Targeting Apoptosis Pathways in Cancer and Perspectives ......Review Targeting Apoptosis Pathways in...

Review

Targeting Apoptosis Pathways in Cancer and Perspectiveswith Natural Compounds from Mother Nature

Faya M. Millimouno1,2,3, Jia Dong1, Liu Yang2, Jiang Li2, and Xiaomeng Li1

AbstractAlthough the incidences are increasing day after day, scientists and researchers taken individually or by

research group are trying to fight against cancer by several ways and also by different approaches and

techniques. Sesquiterpenes, flavonoids, alkaloids, diterpenoids, and polyphenolic represent a large and

diverse groupofnaturally occurring compounds found in a variety of fruits, vegetables, andmedicinal plants

with various anticancer properties. In this review, our aim is to give our perspective on the current status of

the natural compounds belonging to these groups anddiscuss their natural sources, their anticancer activity,

their molecular targets, and their mechanism of actions with specific emphasis on apoptosis pathways,

which may help the further design and conduct of preclinical and clinical trials. Unlike pharmaceutical

drugs, the selected natural compounds induce apoptosis by targeting multiple cellular signaling pathways

including transcription factors, growth factors, tumor cell survival factors, inflammatory cytokines, protein

kinases, and angiogenesis that are frequently deregulated in cancers and suggest that their simultaneous

targeting by these compounds could result in efficacious and selective killing of cancer cells. This review

suggests that they provide a novel opportunity for treatment of cancer, but clinical trials are still required to

further validate them in cancer chemotherapy. Cancer Prev Res; 7(11); 1081–107. �2014 AACR.

IntroductionCancer is a major public health problem and the second

leading cause ofmortality around theworld,mainly Europeand the United States with an incident rate of about 2.6million cases per year (1, 2). It is characterized by unsched-uled anduncontrolled cellular proliferation in the spectrumof cell. Cancer incidence in developing countries has beenprevailed by tumor types that are related to viral, geneticmutations, and bacterial contamination (3). Cancer has ahigh incidence and a long period of latency on its devel-opment and in the progression of the sickness. There arenumerous risk factors known concerning the developmentof cancer including age, geographic area, and race (4).However, cancer is mostly a preventable disease.Regardless of whether a cancer specifically results from a

genetic mutation and viral or bacterial contamination, therecent extensive research indicated that most cancers arecaused by dysfunction of many genes coding for proteins

such as, antiapoptotic proteins, growth factors, growthfactor receptors, transcription factors, and tumor suppres-sors, which constituted the target for cancer treatment.Prevailing treatment options have limited therapeutic suc-cess in cancer in the past decade. The concept of chemo-prevention is gaining increasing attention because it is acost-effective alternative for cancer treatment (5). Cancerchemoprevention by natural compounds, especially phy-tochemicals, minerals, and vitamins, in a number of studiesunder both in vitro and in vivo conditions has shownpromising results against various malignancies (6).

In the development of bioactive chemical, natural pro-ducts have a rich and long history. Herbal medicines, as animportant novel sourcewith awide rangeof pharmaceuticalpotential, are being used to treat human ailments includingalmost all kinds of cancer (7).

The involvement of multiple factors underlying develop-mental stages of cancer at epigenetic, genetic, cellular, andmolecular levels is opening up enormous opportunities tointerrupt and reverse the initiation and progression of thedisease and provide scientists and researchers with numer-ous targets to arrest by physiologic and pharmacologicmechanisms to delay the development of cancer. The aimof this review is to summarize recent researches on twelve(12) natural compounds, such as flavonoids (honokiol,magnolol, jaceosidin, and casticin), sesquiterpenes (parthe-nolide, costunolide, isoalantolactone, and alantolactone),alkaloid (evodiamine), diterpenoids (oridonin and pseu-dolaric acid B), and polyphenolic (wedelolactone) focusingon anticancer activity. The literature was screened fromvarious sites including PubMed, Scopus, and Elsevier

1TheKey Laboratory ofMolecular Epigenetics ofMOE, Institute ofGeneticsand Cytology, Northeast Normal University, Changchun, China. 2DentalHospital, Jilin University, Changchun, China. 3Higher Institute of Scienceand Veterinary Medicine of Dalaba, Dalaba, Guinea.

F.M. Millimouno and J. Dong contributed equally to this work.

Corresponding Authors: Xiaomeng Li, School of Life Sciences, NortheastNormal University, Renmin Street 5268, Changchun, China. Phone: 86-431-85099285; Fax: 86-431-85099285; E-mail: [email protected];and Jiang Li, Jilin University, Changchun 130021, China. Phone: 86-186-86531019; Fax: 86-431-85579335; E-mail: [email protected]

doi: 10.1158/1940-6207.CAPR-14-0136

�2014 American Association for Cancer Research.

CancerPreventionResearch

www.aacrjournals.org 1081

Research. on July 17, 2021. © 2014 American Association for Cancercancerpreventionresearch.aacrjournals.org Downloaded from

Published OnlineFirst August 26, 2014; DOI: 10.1158/1940-6207.CAPR-14-0136

http://cancerpreventionresearch.aacrjournals.org/

Science Direct Journal. Access to the Elsevier Science DirectJournal was made possible through library of NortheastNormal University, Changchun, China. We propose thatthe development of natural compounds into new antican-cer agents has a bright future despite some difficulties.

Natural Sources and Biologic Activities ofAnticancer Chemopreventive Agents

Natural products are important and valuable resourcesfor drug development. Extensive researches have been car-ried out on the phytochemicals for their health-promotingpotential. They have been found in fruits, vegetables, nuts,seeds, herbs, spices, stems, flowers, and tea. The phyto-constituent from these plants was extracted by severaltechniques, mainly high-performance liquid chromatogra-phy, micellar electrokinetic chromatography, microemul-sion electrokinetic chromatography, and their structureswere elucidated on the basis of nuclear magnetic resonanceanalysis (Fig. 1).

The selected natural compounds among diterpenoids,sesquiterpenes, flavonoids, alkaloids, and polyphenolichave been reported for their wide spectrum of biologic

effects, including antifungal, antihelmintic, antimicrobial,anti-inflammatory, antitrypanosomal, and antiproliferativeeffects on various cancer types as described in Tables 1and 2.

Role ofNatural Compounds inCancerPreventionPlants provide an extensive reservoir of natural pro-

ducts, demonstrating important structural diversity, andoffer a wide variety of novel and exciting chemical entitiesand have a long history of use in the treatment of severalillnesses. The significance of natural products in healthcare is supported by a report that 80% of the globalpopulation still relies on plant-derived medicines toaddress their health care needs (8). It is also reportedthat 50% of all drugs in clinical use are natural products,or their derivatives, or their analogs (9), and 74% of themost important drugs consist of plant-derived activeingredients (10). There are more than 3,000 plant speciesthat have been reported to be used in the treatment ofcancer in modern medicine (11–14).

There is a continued interest in the investigation ofextracts of microorganisms, terrestrial plants, and marine

OO

O

H3C

H3CO

H3CO

H3C

H3C

HO

OHOH

OH

OHOH

OH

CH3

CH3

CH2

CH3 OCH3

OCH3

CH2CH2

CH2

CH2

CH3

O

H

H

O

O

OH

HOO

O

O

O

H

COOCH3

H H

HO

O HO

O

OO

O

O

O

OH

OH

OH

OH

OH

OH

O

O OO

H H

HO

O

OH

H N

NNH

O

Sesquiterpenes compounds Flavonoids compounds Diterpenoids compounds

Polyphenolic compound

Alkaloid compound

PARTHINOLIDE HONOKIOL ORIDONIN

PSEUDOLARIC ACID B

WEDELOLACTONE

MAGNOLOLCOSTUNOLIDE

ISOALANTOLACTONE

ALANTOLACTONE

JACEOSIDIN

CASTICINEVODIAMINE

Tanacetum parthenium Magnolia grandiflora Isodon rubescens

Inula helenium Magnolia officinalis Pseudolarix kaempferi

Inula helenium L. Artemisia princepsWedelia chinensis

Evodia rutaecarpa

Vitex rotundifoliaInula racemosa

Figure 1. Chemical structure of the promising natural compounds and major natural sources.

Millimouno et al.

Cancer Prev Res; 7(11) November 2014 Cancer Prevention Research1082




Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Flav

onoids

Hon

okiol

Mag

nolia

officina

lis,M

agno

liagran

diflora,

Mag

nolia

spp.

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

antia

ngioge

nesis,

antia

utop

hagy

,im

mun

omod

ulation,

antic

ance

r,ga

strointestinal

disorders,

coug

h,an

xiety,

andallergies

Glio

blastom

a,melan

oma,

gastric

,leu

kemia,s

kin,

colon,

brea

st,o

varia

n,pan

crea

tic,h

epatoc

ellular,

colorectal,lun

g,prostate,

human

rena

lmes

angial,

head

andne

cksq

uamou

sca

rcinom

a

Fluc

onaz

ole,

Epigalloca

tech

inga

llate

(EGCG),TN

Fa

CDK1?

,Bcl-2#,

Bax

",cy

clin

D1#

,pA

KT#

,g-sec

retase

activ

ity#,

g-se

cretas

eco

mplexproteins#

,PPAR-g?,

COX-2?,

NF-kB

?,EGFR

/P13

K/AKt#;

JunB

#and

JunD

#cas

pas

e-8"

,cas

pas

e-9"

,ca

spas

e-3"

,PARP",

p53

",CD31

staining

#,LH

",p38

?,NF-

kB?,

Bcl-XL#

,Bad

",cy

clin

E#,

(Cdk2

andCdk4

)#,Cdk

",p21

andp27

",NF-k B

#,Bcl-2#,

Mcl-

1#,s

urcivin#

,VEGF#

,STA

T3?,

HG-ind

uced

IL1b

?,IL18

?,TN

Fa?,

-PGE2?

,NO?,

and

TGFb

1?,M

CP-1?,

MIP-1a?

,EGFR

targetingTK

I?,A

kt?

erlotin

ib?,

EGFR

sign

aling?

,MAPK?,

cyclin

D1?

Mag

nolol

Mag

nolia

officina

lis,M

agno

liaob

ovata.

Antiproliferation(cell-cy

cle

arrest,a

pop

tosis),

immun

omod

ulation,

antic

ance

r,an

tianx

iety,

antid

epressan

t,an

tioxidan

t,an

ti-inflam

matory,

antia

ngioge

nesis,

and

hepatop

rotectiveeffects

Glio

blastom

a,bladde

r,breas

t,co

lon,

gastric

,skin,

ovarian,

lung

,prostate,

melan

oma,

liver

canc

er,c

ervica

lep

itheloidca

rcinom

a,leuk

emia,fi

brosa

rcom

a,ne

urob

lastom

a,thyroid

carcinom

a

TNFa

,curcu

min

p21/Cip1"

,p27

/Kip1"

,Hyp

oxia?,

HIF1a

",VEGF"

,AMPK",

Bcl2#

,Bax

",p53

",Bax

/Bcl-2",

casp

ase-3"

,cyc

linB1 #

,cyc

linA#,

CDK-4#,

Cdc2

#,Cip",

casp

ase-8"

,PARP",

NF-kB

#,HER2#

,PI3K/Akt#,

Bad

",Bcl-X(S)",

Bcl-X(L)#,

MMP-2#,

MMP-9#,ca

spas

e-3,

-9",ERK",

Raf-1",

Ca(2þ

)",Cyto-c"

,bc

l-2#

,LTC

4?,L

TB4?

,IgE

?,cP

LA2?

,5-LO?,

MMP-9?,

Ca

(2þ)

",ca

spas

e-7"

,ADP-

ribos

e#,p

hosp

hatase

"(Con

tinue

don

thefollo

wingpag

e)

Targeting Apoptosis Pathways in Cancer

www.aacrjournals.org Cancer Prev Res; 7(11) November 2014 1083




Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

(Con

t'd)

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Jace

osidin

Artem

isia

prince

ps,A

rtem

isia

iway

omog

i,Artem

isia

argy

i,Artem

isia

copa

,Artem

isia

vestita

,Sau

ssurea

med

usa,

Eup

atorium

arno

ttianu

m,

Eup

atorium

lindleyanu

m,

Cen

taurea

phy

lloce

pha

la,

Cen

taurea

nica

eens

is,

Nippon

anthem

umnippon

icum

,Arnica

cham

isso

nis,

Arnica

Mon

tana

,Vervain

officina

lis,

Lantan

amon

teviden

sis,

Erio

dictyon

californicu

m

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation

Hum

anen

dom

etria

l,hu

man

ovaryca

ncer,g

lioblastom

a,breas

t,ep

ithelial,pros

tate,

cervical,m

ammaryep

ithelial

TNFa

Cdc2

#,cy

clin

B1#

,com

plex?

,ca

spas

e-9"

,MMP#,

p53

",Bax

",COX-2",

MMP-9",

TPA?,

proteinE6an

dE7?

,p53

?,Bax

",Bcl-2#,ca

spas

e-3"

,p53

",p2

1",E

RK1/2?

