s o fla anols (ca echins, epi-
ca echins, epigalloca echin, and epigalloca echin galla e),
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abundan in black g apes, ed wine, and g een ea, ha e
been s udied as well (81). Fla anol epigalloca echin-3-galla e
(EGCG) has been ecognized o i s p ominen e ec i eness
in o e coming MDR in cance by a ec ing mul iple signaling
pa hways in i o and in i o (82). Epigalloca echin-3-gal-
la e inhibi ed P-gp and BCRP ac i i y, implica ed in d ug
e flux in b eas adenoca cinoma MCF-7 cells esis an o
amoxi en (83). The chemosensi izing ac ion o epigalloca-
echin-3-galla e was epo ed in doxo ubicin- esis an lung
ca cinoma A549 cells due o supp ession o mul id ug
esis ance signaling (MRP1, EGFR, and ERK), d ug e flux,
and enhancemen o d ug up ake, cell cycle a es , and cell
dea h, and modula ion o an ioxidan machine y and hei
egula o s (84). The s udy by Toden e al. (85) demons a ed
he abili y o epigalloca echin-3-galla e o inc ease he sen-
si i i y o esis an HCT116 and SW480 colon cance cells o
5-fluo ou acil, inhibi colon cance s em cell o ma ion,
down egula e cance s em cell ma ke s (Oc 4, Nanog), and
supp ess umo g ow h in i o. Epigalloca echin-3-galla e
e ficien ly inc eased apop osis in esis an esophageal can-
ce Eca109/ABCG2 cells induced by doxo ubicin, down egu-
la ed ABCG2 exp ession, and inc eased d ug concen a ion
(86). This fla anol caused apop osis and au ophagy in cis-
pla in- esis an o al cance cells and inhibi ed MDR1 and
AKT/STAT3 signaling pa hways (87). I s in i o e ficacy in
mul id ug- esis an o al ca cinoma KBV200 xenog a s
agains inc is ine sul a e, which migh be a ibu ed o
angiogenesis inhibi ion by VEGF down egula ion, has been
demons a ed (88). Liang e al. (89) showed he chemosensi-
izing ac i i y o epigalloca echin-3-galla e in doxo ubicin-
esis an li e cance BEL-7404/DOX cells in i o and in
i o h ough inhibi ion o P-gp and inc easing in acellula
doxo ubicin concen a ion and down egula ion o MDR1
exp ession.
NARINGENIN AND NARINGIN
Isofla ones na ingenin and na ingin a e abundan in ci us
ui s and possess he po en ial o enhance he e ec i eness
o an icance d ugs. Na ingenin in combina ion wi h low con-
cen a ions o cispla in inc eased cy o oxici y and an i-in a-
si e e ec s in 3-D HeLa sphe oids (90). Na ingenin inc eased
he cy o oxic ac i i ies o DNA-damaging an icance d ugs
camp o hecin, doxo ubicin, 5-fluo ou acil, cispla in, e opo-
side, ellip icine, ca bopla in, and cyclophosphamide agains
b eas cance HTB26 and colo ec al cance SW1116 cells (91).
The chemosensi izing e ec o na ingin o doxo ubicin had
been demons a ed in he animal s udy by Ali e al. (92).
P e ea men o adul male Sp ague–Dawley a s wi h na in-
gin be o e ea men wi h doxo ubicin inc eased sensi i i y
o doxo ubicin and down egula ed P-gp exp ession (92).
GENISTEIN
Isofla one genis ein, abundan in soybeans, possesses he
abili y o modula e ABC anspo e s (P-gp, MRP1, MRP2,
MRP4, MRP5, and BCRP) (93). This phy oes ogen inc eased
he sensi i i y o A549 lung cance cells o cispla in and sig-
nifican ly supp essed umo g ow h in i o in he A549 xen-
og a mice model h ough supp ession o he PI3K/Ak
pa hway (94). Genis ein exe ed a chemosensi izing e ec on
bladde cance cells ea ed wi h hyd oxycamp o hecin in
i o and in i o, ac i a ed ATM, and supp essed NEMO/
NF-κB/IKK/caspase signaling pa hway (95). Soy isofla one
inc eased he sensi i i y o di use la ge cell lymphoma WSU-
DLCL2 and WSU-DLCL2-SCID mouse xenog a o CHOP egi-
men (cyclophosphamide, doxo ubicin, inc is ine, and p ed-
nisone) and inhibi ed NF-κB binding o DNA (96). In con as ,
Rigalli e al. (97) showed ha genis ein up egula ed p o ein
le els o ABCC1 and ABCG2 in MCF-7 b eas cance cells,
accompanied by inc eased esis ance o doxo ubicin and
mi oxan one as well as up egula ed ABCC1 p o ein le els in
MDA-MB-231 cells wi hou e ec on esis ance; genis ein sup-
p essed d ug e flux in b eas cance cells.