Cas

ticin

Vite

xrotund

ifolia,V

.agn

usca

stus

,V.trifolia,V

.ne

gund

o,Dap

hnege

nkwa,

Ach

illea

millefolium,F

icus

microca

rpa,

Fruc

tusvitic

is,

Crataeg

uspinn

atifida

,Pavetta

crassipe

s,Nelso

nia

cane

scen

s,Citrus

unsh

u,Cen

tiped

aminim

a,Claus

ena

exca

vate,C

rotonbetulaster,

Artem

isia

abrotanu

mL.,

Cam

ellia

sine

nsis

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

premen

strual

synd

rome,

Anti-inflam

mation,

antia

nxiety,

immun

omod

ulation,

antim

alarial,an

timicrobial,

andan

tifun

galp

ropertie

s

Cervica

l,pan

crea

tic,c

olon

,breas

t,lung

,gas

tric,o

varia

n,liver,c

olorec

tal,leuk

emia,

prostate

TRAIL,T

NFa

,cisplatin

,cu

rcum

inJN

K,B

cl-2#,

Bcl-xL#

,XIAP#,

casp

ase-3"

,cas

pas

e-9"

,cyc

linB1#

,Bax

",TN

F#,D

R5"

,MMP2#

,MMP9#

,NF-kB

#,STA

T3#,

FOXO3a

#,Fo

xM1#

,CDK1#

,cdc2

5B#,

cyclin

B#,

p27K

IP1"

,cyc

linA#,

cFLIP#,

survivin#,

cytoch

romec"

,Bid"

Ses

quite

rpen

esCos

tuno

lide

Inulahe

lenium

,Sau

ssurea

lappa,

Mag

nolia

gran

diflora

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

antic

ance

r,an

ti-inflam

matory,

antiv

iral,

antifun

gal

Live

r,ov

arian,

breas

t,bladde

r,melan

oma,

leuk

emia,

prostate,

human

mon

ocyte,

gastric

,colorec

tal

TNFa

,tax

ol,c

isplatin

Bcl-2#,

casp

ase-3"

,-8"

,and

-9",

Bax

",Fa

s",C

dc2#

,cyc

linB1#

;p2

1WAF1

",proca

spas

e-8"

,proc

aspas

e-3"

;JNK";

PI3-K

;PKC;E

RK",

NF-kB

#,cy

clin

E#;

p21"

,VEGF#

(Con

tinue

don

thefollo

wingpag

e)

Millimouno et al.





Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

(Con

t'd)

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Parthen

olide

Tana

cetum

parthen

ium.,

Tana

cetum

vulgare,

Cen

taurea

aine

tens

is,

Tana

cetum

larvatum

,Helianthu

sAnn

uus,

Anv

illea

radiate,M

agno

liako

bus

,Mag

nolia

virginiana

,Mag

nolia

ovate,

Mag

nolia

gran

diflora,

Lirio

den

dron

tulip

ifera,M

iche

lia,M

agno

liach

ampac

a,Miche

liafloribun

da,

Tsoo

ngioden

dron

odorum

,Artem

isia

ludov

iciana

,Calea

zaca

tech

ichi,P

olym

nia

mac

ulate,

Ach

illea

falcata

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

antia

ngioge

nesis,

autopha

gy,

immun

omod

ulation,

and

cytotoxiceffects

Breas

t,sk

in,m

elan

oma,

maligna

ntglioma,

epidermal

tumorigen

esis,liver,g

astric,

lung

,bladder,p

rostate,

bile

duc

tca

rcinom

as,

pan

crea

tic,m

yeloma,

leuk

emia,c

olorec

tal,Burkitt

lympho

ma,

epith

elial

ovarian,

osteos

arco

ma

TTRAIL,g

emcitabin,

taxo

l,TN

Fa,c

isplatin

,cu

rcum

in,o

kadaic

acid,g

eldan

amyc

in,

buthion

ine

sulfo

ximine

Bax

",Bcl2#

,mRNA#

metalloproteinas

e-9#

,STA

T3?,

JNK",

VEGF?

,IL8

?,ABCB5

tran

sporter#,

Bcl-X(L)#,

survivin#,cy

clinD1#

,IL8

#matrix

metalloproteinas

e9#

,Akt

phos

pho

rylatio

n#,N

F-kB

#,p6

5/NF-kB

#,Ki67#

,p21

",an

tioxidan

tN-ace

tyl-L-

cystein?

,glutathione

S-

tran

sferas

e#STA

T3?,

JAK?,

tBid"o

fca

spas

e-3/8/9"

,poly

(ADP-ribos

e)polym

eras

e?,

p-ERK",

p-p38

",p38

and

SAPK/JNK",

PKC-alpha

?,proc

aspas

e-3#

,p65

#,VEGF?

,IL6mRNA?,

Ikap

paB

-alpha

",p5

3",R

OS",

JNK",

Bid"

Alantolac

tone

Inulahe

lenium

,L.,Inula

japon

icaAuc

klan

dia

lappa,

Rad

ixinulae

Inularace

mos

a

Anti-inflam

matory,

antim

icrobial,an

tican

cer,

cytotoxicity,a

ntifu

ngal,

oxidored

uctase

,and

antip

roliferative

Prostate,

glioblastom

a,co

lon,

leuk

emia,liver,lun

g—

Bax

/Bcl-2",ca

spas

e-3"

,STA

T3?,

casp

ase-8,MMP#,Bid",NF-kB

/p6

5#,p

53",

Bax

",Bcl-2#,

casp

ase-9"

,cas

pas

e-3"

,ADP-

ribos

e#,N

F-kB

?,ROS",ac

tivin/

SMAD3sign

aling"

,Crip

to-1/

ActRII?

,ROS",

cytoch

rome-c"

,Bax

",PARP#,ADP-ribos

e#,N

F-kB

? ,DNA-binding#

,IkB

aph

ospho

rylatio

n#,p

21",

Bcr/

Abl#,

P-glyco

protein#,

cyclin

B1#

,cyc

lin-dep

enden

tprotein

kina

se-1#

Isoa

lantolac

tone

Inulahe

lenium

,L.,Inula

japon

icaAuc

klan

dia

lappa,

Rad

ixinulae

Inularace

mos

a

Anti-inflam

matory,

antim

icrobial,an

tican

cer,

cytotoxicity,a

ntifu

ngal,

oxidored

uctase

,and

antip

roliferative

Prostatega

stric

pan

crea

ticleuk

emia

—p3

8",M

APK",

Bax

",an

dclea

ved

casp

ase-3"

,Bcl-2#,

PI3K/Akt?,

PARP"

(Con

tinue

don

thefollo

wingpag

e)






Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

(Con

t'd)

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Dite

rpen

oids

Orid

onin

Isod

onrubes

cens

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

autopha

gy,a

ndim

mun

omod

ulation

Breas

t,as

troc

ytom

a,leuk

emia,

lung

,hep

atom

a,prostate,

colorectal,p

ancrea

tic,

ovarian,

human

multip

lemye

loma,

human

histoc

ytic

lympho

ma,

hepa

toce

llular,

cervical,n

euroblastom

a,laryng

eal,ga

stric

,murine

fibrosa

rcom

a,melan

oma,

epidermoidca

rcinom

a,os

teos

arco

ma

TRAIL,g

emcitabin,

taxo

l,TN

Fa,c

isplatin

,cu

rcum

in,a

rsen

ictrioxide(As2

O3),

Wog

onin

Cas

pas

e-8#

,NF-kB

(p65

)#,IKKa#

,IKKb#

,pho

spho

-mTO

R#,

Fas",

PPARg",M

MP-2/M

MP-9#,

b1/

FAK?,

casp

ase-3"

,LYN?,

ABL?

,Akt/m

TOR#,

Raf/M

EK/

ERK#a

ndSTA

T5#,AML1

-ETO

#,c-Kit(þ)

?,c-Met-N

F-kB

-COX-

2",c

-Met-B

cl-2-cas

pas

e-3,

Bcl-2/Bax

ratio

",AVOs#,L

C3-

I?,L

C3-II?

,P21

",FA

S?,

SREBP1?

,AP-1#,

NF-kB

#,P38

#,p21

",p27

",p16

",c-myc

p38"

,p53

",(M

APK)-p38

,cyc

linB1an

dp-cdc2

(T16

1)#,

p53

",Akt#,

ROS#,

SIRT1

#,NF-kB

",ca

spas

e-1"

,IL1

b",X

IAP#,

Grp78

",a-

CP1#

,Bcl-2#,

casp

ase-8"

,proca

spas

e-3-9#

,pro-TN

Fa",

p53

#,ca

spas

e-9#

,DeltaPsim#,

ERK#,

p38

",MAPK",

JNK"

Pse

udolaric

AcidB

Pse

udolarixkaem

pferi

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

immun

omod

ulation,

antic

ance

ran

dan

ti-inflam

matory,

and

antia

ngioge

nesiseffects

Microve

ssel

endothe

lial,

prostate,

glioblastom

a,um

bilica

lveinen

dothe

lial,

murinefibros

arco

ma,

bladder,c

olon

,lun

g,breas

t,melan

oma,

ovarian,

leuk

emia,g

astric,liver

Taxo

l,TN

FaNF-kB

?,p65

?,IL2#

,IkB

-a?,

cyclin

B1"

,CDK1"

,cyc

linD1#

p53"

,Bax

",Bcl-2#,

1aan

dcy

clin

E#,

cdc2

",cd

c2#,

survivin#,ca

spas

e-3"

,COX-2?,

STA

T3,I-kB#,

Tubu

lin,b

inding

ofco

lchicine

totubulin?,

bcl-x(L)

?,NAG-1",

JNK",

ERK#,

Wee

1kina

sean

dp2

1",

Bcl-xL#

,Bax

",ca

spas

e-7"

,Fa

s/APO-1",

Bcl-2

binding

with

Bec

lin1?

,Akt

pho

spho

rylatio

n#(Con

tinue

don

thefollo

wingpag

e)

Millimouno et al.





Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

(Con

t'd)

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Polyp

heno

licWed

elolac

tone

Eclipta

alba,

Wed

elia

caland

ulac

eae,

Wed

elia

chinen

sis,

Eclipta

prostrata

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

and

hepatop

rotectiveeffects

Breas

t,prostate,

neurob

lastom

a,pan

crea

tic,

mam

maryca

rcinos

arco

ma,

mye

loma,

leuk

emia,

aden

oma,

glioma

IFNg

NF-kB

#,PARP",

IIa#,

p-p53

",ca

spas

e-3"

,cas

pas

e-7"

,c-

JNK",PKCe#,IKKa#

,Bax

",Bcl-

xL#,

p21

",p2

7",B

cl-2#,

IL6#

,IL6R

#,c-myc

,IKK#,

p-TAK1,

IKKb#

,IKKa#

,IL1

b#,S

TAT-3#

,TL

R-4",

TLR-7",

TLR-8",

Akt#,

TNFa

#,IkB#

Alkaloids

Evo

diamine

Evo

dia

rutaec

arpa

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

antim

icrobial,an

tican

cer,

antim

etas

tatic

,and

antic

arcino

gene

sis

MurineLe

wis

lung

,he

patoc

ellular,leuk

emia,

gastric

,pan

crea

tic,c

olon

,hu

man

thyroidca

ncer,

melan

oma,

colorectal,

breas

t,ce

rvix

carcinom

a,prostate

Gem

citabin,tax

ol,

TNFa

,cisplatin

Atgs",3

-MA?,

IL6#

,STA

T3?,

AP-1?,

PLC

-g1?

,XIAP?,

Bax

",CDK1?

,NDcy

clinB1"

,PI3K?,

Akt?,

PKA?,

mTO

R?,

PTE

N?,

NF-kB

#,cy

clinA#,

cyclinA-

dep

enden

tkina

se2#

,cdc2

5c#,

TUNEL"

,proca

spas

e-3-8-9#

,cd

c25C

",cy

clin

B1"

,cdc2

-p16

1protein",

cdc2

-p15

,ca

spas

e-3-8-9"

,Fas

-L",

p53"

,p21

",Bcl-2#,

TopI?

,Raf-1#,

Bax

",Bcl-2",

Bcl-x(L)#,

Bec

lin1"

,LC3"

,Cdc2

",cy

clin

B1"

,Cdc

2(Thr

161)",Cdc2

(Tyr15

)#,

Myt-1#,

Cdc2

5C#,

casp

ase-

3-9"

,ERKpho

spho

rylatio

n#,

VEGF?

(Con

tinue

don

thefollo

wingpag

e)






Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

(Con

t'd)

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Flav

onoids

Hon

okiol

Mag

nolia

officina

lis,M

agno

liagran

diflora,

Mag

nolia

spp.

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

antia

ngioge

nesis,

antia

utop

hagy

,im

mun

omod

ulation,

antic

ance

r,ga

strointestinal

disorders,

coug

h,an

xiety,

andallergies

Glio

blastom

a,melan

oma,

gastric

,leu

kemia,s

kin,

colon,

brea

st,o

varia

n,pan

crea

tic,h

epatoc

ellular,

colorectal,lun

g,prostate,

human

rena

lmes

angial,

head

andne

cksq

uamou

sca

rcinom

a

Fluc

onaz

ole,

Epigalloca

tech

inga

llate

(EGCG),TN

Fa

CDK1?

,Bcl-2#,

Bax

",cy

clin

D1#

,pA

KT#

,g-sec

retase

activ

ity#,

g-se

cretas

eco

mplexproteins#

,PPARg?

,COX-2?,

NF-kB

?,EGFR

/P13

K/AKt#;

JunB

#and

JunD

#cas

pas

e-8"

,cas

pas

e-9"

,ca

spas

e-3"

,PARP",

p53

",CD31

staining

#,LH

",p3

8?,

NF-kB

?,Bcl-XL#

,Bad

",cy

clin

E#,

(Cdk2

andCdk4

)#,Cdk

",p2

1an

dp27

",NF-k B

#,Bcl-2#,

Mcl-1#,

surcivin#,

VEGF#

,STA

T3?,

HG-ind

uced

IL1b

?,IL18

?,TN

Fa?,

-PGE2?