CURCUMIN
Cu cumin is ecognized as a po en polyphenolic chemo-
sensi ize , able o e e se MDR and enhance he sensi i i y
o esis an cance cells o an icance he apeu ics (98).
Cu cumin e ec i ely inc eased he sensi i i y o b eas can-
ce MCF-7, MDA-MB-231, SK-BR-3, and T47D cells o 5-fluo-
ou acil media ed by down egula ion o NF-κB in MDA-MB-
231 cells (99). The inc ease in sensi i i y o cispla in- esis an
MCF-7/DDP b eas cance cells induced by cu cumin had
been epo ed as well; cu cumin inhibi ed PI3K/AKT/mTOR
pa hway and CCAT1 exp ession and induced au ophagy
(100). Cu cumin was epo ed o e e se MDR o colon cance
in i o and in i o (12,101). I inc eased cy o oxici y o in-
c is ine, cispla in, 5-fluo ou acil, and hyd oxycamp o hecin
in inc is ine- esis an human colon cance cell line HCT-8/
VCR, inhibi ed umo g ow h in mice xenog a , and educed
he exp ession o P-gp (101). In addi ion, cu cumin e e sed
esis ance o oxalipla in in esis an colo ec al ca cinoma
HCT116/OXA, inc eased ac i e caspase-3, and inhibi ed EMT
h ough down egula ion o TGF-b/Smad2/3 pa hway in i o
and in i o (12). Ele a ion o ROS was iden ified as one o he
possible mechanisms unde lying chemosensi izing e ec s o
cu cumin in colon cance cells (102). The sensi i i y inc eases
in MRP5 o e exp essing HEK293 (HEK293/MRP5) cells and
wo panc ea ic cance cell lines, PANC-1 and Mia-PaCa-2,
when cu cumin was appliedin combina ion wi h 5-fluo ou a-
cil was epo ed as well (103). The s udy by S eekan h e al.
(104) p o ided da a abou he chemosensi izing e ficacy o
cu cumin in combina ion wi h pacli axel in wo animal ce i-
cal cance models; cu cumin down egula ed NF-κB pa hway
and inc eased pacli axel-induced p oapop o ic e ec s (104).
Cu cumin also inc eased he e ec s o gemci abine and i a-
dia ion in p os a e adenoca cinoma PC-3 cells and PC-3 xeno-
g a s media ed by down egula ion o MDM2 exp ession
h ough modula ion o PI3K/mTOR pa hway (105).
SILIBININ
Fla onolignan silibinin is a majo bioac i e cons i uen o
silyma in, ex ac ob ained om seeds o milk his le, Silybum
ma ianum [L.] Gae n., well ecognized o he ea men o
li e diseases, as well as i s chemop e en i e and chemosensi-
iza ion ac i i ies (106). Silibinin has been epo ed o enhance
he cy o oxic e ec s o doxo ubicin in esis an MDA-MB-435/
DOX b eas cance cells media ed h ough induc ion o apo-
p osis h ough caspase-3, and inhibi ion o STAT3, AKT, and
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ERK (107). In addi ion, silibinin exe ed syne gis ic e ec s in
combina ion wi h pacli axel in esis an MCF-7/PAC b eas
adenoca cinoma cells (107). Silibinin e e sed MDR in small
cell lung cance VPA17 cell line, which o e exp essed P-gp, o
e oposide and doxo ubicin and showed a syne gis ic e ec
when applied in combina ion (108). The e ec i eness o silibi-
nin and pacli axel was demons a ed in esis an A2780/ axol
o a ian cance cell line; silibinin inc eased apop osis and G2/
M cell cycle a es , supp essed P-gp and su i in exp ession,
and dec eased cell in asi eness (109). In he human gas ic
cance cell line SGC-7901, silibinin inc eased he cy o oxici y
o pacli axel, induced p ominen G2/M cell cycle a es , and
apop osis h ough ex insic pa hway demons a ing syne gis-
ic e ec s (110).
The o e iew o he mechanisms o phenolic compounds
o o e come mul id ug esis ance in cance cells is p esen ed
in Table 1.
TARGETING Mic oRNAs BY NATURAL
PRODUCTS
The s a egies o miRNA molecule silencing o up egula -
ing ha e been ex ensi ely esea ched o e ime, and hey
include inhibi o y small molecules, RNA sponges, miRNA
Zip molecules, miRNA mimics, an i-miRNA oligonucleo-
ides, ca aly ic nucleic acids, exosomes, a ificial DNA mole-
cules, nanopa icles, as well as CRISPR-Cas9 echnique (111,
112). Besides he use o a ificial syn he ic molecules, which
show g ea po en ial, one o he mos p omising s a egies
may be he modula ion o miRNAs by na u al p oduc s and
hei de i a i es, which can be used o he educ ion o
umo p og ession and p opaga ion, and o o e coming
d ug and chemo he apy esis ance. The s a egy o u iliza-
ion o na u al p oduc s om he modula ion o miRNA le -
els may be one s ep close o clinical p ac ice u iliza ion
because na u al p oduc s ha e been al eady app o ed by he
Food and D ug Adminis a ion.
Mic oRNAs, as noncoding RNAs, a e ecognized as media-
o s o a ious disease o ma ion and p og ession. Thei di -
e en ial exp ession is especially impo an in cance
esea ch and ea men . Mic oRNA ep esen s le el changes
ha influence esponse o cance he apy, no only by i s
in e ac ion wi h messenge RNAs (mRNAs), bu h ough he
in e play wi h o he noncoding RNAs, such as ci cula RNAs
(ci cRNAs), compe ing endogenous RNAs (ceRNAs), long
noncoding RNAs (lncRNAs), and miRNA sponges (113).
Mic oRNA molecules can in e ac wi h mul iple a ge s (114)
and ice e sa,canbe he a ge o awidespec umo com-
pounds and molecules (115). Mic oRNAs a e associa ed wi h
he esponse o he apy and clinical ou comes. Pe o iće al.
(116) ha e emphasized ha miR-21/155/34a/146a/221/222/
133/206 a e associa ed wi h esponse o b eas cance , glio-
blas oma, and p os a e cance in asi e po en ial and esponse
o ea men , (117–120), and ha miR-156a and miR-155 le els
change a e he mechanic he apy o pe iodon i is (121).
These findings emphasize he impo ance o miRNAs o be
in es iga ed as po en ial bioma ke s o he esponse o he -
apy. MiRNA exp ession le els a e sensi i e o chemical com-
pounds (122,123), adia ion, na u al p oduc s, he bal ex ac s
(124,125), and compounds ex ac ed om na u al p oduc s in
cance , me abolic diseases, and inflamma ion (126,127).
Regula ion o miRNA le els wi h na u al p oduc s and com-
pounds du ing he ea men o a ious diseases may inc ease
he e ficiency o he apy.
Some na u al agen s and plan ex ac s mani es hei an i-
umo ac i i ies ia modula ing miRNA amoun s and exp es-
sion. Na u al compounds can in e ac wi h p e-miRNA
molecules and enzymes in ol ed in miRNA ma u a ion and
p ocessing, as well as di ec ly bind o miRNA molecules, hus
p e en ing hem om binding o i s a ge s, o can ac indi-
ec ly (126).
Mic oRNAs AND PLANT EXTRACTS IN
CANCER RESEARCH
Va ious plan ex ac s ha e been shown o change miRNA
exp ession le els in bo h ways, up egula ing o down egula -
ing hem (125)(Table 2 and Fig. 2). Fo example, Olea eu opaea
(OLE) ex ac om lea es was shown o inc ease miR-137/145/
153/181b and le -7d exp ession le els and induce apop osis o
glioblas oma T98G, U-87MG, and U-138MG cells. OLE ea -
men was shown o imp o e esponse o emozolomide in
T98G glioblas oma (128). T ea men wi h OLE ex ac , accom-
panied by emozolomide, induced a highe inc ease o
miRNAs han emozolomide solely. Also, OLE emozolomide
ea men educed le els o hei a ge s in ol ed in cell dea h,
educed angiogenesis, and in asi eness (128). Hype icum pe -
o a um ex ac s ha e also been ex ensi ely in es iga ed as
an icance agen s. Thei an icance po en ial, among o he
esea ch, has been in es iga ed agains wo-dimensional (2-D)
and 3-D HeLa cell line models by Ma iće al. (124). This
esea ch has shown ha Hype icum pe o a um L., collec ed
om Samsun, Tu key, a ious plan pa sand ex ac sol en s
di e en ly influence miR128/193a-5p/335 signa u e in HeLa
cells (124). Plan ex ac s con ain nume ous ac i e compounds
ha can influence me aboli e abundance, as well as gene ac i -
i y, and hus p o ein syn hesis. Mos ly in es iga ed na u al
p oduc s wi h he abili y o change le els o miRNA molecules,
associa ed wi h cance esea ch, inflamma ion, diabe es, me -
abolic, and ca dio ascula diseases, a e cu cumin, es e a ol,
and que ce in, accompanied by allicin.