,NO?,

andTG

Fb1?

,MCP-1

?,MIP-

1a?,

EGFR

targetingTK

I?,

Akt?

erlotin

ib?,

EGFR

sign

aling?

,MAPK?,

cyclinD1?

Mag

nolol

Mag

nolia

officina

lis,M

agno

liaob

ovata.

Antiproliferation(cell-cy

cle

arrest,a

pop

tosis),

immun

omod

ulation,

antic

ance

r,an

tianx

iety,

antid

epressan

t,an

tioxidan

t,an

ti-inflam

matory,

antia

ngioge

nesis,

and

hepatop

rotectiveeffects

Glio

blastom

a,bladde

r,breas

t,co

lon,

gastric

,skin,

ovarian,

lung

,prostate,

melan

oma,

liver

canc

er,c

ervica

lep

itheloidca

rcinom

a,leuk

emia,fi

brosa

rcom

a,ne

urob

lastom

a,thyroid

carcinom

a

TNFa

,curcu

min

p21/Cip1"

,p27

/Kip1"

,Hyp

oxia?,

HIF1a

",VEGF"

,AMPK",

Bcl2#

,Bax

",p53

",Bax

/Bcl-2",

casp

ase-3"

,Cyc

linB1#

,Cyc

linA#,

CDK-4#,

Cdc2

#,Cip",

casp

ase-8"

,PARP",

NF-kB

#,HER2#

,-PI3K/Akt#,Bad

",Bcl-X

(S)",

Bcl-X(L)#,

MMP-2#,

MMP-

9#,c

aspas

e-3,

9",E

RK",

Raf-

1",C

a(2þ

)",C

yto-c"

,bcl-2#,

LTC4?

,LTB

4?,IgE

?,cP

LA2?

,5-LO

?,MMP-9?,

Ca(2þ

)",ca

spas

e-7"

,ADP-ribos

e#,

phos

pha

tase

"(Con

tinue

don

thefollo

wingpag

e)

Millimouno et al.





Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

(Con

t'd)

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Jace

osidin

Artem

isia

prince

ps,A

rtem

isia

iway

omog

i,Artem

isia

argy

i,Artem

isia

copa

,Artem

isia

vestita

,Sau

ssurea

med

usa,

Eup

atorium

arno

ttianu

m,

Eup

atorium

lindleyanu

m,

Cen

taurea

phy

lloce

pha

la,

Cen

taurea

nica

eens

is,

Nippon

anthem

umnippon

icum

,Arnica

cham

isso

nis,

Arnica

Mon

tana

,Vervain

officina

lis,

Lantan

amon

teviden

sis,

Erio

dictyon

californicu

m

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation

Hum

anen

dometria

l,hu

man

ovaryca

ncer,g

lioblastom

a,breas

t,ep

ithelial,pros

tate,

cervical,m

ammaryep

ithelial

TNFa

Cdc2

#,cy

clin

B1#

,com

plex?

,ca

spas

e-9"

,MMP.#,

p53

",Bax

",COX-2",

MMP-9",

TPA?,

proteinE6an

dE7?

,p53

?,Bax

",Bcl-2#,ca

spas

e-3"

,p53

",p2

1",E

RK1/2?

Cas

ticin

Vite

xrotund

ifolia,V

.agn

usca

stus

,V.trifolia,V

.ne

gund

o,Dap

hnege

nkwa,

Ach

illea

millefolium,F

icus

microca

rpa,

Fruc

tusvitic

is,

Crataeg

uspinn

atifida

,Pavetta

crassipe

s,Nelso

nia

cane

scen

s,Citrus

unsh

u,Cen

tiped

aminim

a,Claus

ena

exca

vate,C

rotonbetulaster,

Artem

isia

abrotanu

mL.,

Cam

ellia

sine

nsis

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

premen

strual

synd

rome,

anti-inflam

mation,

antia

nxiety,

immun

omod

ulation,

antim

alarial,an

timicrobial,

andan

tifun

galp

ropertie

s

Cervica

l,pan

crea

tic,c

olon

,breas

t,lung

,gas

tric,o

varia

n,liver,c

olorec

tal,leuk

emia,

prostate

TRAIL,T

NFa

,cisplatin

,cu

rcum

inBcl-2#,

Bcl-xL#

,XIAP#,

casp

ase-3"

,cas

pas

e-9"

,Cyc

linB1#

,Bax

",TN

F#,D

R5"

,MMP2#

,MMP9#

,NF-kB

#,STA

T3#,

FOXO3a

#,Fo

xM1#

,CDK1#

,cdc2

5B#,

cyclin

B#,

p27K

IP1"

,Cyc

linA#,

cFLIP#,

survivin#,

cytoch

romec"

,Bid"

Ses

quite

rpen

esCos

tuno

lide

Inulahe

lenium

,Sau

ssurea

lappa,

Mag

nolia

gran

diflora

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

antic

ance

r,an

ti-inflam

matory,

antiv

iral,

antifun

gal

Live

r,ov

arian,

breas

t,bladde

r,melan

oma,

leuk

emia,

prostate,

human

mon

ocyte,

gastric

,colorec

tal

TNFa

,tax

ol,c

isplatin

Bcl-2

#,ca

spas

e-3"

,-8"

,and

-9",

Bax

",Fa

s",C

dc2#

,cyc

linB1#

;p2

1WAF1

",pro-cas

pase

-8",

pro-ca

spas

e-3"

;JNK";

PI3-K

;PKC;E

RK",

NF-k B

#,cy

clin

E#;

p21"

,VEGF#

(Con

tinue

don

thefollo

wingpag

e)






Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

(Con

t'd)

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Parthen

olide

Tana

cetum

parthen

ium.,

Tana

cetum

vulgare,

Cen

taurea

aine

tens

is,

Tana

cetum

larvatum

,Helianthu

sAnn

uus,

Anv

illea

radiate,M

agno

liako

bus

,Mag

nolia

virginiana

,Mag

nolia

ovate,

Mag

nolia

gran

diflora,

Lirio

den

dron

tulip

ifera,M

iche

lia,M

agno

liach

ampac

a,Miche

liafloribun

da,

Tsoo

ngioden

dronod

orum

,Artem

isia

ludo

vician

a,Calea

zaca

tech

ichi,P

olym

nia

mac

ulate,

Ach

illea

falcata

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

antia

ngioge

nesis,

autopha

gy,

immun

omod

ulation,

and

cytotoxiceffects

Breas

t,sk

in,m

elan

oma,

maligna

ntglioma,

epidermal

tumorigen

esis,liver,g

astric,

lung

,bladde

r,prostate,

bile

duc

tca

rcinom

as,

pan

crea

tic,m

yeloma,

leuk

emia,c

olorec

tal,Burkitt

lympho

ma,

epith

elial

ovarian,

osteos

arco

ma

TTRAIL,g

emcitabin,

taxo

l,TN

Fa,c

isplatin

,cu

rcum

in,o

kadaic

acid,g

eldan

amyc

in,

buthion

ine

sulfo

ximine

Bax

",Bcl2#

,mRNA#

metalloproteinas

e-9#

,STA

T-3?

,JNK",

VEGF?

,IL8

?,ABCB5tran

sporter#,

Bcl-X(L)#

,su

rvivin#,cy

clinD1#

,IL8

#matrix

metalloproteinas

e9#

,Akt

pho

spho

rylatio

n#,N

F-kB

#,p65

/NF-kB

#,Ki67#

,p21

",an

tioxidan

tN-ace

tyl-L-

cystein?

,glutathione

S-

tran

sferas

e#STA

T3?,

JAK?,

tBid"o

fca

spas

e-3/8/9"

,poly

(ADP-ribos

e)polym

eras

e?,p

-ERK",

p-p38

",p38

andSAPK/

JNK",

PKC-alpha

?,pro-

casp

ase-3#

,p65

#,VEGF?

,IL6

mRNA?,

Ikap

paB

-alpha

",p53

",ROS",

JNK",

Bid"

Alantolac

tone

Inulahe

lenium

,L.,Inula

japon

icaAuc

klan

dialappa,

Rad

ixinulae

Inularace

mos

a

Anti-inflam

matory,

antim

icrobial,an

tican

cer,

cytotoxicity,a

ntifu

ngal,

oxidored

uctase

,and

antip

roliferative

Prostate,

glioblastom

a,co

lon,

leuk

emia,liver,lun

g—

Bax

/Bcl-2",ca

spas

e-3"

,STA

T3?,

casp

ase-8,

MMP#,

Bid",

NF-B/

p65

#,p53

",Bax

",Bcl-2#,

casp

ase-9"

,cas

pas

e-3"

,ADP-

ribos

e#,N

F-kB

?,ROS",ac

tivin/

SMAD3sign

aling"

,Crip

to-1/

ActRII?

,ROS",

cytoch

rome-c"

,Bax

",PARP#,ADP-ribos

e#,N

F-B?,

DNA-binding#

,Ik B

apho

spho

rylatio

n#,p

21",

Bcr/

Abl#,

P-glyco

protein#,

cyclin

B1#

,cyc

lin-dep

enden

tprotein

kina

se-1#

Isoa

lantolac

tone

Inulahe

lenium

,L.,Inula

japon

icaAuc

klan

dialappa,

Rad

ixinulae

Inularace

mos

a

Anti-inflam

matory,

antim

icrobial,an

tican

cer,

cytotoxicity,a

ntifu

ngal,

oxidored

uctase

,and

antip

roliferative

Prostatega

stric

pan

crea

ticleuk

emia

—p38

",MAPK",

Bax

",an

dclea

ved

casp

ase-3"

,Bcl-2#,

PI3K/Akt?,

PARP"

(Con

tinue

don

thefollo

wingpag

e)

Millimouno et al.





Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

(Con

t'd)

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Dite

rpen

oids

Orid

onin

Isod

onrubes

cens

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

autopha

gy,a

ndim

mun

omod

ulation

Breas

t,as

troc

ytom

a,leuk

emia,

lung

,hep

atom

a,prostate,

colorectal,p

ancrea

tic,

ovarian,

human

multip

lemye

loma,

human

histoc

ytic

lympho

ma,

hepa

toce

llular,

cervical,n

euroblastom

a,laryng

eal,ga

stric

,murine

fibrosa

rcom

a,melan

oma,

epidermoidca

rcinom

a,os

teos

arco

ma

TRAIL,g

emcitabin,

taxo

l,TN

Fa,c

isplatin

,cu

rcum

in,a

rsen

ictrioxide(As2

O3),

Wog

onin

Cas

pas

e-8#

,NF-kB

(p65

)#,IKKa#

,IKKb#

,pho

spho

-mTO

R#,

Fas",

PPARg",M

MP-2/M

MP-9#

,b1/

FAK?,

casp

ase-3"

,LYN?,

ABL?

,Akt/m

TOR#,

Raf/M

EK/

ERK#a

ndSTA

T5#,AML1

-ETO

#,c-Kit(þ)

?,c-Met-N

F-kB

-COX-

2",c

-Met-B

cl-2-cas

pas

e-3,

Bcl-2/Bax

ratio

",AVOs#,L

C3-

I?,L

C3-II?

,P21

",FA

S?,

SREBP1?

,AP-1#

,NF-k B

#,P38

#,p21

",p27

",p16

",c-myc

p38"

,p53

",(M

APK)-p38

,cyc

linB1an

dp-cdc2

(T16

1)#,

p53

",Akt#,

ROS#,

SIRT1

#,NF-kB

",ca

spas

e-1"

,IL-1b

",XIAP#,

Grp78

",a-

CP1#

,Bcl-2#,

casp

ase-

8",p

roca

spas

e-3-9#

,pro-TN

Fa",

p53

#,ca

spas

e-9#

,DeltaPsim#,

ERK#,

p38

",MAPK",

JNK"

Pse

udolaric

AcidB

Pse

udolarixkaem

pferi

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

immun

omod

ulation,

antic

ance

r,an

dan

ti-inflam

matoryan

dan

tiang

ioge

nesiseffects

Microve

ssel

endothe

lial,

prostate,

glioblastom

a,um

bilica

lveinen

dothe

lial,

murinefibros

arco

ma,

bladder,c

olon

,lun

g,breas

t,melan

oma,

ovarian,

leuk

emia,g

astric,liver

Taxo

l,TN

FaNF-kB

?,p65

?,IL2#

,IkB

-a?,

cyclin

B1"

,CDK1"

,cyc

linD1#

p53"

,Bax

",Bcl-2#,

1aan

dcy

clin

E#,

cdc2

",cd

c2#,

survivin#,ca

spas

e-3"

,COX-2?,

STA

T3,I-kB#,

Tubu

lin,b

inding

ofco

lchicine

totubulin?,

bcl-x

(L)?

,NAG-1",

JNK",

ERK#,

Wee

1kina

sean

dp21

",Bcl-xL#

,Bax

",ca

spas

e-7"

,Fas

/APO-1",

Bcl-2

binding

with

Bec

lin1?

,Akt

phos

pho

rylatio

n#(Con

tinue

don

thefollo

wingpag

e)






Tab

le1.