Mic oRNA AND NATURAL COMPOUNDS
AGAINST CANCER DRUG RESISTANCE
CANDIDATES FOR NOVEL ANTICANCER
THERAPEUTICS
I is well-known ha mic oRNAs can modula e chemo-
he apeu ic d ug esis ance and in e ac wi h na u al com-
pounds (135)(Table 2 and Fig. 2). Phenolic compounds we e
shown o influence DNA me hyla ion, ch oma in emodel-
ing, and miRNA exp ession changes. Phenolic compounds
belonging o a class o cu cuminoids, s ilbenes ( es e a ol),
and fla onoids—such as cu cumin, allicin, que ce in, epigal-
loca echin-3-galla e (EGCG), genis ein, and p oan hocyani-
din—ha e been shown o ac i ely con ibu e o a ious
le els and aspec s o epigene ic changes (136,137). EGCG was
shown o ele a e miR-485 exp ession le els in s em-like non-
small cell lung cance A549 cells esis an o cispla in.
Up egula ion o miR-485 le els educed s emness o A549
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Table 1. Summa y o he mechanisms o phenolic compounds o o e come mul id ug esis ance in cance
Phenolic Compound Cance Type E ec and Mechanism Re e ences
Res e a ol Colon cance and leukemia Inhibi ion o P-gp and MRP1 unc ion, CYP3A4 and GST ac i i y, ac i a ion
o apop osis, and dec ease in he exp ession o genes coding MDR-1,
MRP1, and BCRP,CYP3A4,GST, and hPXR, inc eased sensi i i y o
doxo ubicin
(36)
Res e a ol Emb yonic kidney and
glioblas oma
Inc eased MDR cell sensi i i y, SIRT1 o e exp ession (37)
Res e a ol B eas cance Inhibi ion o cell su i al, mig a ion, and in asion, syne gism wi h cispla-
in, a ge s: PI3K/AKT, Smad, NF-κB, JNK, and ERK
(38)
Res e a ol B eas cance Down egula ion o he HER-2-Ak signaling pa hway, o e coming doce-
axel esis ance
(39)
Res e a ol B eas cance Inhibi ion o Ak pa hway and au ophagy flux, cell cycle e ec s, induc ion
o DNA damage and apop osis, es e a ol in combina ion wi h
alazopa ib
(40)
Res e a ol B eas cance Apop osis ac i a ion ia Bax:Bcl-2 and caspase-9, down egula ion: NF-
κB, COX-2, LC3, Beclin-1, and N 2, doxo ubicin, and es e a ol
(41)
Res e a ol Glioblas oma PTEN up egula ion, PI-3K, Ak , and memb ane anspo e P-gp down eg-
ula ion, e e sal o doxo ubicin sensi i i y
(43)
Res e a ol Glioblas oma Cell p oli e a ion and mig a ion inhibi ion, apop osis ac i a ion, MGMT
and STAT3 down egula ion, e e sal o emozolomide sensi i i y
(44)
Res e a ol Panc ea ic cance Inhibi ion o lipid syn hesis, SREBP1 down egula ion, e e sal o he gem-
ci abine sensi i i y
(45)
Res e a ol Lung cance Chemosensi i i y inc ease, apop osis induc ion, an ip oli e a i e e ec ,
inhibi ion o inflamma o y media o s, STAT3/VEGF pa hway, and P-gp,
chemosensi i i y o cispla in, pacli axel, gefi inib, and doxo ubicin
(46,47)
Res e a ol Colo ec al cance P oapop o ic e ec , inhibi ion o STAT3 and Ak pa hways, epi helial-
mesenchymal ansi ion inhibi ion, and an i elome ic e ec , 5-fluo ou -
acil sensi i i y e e sal
(49)
Apigenin B eas cance Down egula ion o MDR1 (P-gp), MRP1, MRP3, MRP5, and BCRP, JAK2
and STAT3 inhibi ion, doxo ubicin sensi iza ion
(51,52)
Apigenin B eas cance P oapop o ic e ec s, DNA damage induc ion, down egula ion o (ABCB1,
ABCC1,ABCC4, and ABCG2), doxo ubicin sensi iza ion
(53)
Apigenin Lung cance P oapop o ic e ec h ough E k/MAPK signaling pa hway, combina ion