Natural

source

,pha

rmac

olog

icac

tion,

andmolec

ular

targetsof

promisingna

turalc

ompou

nds

(Con

t'd)

Compoun

dNatural

source

Modeofac

tion

Typ

eofca

ncers

Syn

ergistic

Majortargets

Polyp

heno

licWed

elolac

tone

Eclipta

alba,

Wed

elia

caland

ulac

eae,

Wed

elia

chinen

sis,

Eclipta

prostrata

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

and

hepatop

rotectiveeffects

Breas

t,prostate,

neurob

lastom

a,pan

crea

tic,

mam

maryca

rcinos

arco

ma,

mye

loma,

leuk

emia,

aden

oma,

glioma

IFNg

NF-kB

#,PARP",

IIa#,

p-p53

",ca

spas

e-3"

,cas

pas

e-7"

,c-

JNK",PKCe#,IKKa#

,Bax

",Bcl-

xL#,

p21

",p2

7",B

cl-2#,

IL6#

,IL6R

#,c-myc

,IKK#,

p-TAK1,

IKKb#

,IKKa#

,IL1

b#,S

TAT-3#

,TL

R-4",

TLR-7",

TLR-8",

Akt#,

TNFa

#,IkB#

Alkaloids

Evo

diamine

Evo

dia

rutaec

arpa

Antioxidan

t,an

tiproliferation

(cell-cy

clearrest,a

pop

tosis),

anti-inflam

mation,

antim

icrobial,an

tican

cer,

antim

etas

tatic

,and

antic

arcino

gene

sis

MurineLe

wis

lung

,he

patoc

ellular,leuk

emia,

gastric

,pan

crea

tic,c

olon

,hu

man

thyroidca

ncer,

melan

oma,

colorectal,

breas

t,ce

rvix

carcinom

a,prostate

Gem

citabin,tax

ol,

TNF-a,

cisp

latin

Atgs",3

-MA?,

IL6#

,STA

T3?,

AP-1?,

PLC

-g1?

,XIAP?,

Bax

",CDK1?

,NDcy

clinB1"

,PI3K?,

Akt?,

PKA?,

mTO

R?,

PTE

N?,

NF-kB

#,cy

clinA#,

cyclinA-

depen

dent

kina

se2#

,cdc2

5c#,

TUNEL"

,proca

spas

e-3-8-9#

,cd

c25C

",cy

clin

B1"

,cdc2

-p1

61protein",

cdc2

-p15

,ca

spas

e-3-8-9"

,Fas

-L"

,p53

",p2

1",B

cl-2#,

TopI?

,Raf-1#,

Bax

",Bcl-2",

Bcl-x(L)#

,Bec

lin1"

,LC3"

,Cdc2

",cy

clin

B1"

,Cdc2

(Thr

161)" ,Cdc2

(Tyr15

)#,

Myt-1#,

Cdc2

5C#,

casp

ase-3-

9",E

RKph

ospho

rylatio

n#,

VEGF?

NOTE

:#,d

ownreg

ulation;

",up

regu

latio

n;?,

inhibition

.

Millimouno et al.





Table 2. Prevention of cancer with natural compounds

Compounds Cancer type Tumor cell lines p53 statusCell-cyclearrest References

FlavonoidsMagnolol Glioblastoma, bladder, breast,

colon, gastric, skin, ovarian,lung, prostate, melanoma,liver cancer, cervicalepitheloid carcinoma,leukemia, fibrosarcoma,neuroblastoma, thyroidcarcinoma

U373, T24, 5637, MDA-MB-231, HCT- 116, SW480,SGC-7901, A431, SKOV3,TOV21G,CH27,A549,H460,PC-3, A375-S2, B16-BL6,COLO-205, HepG2, HEp-2,HeLa, 2H3, HT-1080, SH-SY5Y, CGTH W-2

— G0–G1 phase (39, 40,102, 115,152–161)

Casticin Cervical, pancreatic, colon,breast, lung, gastric, ovarian,liver, colorectal, leukemia

HeLa, CasKi, SiHa, PANC-1,MCF-7, A549, SGC-7901,HO-8910, SKOV3, HepG2,PLC/PRF/5, MN1, MDD2,MCF-7, A431, HeLa, CCRF-CEM, CEM/ADR5000,P27kip1, P21waf1, pCDC2,K562, HL-60, Kasumi-1

Mutantp53

G2–M phase (80, 132, 133,162–165)

Honokiol Glioblastoma, melanoma,gastric, leukemia, skin,colon, breast, ovarian,pancreatic, hepatocellular,colorectal, lung, prostate,human renal mesangial,head and neck squamouscarcinoma

A549, H1299, H460, H226,T98G, U251, B16-F10,UACC903, MKN45, SCM-1,NB4, K562, B-CLL, ChR, B-CLL, MT-2, MT-4, C5/MJ,SLB-1, HUT-102, MT-1, TL-OmI, SKH-1, CT26, HT-29,MCF-7, 4T1, MDA-MB -231,SKOV3, Coc1, A2780,Angelen MiaPaCa, Panc1,HepG2, HCT116, CT26,HCT116-CH2, HCT116-CH3,HepG2, A549, LL2, PC-3,LNCaP, HRMCs 1483, Cal-33

— G2–M phase (38–40, 156,157,166–178)

G0–G1 phase

Jaceosidin Human endometrial, humanovary cancer, glioblastoma,breast, epithelial, cervical,mammary epithelial

Hec1A, CAOV-3, SKOV-3,U87, MCF10A, SiHa, CaSki,MCF10A-ras

— G2–M phase (134, 179–181)

SesquiterpenesCostunolide Hepatocellular carcinoma,

ovarian, breast, bladder,melanoma, leukemia,prostate, human monocyte,gastric

HCC, SKOV3, A2780, MPSC1,MPSC1PT, A2780PT,SKOV3PT, MDA-MB-231,MCF-7, MDA-MB-231, T24,B-16, A2058,HT-29,HepG2,HL-60, U937, A549, SK-MEL-2, XF498, HCT-15,LNCaP,PC-3,DU-145, THP-1, SGC-7901

Mutantp53 wild-type p53

G2–M phase (112, 135, 160,182–186)

Parthenolide Breast, skin, melanoma,malignant glioma, epidermaltumorigenesis, liver, gastric,lung, bladder, prostate, bileduct carcinomas,pancreatic, myeloma,

MCF-7, MDMB-231, LCC9,ABCB5þ, A375, 1205Lu,WM793, U87MG, U373,JB6Pþ, SH-J1, HepG2,Hep3B, SK-Hep1, MKN-28,MKN-45, MKN-74,

— G2–M phase (187–201)

(Continued on the following page)






Table 2. Prevention of cancer with natural compounds (Cont'd )

Compounds Cancer type Tumor cell lines p53 statusCell-cyclearrest References

leukemia, colorectal, Burkittlymphoma, epithelialovarian, osteosarcoma

SGC7901, A549, NSCLC,5637, RT-4, PC3, DU145,VCAP, LAPC4, BxPC-3,PANC-1, MIAPaCa-2,RPMI8226, HL-60, U937,NB4, MV-4-11, MOLM-13,HT-29, SW620, LS174T,Rajiþ, OVCAR-3, K-OV-3,LM8, LM7

Alantolactone Liver, glioblastoma, colon,leukemia, lung

HepG2, Bel-7402, SMMC-7721, U87, HCT-8, HL-60,K562, K562, ADR, A549,MK-1, HeLa and B16F10

— G2–M phase (49, 50, 105,125, 126)

Isoalantolactone Prostate, pancreatic, leukemia,gastric

Hepa1c1c7, BPRc1, LNCaP,PC3, DU-145, SGC-7901,HL-60, HepG2-C8, PANC-1

— G2–M phase (98, 124, 126,136)

DiterpenoidsPseudolaricAcid B

Microvessel endothelial,Prostate, glioblastoma,umbilical vein endothelial,murine fibrosarcoma,bladder, colon, lung, breast,melanoma, ovarian,leukemia, gastric, murinefibrosarcoma, liver

DU-145, PC-3, U87, HUVECs,L929, 5637, HT-29, COLO-205, HCT-15, A-549, HOP-18, MCF-7, MDA-MB-231,MALME-3M,SK-MEL-2,SK-28, OVCAR-3, SK-OV-3, HL-60, CCRF-CEM, K562,MGC803, L929, Bel-7402

— G2–M phase (141, 202–210)

Oridonin Breast, astrocytoma, leukemia,lung, hepatom, prostate,colorectal, pancreatic,ovarian, human multiplemyeloma, human histocyticlymphoma, hepatocellular,cervical, neuroblastoma,laryngeal, gastric, murinefibrosarcoma, melanoma,epidermoid carcinoma,osteosarcoma

MCF-7, MDA-MB-231, C6,Phþ ALL SUP-B15, t(8;21),L1210, A549, SPC-A-1,K562, Bel-7402, PC-3,LNCaP, SW480, SW620,SW1116, Lovo, SW480,BxPC-3, PANC-1, A2780,PTX10, RPMI8266, U937,APL, HepG2, BEL7402,HeLa, SK-N-AS, HEp-2,MKN45, L929, K1735M2,A375-S2, A431, U2OS,MG63, SaOS-2

— G2–M phase (33, 124,211–228)

PolyphenolicWedelolactone Breast, prostate,

neuroblastoma, pancreatic,mammary carcinosarcoma,myeloma, leukemia,adenoma, glioma

MDA-MB-231, MDA-MB-468,PrEC, LNCaP, PC-3, DU145,22Rv1, SK-N-AS, SK-N-BE,PANC-1, MIA-MSLN, W256,U266, B-CLL, GH3, C6

— S and G2–Mphase

(229–237)

AlkaloidsEvodiamine Murine Lewis lung,

hepatocellular, leukemia,gastric, pancreatic, colon,human thyroid cancer,melanoma, colorectal,breast, cervix carcinoma,prostate

LLC, HepG2, SMMC-7721,K562, THP-1, CCRF-CEM,CCRF-CEM/C1, U937,SGC-7901, SW1990, ARO,A375-S2, COLO-205, MCF-7, NCI/ADR-RES, HeLa,DU145, PC-3, LNCaP

— G2–M phase (238–244)

Millimouno et al.





life forms to search for anticancer compounds (12). Indeed,since 1920s with Berren blum, chemopreventive began(11), after a period of relative dormancy, re-entered thecancer research mainstream in the 1970s through the workof Sporn and colleagues (15). Till now, molecules derivedfrom Mother Nature have played and continue to impart adominant role in the discovery of compounds for thedevelopment of conventional drug for the treatment ofmost human diseases (16).Medical indications of natural compounds and related

drugs, including anticancer, antibacterial, antiparasitic,anticoagulant, and immune suppressant agents, are beingused to treat 87% of all categorized human diseases (12).Since 1970s, drug discovery was based on screening of alarge number of natural and synthetic compounds; untilwith the advent of computer and other molecular biologytechniques, resulting in the modern and rational drugdiscovery (17). The selected compounds and many other

natural products have traditionally provided a rich source ofdrugs for cancer treatment (11).

Although different approaches are available for the dis-covery of novel and potential therapeutic agents, naturalproducts from medicinal plants are still one of the bestreservoirs for novel agents with new medicinal activities.Thus, identification of natural compound selectively hasability to not only block or inhibit initiation of carcino-genesis, but also to reverse the promotional stages byinducing apoptosis and growth arrest in cancer cellswithoutcytotoxic effects in normal cells (18). The chemopreventiveproperties and molecular targets of selected promisingnatural compounds are detailed in Table 1, Figs. 2 and 3.

Apoptosis Signaling PathwaysProgrammed cell death also called apoptosis play crucial

roles for embryonic development and tissue homeostasis of

Figure 2. Molecular targets of the promising natural compounds (change to BLACK/WHITE form). The schematic diagram of the molecular machinery andpossible targets for the cell signaling pathways activated by natural compounds is different for different compounds.Multiple growth factor receptors such as,EGFR, insulin-like growth factor 1 receptor, FGF, and platelet-derived growth factor receptor are activated at the cell surface in tumorigenesis. Their activationactivates several downstream signaling pathways including, Ras-MAPK (ERK and JNK) pathways, JAK-STAT pathways, PI3K-AKT pathways, and theNF-kBpathways. The selected natural compounds, for example, inhibit the receptors at the cell surface either by inducing their degradation, which ultimatelymodulate the downstream signaling pathways important for proliferation, angiogenesis, and apoptosis.






multicellular organisms. It is carried out in a regulatedway, which is associated with typical morphologic featureslike cell shrinkage, chromatin condensation, and cyto-plasmic membrane blabbing. Dysregulated apoptosis hasbeen implicated in a variety of diseases, including tumorformation or even development of cancer cell drug resis-tance (19).

Apoptosis is triggered through two well-characterizedpathways in mammalian cells. The first one is extrinsicpathway, depending on triggering of death receptors(e.g., TNF), transmembrane proteins expressed on the cellsurface, and the second is intrinsic pathway, mediated bymolecules released from the mitochondria (e.g., Bcl-2 pro-tein family; ref. 20).

The extrinsic apoptosis pathway is initiated through thebinding of ligand (Fas-associated death domain) to deathreceptors that contain an intracellular deathdomain (death-inducing signaling complexes; refs. 21, 22). The intrinsicpathway is activated by physical or chemical stimulations,such as hypoxia, growth factor deprivation, cell detach-ment, or stress signals.

A set of cysteine proteases, both pathways cause theactivation of the initiator caspases, which then activateeffector caspases. Caspases are cysteine-dependentaspartate-specific proteases and are regulated at a post-translational level which ensures that they can be rap-idly activated. They are first synthesized or expressedin cells as inactive proenzyme which consists of aprodomain, a small subunit, and a large subunit formsthat require oligomerization and/or cleavage for acti-

vation. However, caspase-independent apoptosis is alsoreported (23).