wi h cispla in
(54)
Apigenin Lung cance P oapop o ic e ec , inhibi ion o c-Myc, HIF-1a, EGFR, AMPK pa hway,
au ophagy flux, and glucose up ake, apigenin, and gefi inib
(55)
Apigenin Li e cance Induc ion o apop osis, inhibi ion o HIF-1a h ough AKT/p-AKT pa hway,
and HSP90, apigenin and pacli axel
(56)
Lu eolin B eas cance , o a ian cance Induc ion o apop osis and cell cycle a es , ROS p oduc ion, DNA ag-
men a ion, p38 and ATR/Chk2/p53 pa hway ac i a ion, NF-κB pa hway
supp ession, and educ ion o c-IAP1, claspin, su i in, and XIAP
(60)
Lu eolin Mul iple myeloma Inhibi ion o TGF-bpa hway and deg ada ion o ALK5, o e coming MDR
o bo ezomib
(61)
Lu eolin Esophageal cance P oapop o ic e ec , inhibi ion o cell p oli e a ion, mig a ion, and EMT,
ac i a ion o mi ochond ial apop o ic pa hway h ough ac i a ion o
ROS/JNK pa hway, syne gism wi h pacli axel
(62)
Lu eolin B eas cance Cell cycle a es , cyclin E2 inhibi ion, combina ion wi h amoxi en; s em-
ness- a ge ed b eas cance —dec ease in: N 2, HO-1, Si 3, C ip o-1,
ABCG2, CD44, Oc 4, and ALDH1—pacli axel
(63,64)
Lu eolin O a ian cance Apop osis induc ion, p oli e a ion, mig a ion, and in asion inhibi ion, syn-
e gism wi h cispla in
(65)
Lu eolin Hepa ocellula and colo ec al
cance
p53 s abiliza ion h ough inc easing JNK ac i a ion, combina ion wi h
cispla in
(66)
Que ce in Panc ea ic cance Inc eased d ug sensi i i y, egula ion o oxida i e and inflamma o y
pa hways
(67)
Que ce in Gas ic adenoca cinoma P oapop o ic e ec , down egula ion o CYR61, MRP1, and NF-κB p65,
EMT- ela ed p o eins
(68)
Que ce in Colon cance Inhibi ion o : P-gp anspo ac i i y, SLC1A5, D-glu ama e and D-glu a-
mine me abolism, N 2/HO-1 pa hway
(69,70)
Que ce in B eas cance Chemosensi i i y e e sal, P-gp exp ession supp ession, inhibi ion o YB-
1 nuclea ansloca ion
(71)
Que ce in P os a e cance Inc eased apop osis, inhibi ion o P-gp exp ession, inhibi ion o ac i a ion
o PI3K/Ak signaling pa hways, combina ion wi h doce axel
(72)
Ru in B eas cance Inhibi ion o ac i i y o P-gp and BCRP (75)
Kaemp e ol Colo ec al cance Chemosensi iza ion o 5-fluo ou acil, JAK/STAT3, MAPK, PI3K/AKT, and
NF-κB pa hways modula ion
(76,77)
Kaemp e ol Leukemia Up egula ion o apop o ic genes, down egula ion o ABCB1 and ABCC1,
PI3K,AKT, and Bcl-2
(78)
Kaemp e ol O a ian cance Supp ession o ABCC6 and c-Myc, sensi iza ion o cispla in (79)
Kaemp e ol B eas cance Supp ession o SOX2, OCT4, NANOG, MDR1, and CD44, wi h e apamil (80)
Con inued
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cispla in- esis an cells. Fu he mo e, he educ ion o
miR-485 le els by inhibi o s boos ed s emness, whe eas
p ope doses o EGCG lowe ed s emness, indica ing ha
p ope dose and consump ion o EGCG may be u ilized
sho ly o o e come esis ance o cispla in chemo he apy
(129). Fu he mo e, EGCG up egula ed umo supp essi e
miR-34a/145/200c in colo ec al ca cinoma, and induced che-
mosensi i i y o CRC cells o 5-fluo ou acil (85). Acco ding o
Zhou e al. (138), EGCG die in nude mice wi h obacco ca cin-
ogen-induced lung cance , 12 mic oRNAs we e o e - ep e-
sen ed, and 9 we e unde - ep esen ed, which we e in ol ed
in cance signaling pa hways, among o he s.