Apoptosis is characterized by chromatin condensationand DNA fragmentation, and it is mediated by caspases(24). Many apoptotic signals are mediated to cell deathmachinery through p53 with other proteins such as TNF,Fas, and TRAIL receptors that are highly specific physi-ologic mediators of the extrinsic signaling pathway ofapoptosis. Mitochondria are involved in a variety of keyevents, such as release of caspases activators, changes inelectron transport, loss of mitochondrial membranepotential (MMP), and participation of both pro-andantiapoptotic Bcl-2 family proteins (25, 26). This break-through finding may have important implication fortargeted cancer therapy and modern application of nat-ural compounds.

Molecular Targets of Natural ChemopreventiveAgents

Natural compounds, including flavonoids, sesquiter-penes lactones, alkaloid, diterpenoid, and polyphenolichave been extensively studied and found to exhibit a broadspectrum of chemo preventive properties against multiplecancer types in both cell culture and animal models.Currently, several preventive trials are ongoing. For insis-tence, the cell signaling pathways activated by anticancernatural compound agents are numerous and different fordifferent targets. Moreover, the same compound activatesdifferent signaling pathways depending on the cell types.

Figure 3. Anticancer properties ofthe promising natural compounds(change to BLACK/WHITE form).The selected natural compoundsrestrain cancer by modulatingmultiple signaling pathways,resulting in the inhibition of theinitiation of carcinogenesis,proliferation, angiogenesis, andoxidation so forth, and induction ofcell-cycle arrest, apoptosis,autophagy, or differentiation.

Millimouno et al.





The main signaling pathways activated by anticancer che-mopreventive agents are illustrated in Fig. 2.

Targeting Cancer Cells by RegulatingApoptosis-Related Proteins PathwayIn normal cells, certain cellular signals control and reg-

ulate their growth and all other mechanisms. When thesesignals and mechanisms are altered because of variousfactors, including mutations that prevent cells to undergoapoptosis, normal cells are transformed into cancerouscells. Studies thus so far suggest that inhibition of any oneof these altered signals ormechanisms together is helpful inalleviation of cancer.

p53 and its family members pathwayThe tumor suppressor p53 considered as guardian of the

genome plays a pivotal role in controlling the cell cycle,apoptosis, genomic integrity, andDNA repair in response tovarious genotoxic stresses (25, 27, 28). Once active, p53 canbind to regulatory DNA sequences and activate the expres-sion of target genes, which is important for the suppressionof tumor formation as well as for mediating the cellularresponses to many standard DNA damage inducing cancertherapies by cycle inhibition (p21, reprimo, cyclin G1,GADD45, 14-3-3) and angiogenesis (TSP1, Maspin, BAI1,GD-AIF), induction of apoptosis (PERP, NOXA, PUMA,p53AIP1, ASPP1/2, Fas, BAX, PIDD), and genetic stability(p21, DDB2, MSH2, XPC; refs. 29–32).Recently, it has also been documented that many natural

chemopreventive agents induce cell-cycle arrest and apo-ptosis by activating p53 and its target genes. Oridonininduced upregulation of the functional p53 protein inA2780 (33). Oridonin increased p53 and its target Bax andp21waf1 inprostate cancer LNCaP andNCI-H520 cellswithwild-type p53 gene (33, 34). Oridonin also stabilizes p53protein and sensitizes TRAIL (TNF receptor apoptosis-inducing ligand)-induced apoptosis, and prevents or delayschemotherapy resistance in A2780 cells (35). In humanprostate cancer, honokiol activated p21 (PC-3 and LNCaP)and p53 protein expression (LNCaP; ref. 36).Honokiol increased phosphorylated p53 in both

HCT116H and CT116-CH3 cell lines (37). In skin cancer,p53 activation is lead to the induction of DNA fragmenta-tionand apoptosis (38).Honokiol is particularly effective inseveral tumor xenograft systems with deficits in p53 signal-ing, including PC3, MDA-MD-231, and SVR cells (39).Furthermore, honokiol in a concentration- and time-depen-dentmanner independent of their androgen responsivenessor p53 status induced Bax, Bak, and Bad in PC-3, LNCaP,and C4-2 cells (40). p53 expression had no remarkablechanges in honokiol induced in human colorectal RKO cellline (41).Casticin also induced p53-mediated apoptosis by acti-

vating its proapoptotic protein Bax inU251,U87, andU373glioma cells (42). Casticin induces a p53-independentapoptosis in a human non–small cell lung carcinoma celllines H460, A549, and H157 (43). Mechanism of casticin

for malignant tumors is suppressed through c-Myc in p53-mutated Hs578T cells (44).

The signaling pathways that depend on p53 are essentialcomponents of cellular responses to stress. Parthenolide infour cell lines, HCT116, RKO colon carcinoma,NCI-H1299lung carcinoma, and HL60 myeloblastoma, induced a sig-nificant reduction in the frequency of apoptotic cells in UV-irradiated p53-proficient lines (45, 46). Parthenolide acti-vated p53 and other MDM2-regulated tumor-suppressorproteins (47). Synergistic apoptotic effects of parthenolideand okadaic acid treatment increased p53 accompanied bylowering in p-Akt and pS166-Mdm2 levels under PTENaction (48).

It has also been documented that alantolactone signifi-cantly increased the expression of p53 in HepG2 cells (49,50) with concomitant increase of its downstream targetgenes, mainly cyclin-dependent kinase inhibitor p21 inadriamycin-resistant human erythroleukemia cell lineK562/ADR (51). Alantolactone induces p53-independentapoptosis in prostate cancer PC-3 cells (52).

NF-kB and its family member pathwayThe pro-oncogenic NF-kB is a master transcription factor

consisting of closely related proteins that generally exist asdimers and bind to a common DNA sequence within thepromoters of target genes, called the kB B site, whichpromote transcription of target genes through the recruit-ment of coactivators and corepressors (53). The NF-kBpathway plays an important role in tumorigenesis throughtransactivation of genes involved in cell proliferation, apo-ptosis, tumor cell invasion, metastasis, and angiogenesis(54). The NF-kB1 family of transcription factors consists offive members, NF-kB1 (p50), NF-kB2 (p52), c-Rel, RelB,and RelA (p65), which share an N-terminal Rel homologydomain responsible for DNA binding and homodimeriza-tion and heterodimerization through ankyrin repeats, cov-ering the nuclear localization sequence of NF-kB (53, 55).In this momentum, NF-kB is normally sequestered in thecytoplasm via association with its endogenous inhibitorIkB. Furthermore, IkB-a is rapidly phosphorylated bykinase IKK (IkB kinase) in two catalytic subunits, IKK-aand IKK-b, and one regulatory subunit IKK-g (56).

NF-kB and other signaling pathways that are involved inits activation by free radicals, inflammatory stimuli, cyto-kines, carcinogens, tumor promoters, endotoxins, g-radia-tion, UV light, and X-rays are highly significant in cellulargrowth and transformation, suppression of apoptosis, inva-sion, metastasis, chemotherapy resistance, radio resistance,and inflammation (57). Furthermore, other agents includ-ing TNFa, IL1, IL6, and COX-2, 5 in an inflammatorymicroenvironment are also highly involved in tumor pro-gression, incursion of adjoining tissues, angiogenesis, andmetastasis (58).

Activation of NF-kB inhibits apoptosis by inducing theexpression of Bcl-2 family members and caspases inhibitor(59). The major activity of NF-kB and its family membersis to help proteolytic matrix metalloproteinase’s enzymethat promotes tumor invasion. Hence, IKKa promotes






metastasis in prostate cancer via inhibition of mammaryserine protease inhibitor (maspin; refs. 60, 61) and alsostimulates angiogenesis, by activating IL8 and VEGF (58).However, accumulation of the IkBa protein through pro-teasome inhibition prevents the activation of antiapoptoticNF-kB resulting in tumor cell apoptosis (62).

Thedetail of these studies validatedNF-kBas apotent andnovel target for cancer therapy. They demonstrated that NF-kB signaling pathways played critical role in a wide varietyof biologic, physiologic, and pathologic processes, mainlyin promoting cell survival through induction of its targetgenes. Each study individually taken, stimulate the moti-vation and dedicated insight for developing natural com-pound NF-kB inhibitors.

Many studies have been carried out on whether naturalcompound-related cancer inhibits expression of NF-kB ornot. All the selected natural compound chemopreventiveagents act as potent inhibitors of the NF-kB pathways.Wedelolactone, an inhibitor of IkB kinase, suppressed bothTNFa-induced IkB phosphorylation and NF-kB phosphor-ylation at Ser 536 and Ser 468 (63), parthenolide (64–66),and honokiol (67, 68). Costunolide inhibited the activa-tion of Akt and NF-kB and the expression of antiapoptoticfactors B-cell lymphoma-extra large (Bcl-xL) and X-linkedinhibitor of apoptosis protein (XIAP) in 11Z cells (69–71),magnolol inhibits ERK1/2 phosphorylation and NF-kBtranslocation (72, 73), PI3K/Akt/caspase and Fas-L/NF-kBsignaling pathways might account for the responses ofA375-S2 cell death induced by evodiamine (74, 75). Ori-donin (76), alantolactone (77, 78), isoalantolactone (79),casticin (80), pseudolaric acid B (81), and jaceosidin (82),each of them has an inhibitory effect on NF-kB and itsassociated proteins. These compounds may inhibit one ormore steps in NF-kB signaling pathway and its upstreamgrowth factor receptors that activate the signaling cascade,translocation of NF-kB to the nucleus, DNA binding of thedimers, or interactions with the basal transcriptionalmachinery. Thereupon, they can induce apoptosis in cancercells, offering a promising strategy for the treatment ofdifferent malignancies including cancer (Table 1 and Fig.2; ref. 83).

Nuclear factor-related factor 2 signaling pathwayIn cancer chemoprevention, nuclear factor-related factor

2 (Nrf2) is a potential molecular target for natural com-pounds. Several selected natural compounds are reported asa potential candidate for chemoprevention, by stimulatingthe accumulation of NrF2 in the nucleus and play a majorrole in transcriptional activation of phase II detoxificationenzymes. Low concentrations of parthenolide led to Nrf2-dependent HO-1 induction accompanied by the attenua-tion of its apoptogenic effect in Choi-CK and SCK cells.Furthermore, with the protein kinase C-a inhibitorRo317549 (Ro), parthenolide-mediated apoptosis inhibitsexpression and nuclear translocation of Nrf2, resulting inblockage of HO-1 expression. Parthenolide also stimulatedoxidation of KEAP1 in normal prostate epithelial cells,leading to increased Nrf2 (NFE2L2) levels and subsequent

Nrf2-dependent expression of antioxidant enzymes (84,85). Costunolide and CH2-BL induced HO-1 expressionand Nrf2 nuclear accumulation in RAW264.7macrophages(86). Oridonin activates Nrf2 signaling pathway, leading toaccumulationof theNrf2protein and activationof theNrf2-dependent cytoprotective response (87). Isoalantolactonestimulates the accumulation of Nrf2 in the nucleus of bothHepa1c1c7 cells and its mutant BPRc1 cells (88). Alanto-lactone also stimulated the nuclear accumulation of Nrf2 inHepG2-C8 cells (89).

Transducers and activators of transcription and itsfamily member pathways

STAT is a novel signal transduction pathway to thenucleus that has been uncovered through the study oftranscriptional activation in response to IFN. It has beenimplicated in many processes including development, dif-ferentiation, immune function, proliferation, survival, andepithelial-to-mesenchymal transition (90, 91).

Activation of various tyrosine kinases leads to phosphor-ylation, dimerization, and nuclear localization of the STATproteins, binding to specific DNA elements and directtranscription. Constitutive activation of STAT3 and STAT5has been reported to be implicated in many cancers such asmyeloma, lymphoma, leukemia, and several solid tumors(90–92). Furthermore, seven mammalian STAT familymembers known such as STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, and STAT6 have been cloned and sharecommon structural elements.

During the last decade, the natural compounds have beenimplicated to modulate STAT activation in tumor cells.Some selected agents are part, such as honokiol increasesexpression and activity of SPH-1 that further deactivates theSTAT3 pathway (93), wedelolactone inhibits STAT1dephosphorylation through specific inhibition of T-cellprotein tyrosine phosphatase, which is important tyrosinephosphatase for STAT1 (94). Parthenolide shows strongSTAT inhibition-mediated transcriptional suppression ofproapoptotic genes (64–66), and alantolactone inhibitsSTAT3 activation in HepG2 cells (49). Therefore, thesecumulative observations from both in vitro and/or in vivostudies have not only validated STAT as a novel target forcancer chemotherapy, and also hence provided the ratio-nale for developing natural compound STAT inhibitors.

Growth factors and their receptors family pathwayGrowth factors are proteins that bind to receptors on the

cell surface and are reported to regulate a number of cellularprocesses, with the primary result of activating cellularproliferation and differentiation (95), apoptosis, and rear-rangement of cytoskeleton (96). Several growth factor sig-naling molecules are implicated in carcinogenesis. Amongthem are endothelial growth factor, platelet-derived growthfactor, FGF, transforming growth factor, insulin-like growthfactor, and colony-stimulating factor (97).