Cu cumin can al e miRNAs in an epigene ic manne
by in e ac ing wi h me hyl g oups o miRNA gene p o-
mo e s (126). In he case o miR-203, cu cumin eleases
and unlocks i s exp ession ansc ip ion by p omo e
deme hyla ion (139). Cu cumin was shown o modula e
le els o miR-9/19/34a/181/192-5p and miR-21 molecule
(140,141), showing i s po en ial o be used as an an i-
cance agen and o e e se esis ance o chemo he apy. I
has been shown ha cu cumin sensi izes U-87 MG malig-
nan glioma cells o emozolomide by up egula ing miR-
146a and inhibi ing NF-κBsignaling(130). The di e ence
in 67 miRNA exp ession le els was shown among MCF-7
sensi i e, esis an , and cu cumin- ea ed doxo ubicin-
esis an cells. In he same s udy, i has been also shown
ha highe le els o miR-29b-1-5p dec eased he e ec o
cu cumin ea men and sensi izing MCF-7 cells o doxo -
ubicin. Cu cumin a ec s miRNA exp ession le els and
has he po en ial o help o e come d ug esis ance in
b eas cance cells. In addi ion, miRNA le els could a ec
cu cumin e ec i eness, and he syne gy o doxo ubicin
and cu cumin inhibi s b eas cance cell p oli e a ion and
p og ession (131).
Allicin, al hough no a phenolic compound, was no ewo -
hy o be men ioned in e ms o combining e ec wi h
miRNA in o e coming esis ance o cance d ugs. Allicin is
an o ganosul u compound, mos ly ound in ga lic, was
desc ibed o ha e an ioxidan , an ibac e ial, and an i umo
e ec s, and ha among o he s, can educe p opaga ion o
he wo gas ic cance cell lines AGS and HGC27 by inhibi-
ing in asion and mig a ion by inc easing le el o umo
supp essi e miR-383-5p, and dec easing he componen s o
e b-b2 ecep o y osine kinase 4 (ERBB4) oncogene singling
pa hway (142). Also, allicin has been shown o induce up eg-
ula ion o miR-486-3p, which inc eases he sensi i i y o
emozolomide- esis an U251-TR cells h ough O
6
-me hyl-
guanine-DNA me hyl ans e ase (MGMT) down egula ion
(132). Acco ding o his finding, he au ho s ha e sugges ed
ha allicin can be p oposed as an addi i e o he apy wi h
TMZ o imp o e he pa ien s’su i al a es, and also in com-
bina ion wi h miR-486-3p as i s a ge (132).