As an important intracellular pathway consequence ofgrowth factor receptor activation, several downstream sig-nalings, such as PI3K-Akt and Ras-MAPK also become

Millimouno et al.





active. These signaling pathways have significant impacts onthe fact that it is associated with poor prognosis, tumorprogression, and become targets for many natural chemo-preventive and chemotherapeutic agents.Isoalantolactone inhibits phosphorylation of PI3K/Akt

on SGC-7901 cells (98), and alantolactone seems to inducedetoxifying enzymes via activation of the PI3K and JNKsignaling pathways (89). In cervical carcinoma HeLa cellline, oridonin may suppress constitutively activated targetsof phosphatidylinositol 3-kinase (Akt, FOXO, and GSK3;ref. 99). In pancreatic cancer, evodiamine augments thetherapeutic effect of gemcitabine through direct or indirectnegative regulation of the PI3K/Akt pathway (100) and alsoin A375-S2 cells (74).Magnolol protects SH-SY5Y cells against acrolein-

induced oxidative stress and prolongs SH-SY5Y cell survivalthrough regulating the JNK/mitochondria/caspase, PI3K/MEK/ERK, and PI3K/Akt/FoxO1 signaling pathways (101).In addition, in SGC-7901 cells,magnolol induces apoptosisthrough mitochondria and PI3K/Akt-dependent pathways(102). Magnolol also suppressed the activation of MAPKs(ERK, JNK, and p38) and the PI3K/AKT/mTOR signalingpathway in mES/EB-derived endothelial-like cells(23708970). Honokiol decreases the PI3K/mTOR pathwayactivity in tumor cells, but not in freshly stimulated T cells(103). It seems to be mediated by interrupting the earlyactivated intracellular signalingmolecule PI3K/Akt, but notSrc, the extracellular signal-regulated kinase, andp38 (104).These reports showed that natural compounds, mainly theselected one, rapidly induce the phosphorylation of Aktafter the stimulation and they can be used as a potentinhibitor against cancer cells.

Cripto-1 and its allied protein signaling pathwaysIn the process of normal cellular function, the dysfunc-

tion of activin signaling constituted an active part of tumorformation. To address this phenomenon, activin is blockedin cancer cells by the complex formed by Cripto-1, activin,and activin receptor type II (ActRII). In human colonadenocarcinoma HCT-8 cells, alantolactone performs itsantitumor effect by interrupting the interaction betweenCripto-1 and the ActRIIA in the activin signaling pathway(105).

Targeting Cancer Cells by Mitochondria-Mediated Apoptosis PathwayMitochondria dysfunction is the key link in the chain of

development of pathologies associatedwith the violation ofcellular energy metabolism, including cancer. Mitochon-driahavebecomean important component of the apoptosisexecution machinery, cytochrome c, initiator in the mito-chondrial apoptosis pathway, and can be released from theintermembrane of mitochondria after mitochondria depo-larization (106–108).Recently, many studies reported that the mitochondria

play a fundamental role in the processes leading to celldeath (109). Identification of the loss of MMP through

toxicity is the key piece of natural compounds’ process(110). Several reports reveal that the effects of selectednatural compounds on the intrinsic and extrinsic pathwaysof apoptosis have been examined inmany cell lines, includ-ing HL-60, costunolide induces the reactive oxygen species(ROS)–mediated mitochondrial permeability transitionand resultant cytochrome c release associated withincreased expression of Bax, downregulation of Bcl-2, sur-vivin and significant activation of caspase-3, and its down-stream target PARP (111, 112). Honokiol induced release ofcytochrome c into cytosol and a loss of MMP (Dcm),associated with inhibition of EGFR-STAT3 signaling anddownregulation of STAT3 target genes and downregulationof Bcl-2 and upregulation of Bax expression inMDRKB andRASMCs cells (113, 114). Magnolol induced apoptosis inMCF-7 and HCT-116 cells via the intrinsic pathway withrelease of AIF from mitochondria accompanied by down-regulation of antiapoptotic protein Bcl-2 and upregulationof proapoptotic protein p53 and Bax (115, 116). To get abetter insight into themechanism of delaying cellular agingbymitochondria-targeted natural compound-induced cyto-toxicity, the changes inmembrane permeability, MMP, andcytochrome c localization, which influence mitochondrialbiologic mechanisms, development of mitochondria-addressed compounds highly specific for chemical process-es is one of themost promising ways to develop approachesfor chemotherapy.

Targeting Cancer Cells by ROS-MediatedApoptosis Pathway

The human body constantly generates free radicals suchas superoxide (O2�), hydrogen peroxide (H2O2), nitricoxide, peroxynitrile, and hypochlorous acid and other ROSas a result of aerobic metabolism (117, 118). ROS arecellular signals generated ubiquitously by all mammaliancells, and long-term exposure to physiologic or psychologicstress is associated with the production of oxidative speciesthrough intracellular damage to DNA, RNA, proteins, andlipids but their regulation induced cell proliferation, dif-ferentiation, and apoptosis, which are essential for propercell functioning (119, 122). ROS are well knownmediatorsof intracellular signaling of cascades. During cellular redox,the excessive generation of ROS can induce oxidative stress,loss of cell functioning, and apoptosis (123).

Induction of apoptosis of cancer cells by n-hexane frac-tion of sesquiterpene is mediated through activation ofproteases, which act on specific substrates leading to thedegradation of PARP and other cytoskeletal proteins,responsible for many of the morphologic and biochemicalfeatures of apoptosis in cancer cells (49, 50, 124–126).Furthermore, once caspases activated, it might target thepermeability of mitochondria, resulting in the loss of MMPconcomitant with increased production of ROS, and thisactivity eventually causes disruption of membrane integrity(123). In addition, several studies revealed that apoptosisinduction in chemotherapy depends on many factors likeincrease in ROS, oxidation of cardiolipin, reduced MMP,






and release of cytochrome c (124). To restored cell viability,N-Acetyl Cysteine (NAC), a specific ROS inhibitor blockscompletely apoptosis mediated by several natural com-pounds such as isoalantolactone in PANC-1 cells. Theactivation of p38 MAPK and Bax is directly dependent onROS generation.

Cancer chemotherapy involves deregulation of cell pro-liferation and survival, inducing cell-cycle arrest, cell death,and apoptosis by generating ROS and their various enzymesystems, including the mitochondrial electron transportchain, cytochrome, lipoxygenase, COX, the NADPHoxidase complex, xanthine oxidase, and peroxisomes(127, 128).

Several studies reported that the promising natural com-pounds influenced the generation of ROS. In microglialcells, honokiol and magnolol-induced apoptosis associatedwith the inhibition of IFNg � LPS-induced iNOS expression,NO, and ROS production (129, 130). Jaceosidin increasedintracellular accumulation of ROS in MCF10A-ras cells(131). In HeLa, CasKi, SiHa cell lines, casticin markedlyincreased the levels of intracellular ROS (132, 133). Parthe-nolide enhanced geldanamycin-induced changes in theapoptosis-related protein levels, ROS formation, nucleardamage, and cell death in human epithelial ovarian carci-noma OVCAR-3 and SK-OV-3 cell lines (134).

Induction of apoptosis in T24 andMDA-MB-231 cells bycostunolide is associated with the generation of ROS anddisruption of MMP (Dcm; ref. 112). In ovarian cancer celllines [MPSC1 (PT), A2780 (PT), and SKOV3 (PT)], costu-nolide induced a significant increase in intracellular ROS(135). The specific ROS inhibitor, NAC, restored cell via-bility and completely blocked isoalantolactone-mediatedapoptosis indicating that isoalantolactone induces ROS-dependant apoptosis through intrinsic pathway in humanpancreatic PANC-1 cells (124). It also induced apoptosis inboth androgen-sensitive (LNCaP) as well as androgen-independent (PC3 and DU-145) prostate cancer cells withthe generation of ROS and dissipation of MMP (Dcm;ref. 136). Alantolactone induced apoptosis accompaniedby ROS generation and mitochondrial transmembranepotential dissipation (49, 137). In hepatic stellate, HeLa,andU937 cells, oridonin induced biologic processes, main-ly intracellular ROS generation (138, 139). Pseudolaric acidB induced ROS generation and mitochondrial dysfunctionin L929 cells (140). It also caused the elevation of ROS levelin DU145 cells (141). In human malignant melanomaA375-S2 and cervix carcinoma HeLa cells, evodiamineinduced apoptotic process associated with ROS releasethrough both extrinsic and intrinsic pathways (142, 143).

Targeting Cancer Cells by Cell-Cycle–MediatedApoptosis Pathway

Checkpoint controls function to ensure that chromo-somes are intact and that critical stages of the cell cycle arecompleted before the following stage is initiated. Onecheckpoint operates during S and G2 to prevent the acti-vation of mitosis-promoting factor, which is composed of a

cyclin and cyclin-dependent kinase (Cdk) that triggersentrance of a cell into mitosis by inducing chromatincondensation and nuclear envelope breakdown; it is alsocalled maturation-promoting factor. Another checkpointoperates during early mitosis to prevent activation of ade-nomatous polyposis coli and the initiation of anaphaseuntil themitotic spindle apparatus is completely assembledand all chromosome kinetochores are properly attached tospindle fibers. Checkpoints that function in response toDNA damage prevent entry into S or M until the damage isrepaired (144–146).

When these signals are altered because of various muta-tions that prevent cells from undergoing apoptosis, normalcells are transformed into cancerous cells and undergo highproliferation. Therefore, to arrest cancerous cell prolifera-tion, regulationof apoptosis and its signaling pathways playa critical role (8, 147, 148). This behavior may lead to cell-cycle arrest and upregulation of proapoptotic-related pro-teins expression (49–51). In addition, it also documentedthat the selected natural compounds induced cell-cyclearrest either G2–M, or S or G0–G1 phase. We have reviewedthe effects of various signaling pathways that have beenreported in selected natural compound-induced apoptosis(Fig. 3 and Table 2).

Cancer Clinical StudyAntiangiogenic therapy is at the forefront of drug devel-

opment. Knowledge of the multiple activities of naturalcompounds can assist with the development of naturalcompound derivatives and the design of preclinical andclinical trials that will maximize the potential benefit ofnatural compounds in the patient setting for cancer dis-orders. Thereupon, the natural compounds have beenexamined in human and recently reported. Parthenolidewas found to inhibit the expression of matrix metallopro-teinase-9 and urinary plasminogen activator and themigra-tion of carcinoma cells in vitro, as well as osteolytic bonemetastasis associated with breast cancer in vivo (149). Atdoses up to 4 mg daily by oral capsule to treat fever, it isbarely detectable in the plasma (150) . In combination withciclopirox, parthenolide demonstrates greater toxicityagainst acute myeloid leukemia than treatment with eithercompound alone (151).

Conclusion and Future PerspectivesNatural products have been, and continue to be, a

highly useful source of bioactive molecules. In thisreview, we have highlighted the recent progress of thenatural compounds from Mother Nature with cytotoxicactivities. Plants provide a broad spectrum of sources formodern anticancer drugs. Various preclinical findings andresults of several in vitro and in vivo studies convincinglyargue for potent role of natural compounds in the pre-vention and treatment of many types of cancer. Manyreports on mechanism of actions of the promising com-pounds target multiple signaling pathways, which varywidely depending on cancer origin (11, 51).

Millimouno et al.





According to the literature, the major molecular targetsthat have been characterized are the key challenge forresearchers and scientists to use this information foreffective cancer prevention in populations with differentcancer risks. Moreover, low potency and poor bioavail-ability of natural compounds pose further challenges toscientists and researchers. The future, full with conver-gence of chemoprevention and chemotherapy drug devel-opment will open new avenues for natural compounds inreducing the public health impact of major cancers.However, additional preclinical studies and clinical trialsare certainly yet required to elucidate the full spectrum ofcytotoxic activities of the selected natural compoundseither alone or in synergistic combination with other

small molecules to further validate the usefulness of theseagents as potent anticancer agents.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

Grant SupportThis work was supported by Ministry of Science and Technology (No.

2010DFA31430), Ministry of Education of China (NCET-10–0316), NationalNatural Science Foundation of China (No. 30871301, 30700827), Jilin Pro-vincial Science & Technology Department (20130521010JH, YYZX201241),Changchun Science & Technology Department (No. 2011114-11GH29), theProgram for Introducing Talents to Universities (No. B07017), and theFundamental Research Funds for the Central Universities (12SSXM005).

Received April 24, 2014; revised July 23, 2014; accepted August 6, 2014;published OnlineFirst August 26, 2014.

References1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer

statistics. CA Cancer J Clin 2008;58:71–96.2. Siegel R, Naishadham D, Jemal A. Cancer statistics for Hispanics/

Latinos. CA Cancer J Clin 2012;62:283–98.3. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin

2010;60:277–300.4. Wiart C. Goniothalamus species: a source of drugs for the treatment

of cancers andbacterial infections?EvidBasedComplementAlternatMed 2007;4:299–311.

5. Glade MJ. Food, nutrition, and the prevention of cancer: a globalperspective. American Institute for Cancer Research/World CancerResearch Fund, American Institute for Cancer Research. Nutrition1999;15:523–6.

6. Manson MM. Cancer prevention –the potential for diet to modulatemolecular signalling. Trends Mol Med 2003;9:11–8.

7. Christen P, Cuendet M. Plants as a source of therapeutic and healthproducts. Chimia (Aarau) 2012;66:320–3.

8. Fulda S. Evasion of apoptosis as a cellular stress response in cancer.Int J Cell Biol 2010;2010:370835.

9. Hsu CL, Yu YS, Yen GC. Anticancer effects of Alpinia pricei Hayataroots. J Agric Food Chem 2010;58:2201–8.

10. Jaganathan SK, Mandal M. Antiproliferative effects of honey andof its polyphenols: a review. J Biomed Biotechnol 2009;2009:830616.

11. Amin AR, Kucuk O, Khuri FR, Shin DM. Perspectives for cancerprevention with natural compounds. J Clin Oncol 2009;27:2712–25.