Table 1.—Con inued
Phenolic Compound Cance Type E ec and Mechanism Re e ences
Epigalloca echin-
3-galla e
B eas cance Inhibi ion o P-gp and BCRP ac i i y (83)
Epigalloca echin-
3-galla e
Lung cance O e coming MDR o doxo ubicin, inhibi ion o MRP1, EGFR, ERK, d ug
e flux, and modula ion o edox s ess signaling
(84)
Epigalloca echin-
3-galla e
Colo ec al cance Supp ession o cance s em cell ma ke s (Oc 4, Nanog), combina ion
wi h 5-fluo ou acil
(85)
Epigalloca echin-
3-galla e
Esophageal cance Dec ease in ABCG2 exp ession and inc eased ad iamycin le els (86)
Epigalloca echin-
3-galla e
O al cance Apop osis, au ophagy, supp ession o MDR1, and AKT/STAT3 (87)
Epigalloca echin-
3-galla e
Li e cance Inhibi ion o P-gp and MDR1 exp ession, doxo ubicin accumula ion (89)
Na ingenin Ce ical cance Cy o oxici y ac i i y and an i-in asi e e ec s (90)
Na ingenin B eas and colo ec al cance S onge cy o oxic e ec s when combined wi h an icance d ugs (91)
Genis ein Lung cance PI3K/Ak pa hway inhibi ion, chemosensi iza ion o cispla in (94)
Genis ein Bladde cance ATM ac i a ion, NEMO/NF-κB/IKK/caspase pa hway inhibi ion (95)
Genis ein Lymphoma Inc eased sensi i i y o CHOP, NF-κB binding supp ession (96)
Cu cumin B eas cance Chemosensi iza ion o 5-fluo ou acil, NF-κB down egula ion (99)
Cu cumin B eas cance Au ophagy, inhibi ion o PI3K/AKT/mTOR pa hway and CCAT1 exp es-
sion, chemosensi iza ion o cispla in
(100)
Cu cumin Colon cance Chemosensi izing e ec s o an icance d ugs, down egula ion o P-gp,
down egula ion o TGF-b/Smad2/3 pa hway-media ed inhibi ion o
EMT
(101,102)
Cu cumin Panc ea ic cance Chemosensi izing e ec s o 5-fluo ou acil (103)
Cu cumin Ce ical cance Chemosensi izing e ec s o pacli axel, p oapop o ic e ec s, NF-κB pa h-
way down egula ion
(104)
Cu cumin P os a e cance Combina ion wi h gemci abine and i adia ion, PI3K/mTOR pa hway mod-
ula ion, supp ession o MDM2 exp ession
(105)
Silibinin B eas cance Inc eased sensi i i y o doxo ubicin, apop osis, caspase-3 ac i a ion,
STAT3, AKT, and ERK inhibi ion
(107)
Silibinin Lung cance MDR e e sal o e oposide and doxo ubicin (108)
Silibinin O a ian cance Apop osis, cell cycle a es , an i-in asi e e ec s, down egula ion o P-gp
and su i ing, combina ion wi h pacli axel
(109)
Silibinin Gas ic cance Apop osis, cell cycle a es , syne gism wi h pacli axel (110)
BCRP, b eas cance esis ance p o ein; EGFR, epide mal g ow h ac o ecep o ; MDR, mul id ug esis ance; MGMT, O
6
-me hylgua-
nine-DNA me hyl ans e ase; PTEN, phospha ase and ensin homolog; ROS, eac i e oxygen species; SIRT1, si uin 1; SREBP1, s e ol eg-
ula o y elemen -binding p o ein 1; STAT3, signal ansduce and ac i a o o ansc ip ion 3.
NATURAL COMPOUNDS AGAINST DRUG RESISTANCE IN CANCER
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A combina ion o que ce in and 5-fluo ou acil ea men
o Caco-2 and HCT-116 colon cance cell line showed a syne -
gis ic e ec on apop osis induc ion. The combina ion o
hese wo compounds significan ly dec eased le els o miR-
27a, an oncomiRNA in ol ed in he p omo ion o colon can-
ce cell p oli e a ion. Reduc ion o miR-27a le els led o sup-
p ession o miR-Wn /b-ca enin signaling and significan ly
lowe ed cell g ow h (133).
A chemically modified de i a i e o que ce in, 7-O-ge a-
nylque ce in (GQ), was shown o enhance he sensi i i y o
MCF-7-ad iamycin- esis an b eas cance cells h ough
up egula ion o miR-451. O e exp ession o miR-451 in u n
lowe ed P-glycop o ein, and mul id ug esis ance-associa ed
p o ein (MDR1), as well as on mice xenog a model indica -
ing ha que ce in-based syn he ic de i a i e and miR-451
ha e addi i e e ec s agains o e coming doxo ubicin esis -
ance, and ha he be e e ec o silencing is accomplished
when bo h agen s a e p esen , GQ and miR-451 (134).
Fu he mo e, i has been shown ha miR-155 was signifi-
can ly up egula ed in BRCA1 me hyla ed HCC-38 and UACC-
3199 cells compa ed wi h BRCA1 mu a ion-con aining b eas
cance cell lines, bo h iple-nega i e and es ogen ecep o -
posi i e MDA-MB-231 and HCC-1937 cells, indica ing ha
miR-155 ac s as an “epi”miRNA (143). In his esea ch, i has
been shown ha cu cumin-induced deme hyla ion o
BRCA1 p omo e , es o ed BRCA1 ac i i y, which in u n
educed miR-155 le els in HCC-38 cells, unlike in HCC-1937
cells, meaning ha cu cumin has he po en ial o silence
miR-155 h ough in cells wi h hype me hyla ed BRCA1-
me hyla ed cells bu no in cells con aining BRCA1 mu a ion.
Also, hese esul s indica e ha cu cumin can educe he
oncogenic e ec s o miR-155 in specific cell ypes, highligh -
ing i s an i umo po en ial (143). Acco ding o his, some na -
u al agen s undoub edly influence epigenome emodeling.
Cu cumin also al e s le els o miRNAs miR-30c/200b/200c/
22/101/27 in colo ec al, lung, gas ic, and hy oid cance , and
miR-21, which was down egula ed a e cu cumin ea men
in lung, hepa ocellula , and b eas cance (144).
Besides he cu cumin, miR-155 was shown o be a po en-
ial a ge o es e a ol, as well. Acco ding o Su e al.
(145), miR-155-5p was significan ly up egula ed in MGC803,
SGC7901, and AGS cell lines and gas ic ca cinoma issue
samples compa ed wi h no mal GES-1 line and pa acance -
ous noncance ous issue, which was e e sed in cell lines
a e he ea men wi h es e a ol who inhibi ed cell p oli -
e a ion and g ow h, and educed miR-155 exp ession le els.
Ano he s udy has shown ha es e a ol in e ac s wi h
miR-21 ia ac i a ion o phospha ase and ensin homolog
(PTEN) exp ession in colon cance cells, whe eas in p os a e
cance cells ia es o a ion o supp esso p og ammed cell
dea h 4 (PDCD4)(137). The influence o es e a ol on
miRNA is associa ed wi h inflamma ion and cance by
up egula ion o miR-663, whose a ge genes a e pa o
inflamma o y and cance pa hways, including a he oscle o-
sis as well (146). Conside ing ha miR-663 is shown o ha e a
la ge numbe o a ge s, and ha es e a ol induces and
es o es i s exp ession in a dose-dependen manne , he
au ho s p oposed ea men wi h a low dose o a longe
Table 2. Na u al compounds a ge ing miRNA le els agains cance d ug esis ance
Ex ac /Na u al Compound Mic oRNA
How o O e come
Resis ance/Induce
Sensi i i y Desc ip ions Re e ences
Olea eu opaea lea
ex ac (OLE)
miR-137, miR-145, miR-153,
miR-181b, le -7d
:T ea men wi h OLE and emozolomide gi es be e
esul s han emozolomide solely in e ms o cell
dea h and in asi eness enhances sensi i i y o emo-
zolomide (syne gis ic e ec ) agains glioblas oma
cells T98G, U-138MG, and U-87MG
(128)
Epigalloca echin-3-gal-
la e (EGCG)
miR-145, miR-200c, miR-34a :Up egula ed umo -supp essi e miRNAs in HCT116 and
SW480 colo ec al cance fluo ou acil- esis an cells
and sensi ized hem o 5FU
(85)
miR-485 :O e exp ession o miR-485 induced by EGCG ea -
men o lung cance A549 educed s emness,
esponsible o esis ance o cispla in in EGCG-miR-
485 dose-dependen manne
(129)
Cu cumin miR-146a :Cu cumin sensi izes glioblas oma cells o emozolomide
ia miR-146a up egula ion
(130)
miR-29b-1-5p ;Liposomal cu cumin changes miRNA le els in MCF-7
b eas cance cells. Highe miR-29b-1-5p le els
dec ease he e ec o cu cumin on sensi izing MCF-7
cells o doxo ubicin
(131)
Allicin miR-486-3p :Allicin induces sensi i i y o emozolomide by up egu-
la ing miR-486-3p and inhibi ion o 6-me hylguanine-
DNA me hyl ans e ase in esis an U251-TR glioblas-
oma cells
(132)
Que ce in miR-27a ;Que ce in oge he wi h 5-fluo ou acil syne gis ically
induced apop osis o Caco-2 and HCT-116 colon can-
ce cells. Que ce in may ha e he po en ial o sensi-
ize colon cance cells o 5-fluo ou acil
(133)
7-O-ge anylque ce in
(GQ)
miR-451 :GQ-induced miR-451 up egula ion enhanced sensi i i y
o MCF-7-ad iamycin- esis an b eas cance cells o
doxo ubicin
(134)
The up a ow sugges s ha up egula ion o pa icula miRNA may be conside ed o he imp o emen o he ea men , enhancemen
o sensi i i y o he d ug, and/o o e coming d ug esis ance. 5FU, 5-fluo ou acil.
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