12. Cragg GM, Newman DJ. Plants as a source of anti-cancer agents.J Ethnopharmacol 2005;100:72–9.

13. Elmore S. Apoptosis: a review of programmed cell death. ToxicolPathol 2007;35:495–516.

14. Koehn FE, Carter GT. The evolving role of natural products in drugdiscovery. Nat Rev Drug Discov 2005;4:206–20.

15. Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chem-ical carcinogenesis by vitamin A and its synthetic analogs (retinoids).Fed Proc 1976;35:1332–8.

16. Koehn FE, Carter GT. Rediscovering natural products as a source ofnew drugs. Discov Med 2005;5:159–64.

17. Patwardhan B. Ethnopharmacology and drug discovery. J Ethno-pharmacol 2005;100:50–2.

18. Lekphrom R, Kanokmedhakul S, Kanokmedhakul K. Bioactive styr-yllactones and alkaloid from flowers of Goniothalamus laoticus.J Ethnopharmacol 2009;125:47–50.

19. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link betweencancer genetics and chemotherapy. Cell 2002;108:153–64.

20. Green DR. Apoptotic pathways: paper wraps stone blunts scissors.Cell 2000;102:1–4.

21. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation.Science 1998;281:1305–8.

22. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer pre-vention: a review of the epidemiological evidence. Nutr Cancer 1992;18:1–29.

23. Anichini A,Mortarini R, SensiM, ZanonM.APAF-1 signaling in humanmelanoma. Cancer Lett 2006;238:168–79.

24. Hengartner MO. The biochemistry of apoptosis. Nature 2000;407:770–6.

25. HeinrichM, RoblesM,West JE, Ortiz deMontellanoBR, Rodriguez E.Ethnopharmacology of Mexican asteraceae (Compositae). Annu RevPharmacol Toxicol 1998;38:539–65.

26. Kreuger MR, Grootjans S, Biavatti MW, Vandenabeele P, D'Herde K.Sesquiterpene lactones as drugs with multiple targets in cancertreatment: focus on parthenolide. Anticancer Drugs 2012;23:883–96.

27. Bode AM, Dong Z. Post-translational modification of p53 in tumor-igenesis. Nat Rev Cancer 2004;4:793–805.

28. Budram-MahadeoV,MorrisPJ, LatchmanDS. TheBrn-3a transcriptionfactor inhibits the pro-apoptotic effect of p53 and enhances cell cyclearrest by differentially regulating the activity of the p53 target genesencoding Bax and p21(CIP1/Waf1). Oncogene 2002;21:6123–31.

29. Carr AM. Cell cycle. Piecing together the p53 puzzle. Science2000;287:1765–6.

30. Lu C, El-Deiry WS. Targeting p53 for enhanced radio-and chemo-sensitivity. Apoptosis 2009;14:597–606.

31. Sherr CJ, Weber JD. The ARF/p53 pathway. Curr Opin Genet Dev2000;10:94–9.

32. Vogelstein B, Kinzler KW. Achilles' heel of cancer? Nature 2001;412:865–6.

33. Chen S, Cooper M, Jones M, Madhuri TK, Wade J, Bachelor A, et al.Combined activity of oridonin and wogonin in advanced-stage ovar-ian cancer cells: sensitivity of ovarian cancer cells to phyto-activechemicals. Cell Biol Toxicol 2011;27:133–47.

34. Chen S, Gao J, Halicka HD, Huang X, Traganos F, Darzynkiewicz Z.The cytostatic and cytotoxic effects of oridonin (Rubescenin), aditerpenoid from Rabdosia rubescens, on tumor cells of differentlineage. Int J Oncol 2005;26:579–88.

35. Chen SS, Michael A, Butler-Manuel SA. Advances in the treatment ofovarian cancer: a potential role of antiinflammatory phytochemicals.Discov Med 2012;13:7–17.

36. Hahm ER, Singh SV. Honokiol causes G0-G1 phase cell cycle arrestin human prostate cancer cells in association with suppression ofretinoblastoma protein level/phosphorylation and inhibition of E2F1transcriptional activity. Mol Cancer Ther 2007;6:2686–95.

37. He Z, Subramaniam D, Ramalingam S, Dhar A, Postier RG, Umar S,et al. Honokiol radiosensitizes colorectal cancer cells: enhancedactivity in cells with mismatch repair defects. Am J Physiol Gastro-intest Liver Physiol 2011;301:G929–37.

38. Chilampalli S, Zhang X, FahmyH, Kaushik RS, ZemanD, HildrethMB,et al. Chemopreventive effects of honokiol on UVB-induced skincancer development. Anticancer Res 2010;30:777–83.






39. Fried LE, Arbiser JL. Honokiol, a multifunctional antiangiogenic andantitumor agent. Antioxid Redox Signal 2009;11:1139–48.

40. Hahm ER, Arlotti JA, Marynowski SW, Singh SV. Honokiol, a con-stituent of oriental medicinal herbmagnolia officinalis, inhibits growthof PC-3 xenografts in vivo in association with apoptosis induction.Clin Cancer Res 2008;14:1248–57.

41. Wang T, Chen F, Chen Z, Wu YF, Xu XL, Zheng S, et al. Honokiolinduces apoptosis through p53-independent pathway in humancolorectal cell line RKO. World J Gastroenterol 2004;10:2205–8.

42. Liu E, Kuang Y, He W, Xing X, Gu J. Casticin induces human gliomacell death through apoptosis andmitotic arrest. Cell Physiol Biochem2013;31:805–14.

43. Zhou Y, PengY,MaoQQ, Li X, ChenMW,Su J, et al. Casticin inducescaspase-mediated apoptosis via activation ofmitochondrial pathwayand upregulation of DR5 in human lung cancer cells. Asian Pac J TropMed 2013;6:372–8.

44. SongYC,ZhangX, LeiGY,DangCX. [Vitexicarpin affects proliferationand apoptosis in mutated p53 breast cancer cell]. Zhonghua Yi XueZa Zhi 2010;90:703–7.

45. Guzman ML, Rossi RM, Neelakantan S, Li X, Corbett CA, HassaneDC, et al. An orally bioavailable parthenolide analog selectivelyeradicates acute myelogenous leukemia stem and progenitor cells.Blood 2007;110:4427–35.

46. Szoltysek K, Pietranek K, Kalinowska-Herok M, Pietrowska M, Kim-melM,Widlak P. TNFalpha-induced activation of NFkappaB protectsagainst UV-induced apoptosis specifically in p53-proficient cells.Acta Biochim Pol 2008;55:741–8.

47. Gopal YN, Chanchorn E, Van Dyke MW. Parthenolide promotes theubiquitination of MDM2 and activates p53 cellular functions. MolCancer Ther 2009;8:552–62.

48. Di Fiore R, Drago-Ferrante R, D'Anneo A, Augello G, Carlisi D, DeBlasio A, et al. In human retinoblastoma Y79 cells okadaic acid-parthenolide co-treatment induces synergistic apoptotic effects,with PTEN as a key player. Cancer Biol Ther 2013;14:922–31.

49. Khan M, Li T, Ahmad Khan MK, Rasul A, Nawaz F, Sun M, et al.Alantolactone induces apoptosis in HepG2 cells through GSH deple-tion, inhibition of STAT3 activation, and mitochondrial dysfunction.Biomed Res Int 2013;2013:719858.

50. Lei JC, Yu JQ, Yin Y, Liu YW, Zou GL. Alantolactone inducesactivation of apoptosis in human hepatoma cells. FoodChemToxicol2012;50:3313–9.

51. Yang C, Yang J, Sun M, Yan J, Meng X, Ma T. Alantolactone inhibitsgrowth of K562/adriamycin cells by downregulating Bcr/Abl and P-glycoprotein expression. IUBMB Life 2013;65:435–44.

52. Rasul A, Khan M, Ali M, Li J, Li X. Targeting apoptosis pathways incancer with alantolactone and isoalantolactone. ScientificWorld-Journal 2013;2013:248532.

53. Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell2004;6:203–8.

54. Orlowski RZ, Baldwin AS Jr. NF-kappaB as a therapeutic target incancer. Trends Mol Med 2002;8:385–9.

55. Baud V, Karin M. Is NF-kappaB a good target for cancer therapy?Hopes and pitfalls. Nat Rev Drug Discov 2009;8:33–40.

56. Solt LA, May MJ. The IkappaB kinase complex: master regulator ofNF-kappaB signaling. Immunol Res 2008;42:3–18.

57. Ghosh S, HaydenMS. New regulators of NF-kappaB in inflammation.Nat Rev Immunol 2008;8:837–48.

58. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: frominnocent bystander to major culprit. Nat Rev Cancer 2002;2:301–10.

59. LinWW, KarinM. A cytokine-mediated link between innate immunity,inflammation, and cancer. J Clin Invest 2007;117:1175–83.

60. Affara NI, Coussens LM. IKKalpha at the crossroads of inflammationand metastasis. Cell 2007;129:25–6.

61. Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing lifeand death–a new approach to cancer therapy. J Clin Invest 2005;115:2625–32.

62. Biswas DK, Iglehart JD. Linkage between EGFR family receptors andnuclear factor kappaB (NF-kappaB) signaling in breast cancer. J CellPhysiol 2006;209:645–52.

63. Tanabe K, Matsushima-Nishiwaki R, Yamaguchi S, Iida H, Dohi S,Kozawa O. Mechanisms of tumor necrosis factor-alpha-inducedinterleukin-6 synthesis in glioma cells. J Neuroinflammation 2010;7:16.

64. Legendre F, Dudhia J, Pujol JP, Bogdanowicz P. JAK/STAT but notERK1/ERK2 pathwaymediates interleukin (IL)-6/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein tran-scription in articular chondrocytes. Association with a down-regula-tion of SOX9 expression. J Biol Chem 2003;278:2903–12.

65. Mathema VB, Koh YS, Thakuri BC, Sillanpaa M. Parthenolide, asesquiterpene lactone, expresses multiple anti-cancer and anti-inflammatory activities. Inflammation 2012;35:560–5.

66. Nakshatri H, Rice SE, Bhat-Nakshatri P. Antitumor agent partheno-lide reverses resistance of breast cancer cells to tumor necrosisfactor-related apoptosis-inducing ligand through sustained activa-tion of c-Jun N-terminal kinase. Oncogene 2004;23:7330–44.

67. Yamaguchi M, Arbiser JL, Weitzmann MN. Honokiol stimulatesosteoblastogenesis by suppressing NF-kappaB activation. Int J MolMed 2011;28:1049–53.

68. Zhu X, Wang Z, Hu C, Li Z, Hu J. Honokiol suppresses TNF-alpha-induced migration and matrix metalloproteinase expression byblocking NF-kappaB activation via the ERK signaling pathway in rataortic smooth muscle cells. Acta Histochem 2014;116:588–95.

69. Butturini E, Di Paola R, Suzuki H, Paterniti I, Ahmad A, Mariotto S,et al. Costunolide and Dehydrocostuslactone, two natural sesqui-terpene lactones, ameliorate the inflammatory process associatedto experimental pleurisy in mice. Eur J Pharmacol 2014;730C:107–115.

70. Kim JH, Yang YI, Lee KT, Park HJ, Choi JH. Costunolide inducesapoptosis in human endometriotic cells through inhibition of theprosurvival Akt and nuclear factor kappa B signaling pathway. BiolPharm Bull 2011;34:580–5.

71. Whipple RA, Vitolo MI, Boggs AE, Charpentier MS, Thompson K,Martin SS. Parthenolide and costunolide reduce microtentacles andtumor cell attachment by selectively targeting detyrosinated tubulinindependent fromNF-kappaB inhibition. Breast Cancer Res 2013;15:R83.

72. Karki R, Ho OM, Kim DW. Magnolol attenuates neointima formationby inducing cell cycle arrest via inhibition of ERK1/2 and NF-kappaBactivation in vascular smooth muscle cells. Biochim Biophys Acta2013;1830:2619–28.

73. Li MH, Kothandan G, Cho SJ, Huong PT, Nan YH, Lee KY, et al.Magnolol inhibits LPS-induced NF-kappaB/Rel activation by block-ing p38 kinase in murine macrophages. Korean J Physiol Pharmacol2010;14:353–8.

74. Wang C, Li S, Wang MW. Evodiamine-induced human melanomaA375-S2 cell death was mediated by PI3K/Akt/caspase and Fas-L/NF-kappaB signaling pathways and augmented by ubiquitin-protea-some inhibition. Toxicol In Vitro 2010;24:898–904.

75. Yang J,Wu LJ, Tashiro S, Onodera S, Ikejima T. Nitric oxide activatedby p38 and NF-kappaB facilitates apoptosis and cell cycle arrestunder oxidative stress in evodiamine-treated human melanomaA375-S2 cells. Free Radic Res 2008;42:1–11.

76. Zang L, He H, Ye Y, Liu W, Fan S, Tashiro S, et al. Nitric oxideaugments oridonin-induced efferocytosis by human histocytic lym-phoma U937 cells via autophagy and the NF-kappaB-COX-2-IL-1beta pathway. Free Radic Res 2012;46:1207–19.

77. Chun J, Choi RJ, Khan S, Lee DS, Kim YC, Nam YJ, et al. Alanto-lactone suppresses inducible nitric oxide synthase and cyclooxy-genase-2 expression by down-regulating NF-kappaB, MAPK andAP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7cells. Int Immunopharmacol 2012;14:375–83.

78. Wei W, Huang H, Zhao S, Liu W, Liu CX, Chen L, et al. Alantolactoneinduces apoptosis in chronic myelogenous leukemia sensitive orresistant to imatinib through NF-kappaB inhibition and Bcr/Abl pro-tein deletion. Apoptosis 2013;18:1060–70.

79. Jia QQ, Wang JC, Long J, Zhao Y, Chen SJ, Zhai JD, et al. Sesqui-terpene lactones and their derivatives inhibit high glucose-inducedNF-kappaB activation and MCP-1 and TGF-beta1 expression in ratmesangial cells. Molecules 2013;18:13061–77.

Millimouno et al.





80. Koh DJ, Ahn HS, Chung HS, Lee H, Kim Y, Lee JY, et al. Inhibitoryeffects of casticin on migration of eosinophil and expression ofchemokines and adhesion molecules in A549 lung epithelial cells viaNF-kappaB inactivation. J Ethnopharmacol 2011;136:399–405.

81. Li T, Wong VK, Yi XQ, Wong YF, Zhou H, Liu L. Pseudolaric acid Bsuppresses T lymphocyte activation through inhibition of NF-kappaBsignaling pathway and p38 phosphorylation. J Cell Biochem2009;108:87–95.

82. Lee SH, Bae EA, Park EK, Shin YW, Baek NI, Han EJ, et al. Inhibitoryeffect of eupatilin and jaceosidin isolated from Artemisia princeps inIgE-induced hypersensitivity. Int Immunopharmacol 2007;7:1678–84.

83. Karin M. The IkappaB kinase -a bridge between inflammation andcancer. Cell Res 2008;18:334–42.

84. Xu Y, Fang F, Miriyala S, Crooks PA, Oberley TD, Chaiswing L, et al.KEAP1 is a redox sensitive target that arbitrates the opposingradiosensitive effects of parthenolide in normal and cancer cells.Cancer Res 2013;73:4406–17.

85. Yun BR, Lee MJ, Kim JH, Kim IH, Yu GR, Kim DG. Enhancement ofparthenolide-induced apoptosis by a PKC-alpha inhibition throughheme oxygenase-1 blockage in cholangiocarcinoma cells. Exp MolMed 2010;42:787–97.

86. Pae HO, Jeong GS, Kim HS, Woo WH, Rhew HY, Kim HS, et al.Costunolide inhibits production of tumor necrosis factor-alpha andinterleukin-6 by inducing heme oxygenase-1 in RAW264.7 macro-phages. Inflamm Res 2007;56:520–6.

87. Du Y, Villeneuve NF, Wang XJ, Sun Z, Chen W, Li J, et al. Oridoninconfers protection against arsenic-induced toxicity through activa-tion of the Nrf2-mediated defensive response. Environ Health Per-spect 2008;116:1154–61.

88. Seo JY, Park J, KimHJ, Lee IA, Lim JS, LimSS, et al. Isoalantolactonefrom Inula helenium caused Nrf2-mediated induction of detoxifyingenzymes. J Med Food 2009;12:1038–45.

89. Seo JY, Lim SS, Kim JR, Lim JS, Ha YR, Lee IA, et al. Nrf2-mediatedinduction of detoxifying enzymes by alantolactone present in Inulahelenium. Phytother Res 2008;22:1500–5.

90. Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, et al.Keratinocyte-specific ablation of Stat3 exhibits impaired skin remo-deling, but does not affect skin morphogenesis. EMBO J 1999;18:4657–68.

91. Silver DL, Montell DJ. Paracrine signaling through the JAK/STATpathway activates invasive behavior of ovarian epithelial cells inDrosophila. Cell 2001;107:831–41.

92. Grandis JR, Drenning SD, Chakraborty A, Zhou MY, Zeng Q, Pitt AS,et al. Requirement of Stat3 but not Stat1 activation for epidermalgrowth factor receptor-mediated cell growth In vitro. J Clin Invest1998;102:1385–92.

93. Liu SH, Wang KB, Lan KH, Lee WJ, Pan HC, Wu SM, et al. Calpain/SHP-1 interaction by honokiol dampening peritoneal disseminationof gastric cancer in nu/nu mice. PLoS ONE 2012;7:e43711.

94. Chen Z, Sun X, Shen S, Zhang H, Ma X, Liu J, et al. Wedelolactone, anaturally occurring coumestan, enhances interferon-gamma signal-ing through inhibiting STAT1 protein dephosphorylation. J Biol Chem2013;288:14417–27.

95. Klippel A, Reinhard C, Kavanaugh WM, Apell G, Escobedo MA,Williams LT. Membrane localization of phosphatidylinositol 3-kinaseis sufficient to activate multiple signal-transducing kinase pathways.Mol Cell Biol 1996;16:4117–27.

96. Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P,Downward J, et al. Suppression of c-Myc-induced apoptosis by Rassignalling through PI(3)K and PKB. Nature 1997;385:544–8.

97. Han Z, Hong L, Han Y, Wu K, Han S, Shen H, et al. Phospho Aktmediates multidrug resistance of gastric cancer cells through regu-lation of P-gp, Bcl-2 and Bax. J Exp Clin Cancer Res 2007;26:261–8.

98. Rasul A, KhanM, YuB, Ali M, Bo YJ, YangH, et al. Isoalantolactone, asesquiterpene lactone, induces apoptosis in SGC-7901 cells viamitochondrial and phosphatidylinositol 3-kinase/Akt signaling path-ways. Arch Pharm Res 2013;36:1262–9.

99. Hu HZ, Yang YB, Xu XD, Shen HW, Shu YM, Ren Z, et al. Oridonininduces apoptosis via PI3K/Akt pathway in cervical carcinoma HeLacell line. Acta Pharmacol Sin 2007;28:1819–26.

100. Wei WT, Chen H, Wang ZH, Ni ZL, Liu HB, Tong HF, et al.Enhanced antitumor efficacy of gemcitabine by evodiamine onpancreatic cancer via regulating PI3K/Akt pathway. Int J Biol Sci2012;8:1–14.

101. Dong L, Zhou S, Yang X, Chen Q, He Y, HuangW. Magnolol protectsagainst oxidative stress-mediated neural cell damage by modulatingmitochondrial dysfunction and PI3K/Akt signaling. J Mol Neurosci2013;50:469–81.

102. Rasul A, Yu B, Khan M, Zhang K, Iqbal F, Ma T, et al. Magnolol, anatural compound, induces apoptosis of SGC-7901 human gastricadenocarcinoma cells via the mitochondrial and PI3K/Akt signalingpathways. Int J Oncol 2012;40:1153–61.

103. Crane C, Panner A, Pieper RO, Arbiser J, Parsa AT. Honokiol-medi-ated inhibition of PI3K/mTOR pathway: a potential strategy to over-come immunoresistance in glioma, breast, and prostate carcinomawithout impacting T cell function. J Immunother 2009;32:585–92.

104. Kim BH, Cho JY. Anti-inflammatory effect of honokiol is mediated byPI3K/Akt pathway suppression. Acta Pharmacol Sin 2008;29:113–22.

105. Shi Y, Bao YL, Wu Y, Yu CL, Huang YX, Sun Y, et al. Alantolactoneinhibits cell proliferation by interrupting the interaction betweenCripto-1 and activin receptor type II A in activin signaling pathway.J Biomol Screen 2011;16:525–35.

106. Qiu J, Luo M, Wang J, Dong J, Li H, Leng B, et al. Isoalantolactoneprotects against Staphylococcus aureus pneumonia. FEMS Micro-biol Lett 2011;324:147–55.

107. Schmidt TJ, Brun R,Willuhn G, Khalid SA. Anti-trypanosomal activityof helenalin and some structurally related sesquiterpene lactones.Planta Med 2002;68:750–1.

108. Xin XL, Ma XC, Liu KX, Han J, Wang BR, Guo DA. Microbial trans-formation of alantolactone byMucor polymorphosporus. J Asian NatProd Res 2008;10:933–7.

109. Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention:flavonoids and isoflavonoids. Pharmacol Ther 2001;90:157–77.

110. Blagosklonny MV. Aging: ROS or TOR. Cell Cycle 2008;7:3344–54.111. LeeMG, Lee KT, Chi SG, Park JH. Costunolide induces apoptosis by

ROS-mediated mitochondrial permeability transition and cyto-chrome C release. Biol Pharm Bull 2001;24:303–6.

112. Rasul A, Bao R, Malhi M, Zhao B, Tsuji I, Li J, et al. Induction ofapoptosis by costunolide in bladder cancer cells is mediated throughROS generation and mitochondrial dysfunction. Molecules 2013;18:1418–33.

113. Fan S, Li X, Lin J, Chen S, Shan J, Qi G. Honokiol inhibits tumornecrosis factor-alpha-stimulated rat aortic smooth muscle cell pro-liferation via caspase-and mitochondrial-dependent apoptosis.Inflammation 2014;37:17–26.

114. Wang X, Beitler JJ, Wang H, Lee MJ, Huang W, Koenig L, et al.Honokiol enhances paclitaxel efficacy in multi-drug resistant humancancer model through the induction of apoptosis. PLoS ONE 2014;9:e86369.

115. Park JB, Lee MS, Cha EY, Lee JS, Sul JY, Song IS, et al. Magnolol-induced apoptosis in HCT-116 colon cancer cells is associated withthe AMP-activated protein kinase signaling pathway. Biol Pharm Bull2012;35:1614–20.

116. ZhouY,BiY,YangC,YangJ, JiangY,MengF, et al.Magnolol inducesapoptosis in MCF-7 human breast cancer cells through G2/M phasearrest and caspase-independent pathway. Pharmazie 2013;68:755–62.

117. Halliwell B. Free radicals, antioxidants, and human disease: curiosity,cause, or consequence? Lancet 1994;344:721–4.

118. Poulsen HE, Prieme H, Loft S. Role of oxidative DNA damage incancer initiation and promotion. Eur J Cancer Prev 1998;7:9–16.

119. Coso S, Harrison I, Harrison CB, Vinh A, Sobey CG, Drummond GR,et al. NADPH oxidases as regulators of tumor angiogenesis: currentand emerging concepts. Antioxid Redox Signal 2012;16:1229–47.

120. Guzik TJ, Harrison DG. Vascular NADPH oxidases as drug targets fornovel antioxidant strategies. Drug Discov Today 2006;11:524–33.

121. Hong IS, Lee HY, Kim HP. Anti-oxidative effects of Rooibos tea(Aspalathus linearis) on immobilization-induced oxidative stress inrat brain. PLoS ONE 2014;9:e87061.






122. Maraldi T. Natural compounds as modulators of NADPH oxidases.Oxid Med Cell Longev 2013;2013:271602.

123. Slater AF, Stefan C, Nobel I, van den Dobbelsteen DJ, Orrenius S.Signallingmechanismsandoxidative stress in apoptosis. Toxicol Lett1995;82–83:149–53.

124. Khan M, Ding C, Rasul A, Yi F, Li T, Gao H, et al. Isoalantolactoneinduces reactive oxygen species mediated apoptosis in pancreaticcarcinoma PANC-1 cells. Int J Biol Sci 2012;8:533–47.

125. Khan M, Yi F, Rasul A, Li T, Wang N, Gao H, et al. Alantolactoneinduces apoptosis in glioblastoma cells via GSH depletion, ROSgeneration, and mitochondrial dysfunction. IUBMB Life 2012;64:783–94.

126. Pal HC, Sehar I, Bhushan S, Gupta BD, Saxena AK. Activation ofcaspases and poly (ADP-ribose) polymerase cleavage to induceapoptosis in leukemia HL-60 cells by Inula racemosa. Toxicol In Vitro2010;24:1599–609.

127. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis incancer. Nature 2001;411:342–8.

128. Inoue M, Sato EF, Nishikawa M, Park AM, Kira Y, Imada I, et al.Mitochondrial generation of reactive oxygen species and its role inaerobic life. Curr Med Chem 2003;10:2495–505.

129. Chuang DY, Chan MH, Zong Y, Sheng W, He Y, Jiang JH, et al.Magnolia polyphenolsattenuateoxidativeand inflammatory responsesin neurons and microglial cells. J Neuroinflammation 2013;10:15.

130. Han LL, Xie LP, Li LH, Zhang XW, Zhang RQ, Wang HZ. Reactiveoxygen species production and Bax/Bcl-2 regulation in honokiol-induced apoptosis in human hepatocellular carcinoma SMMC-7721cells. Environ Toxicol Pharmacol 2009;28:97–103.

131. Kim MJ, Kim DH, Lee KW, Yoon DY, Surh YJ. Jaceosidin inducesapoptosis in ras-transformed human breast epithelial cells throughgeneration of reactive oxygen species. Ann N Y Acad Sci 2007;1095:483–95.

132. Chen D, Cao J, Tian L, Liu F, Sheng X. Induction of apoptosis bycasticin in cervical cancer cells through reactive oxygen species-mediated mitochondrial signaling pathways. Oncol Rep 2011;26:1287–94.

133. Zeng F, Tian L, Liu F, Cao J, QuanM, Sheng X. Induction of apoptosisby casticin in cervical cancer cells: reactive oxygen species-depen-dent sustained activation of Jun N-terminal kinase. Acta BiochimBiophys Sin 2012;44:442–9.

134. Lee CS, Kim YJ, Lee SA, Myung SC, Kim W. Combined effect ofHsp90 inhibitor geldanamycin and parthenolide via reactive oxygenspecies-mediated apoptotic process on epithelial ovarian cancercells. Basic Clin Pharmacol Toxicol 2012;111:173–81.

135. Yang YI, Kim JH, Lee KT, Choi JH. Costunolide induces apoptosis inplatinum-resistant human ovarian cancer cells by generating reactiveoxygen species. Gynecol Oncol 2011;123:588–96.

136. Rasul A, Di J, Millimouno FM, Malhi M, Tsuji I, Ali M, et al. Reactiveoxygen species mediate isoalantolactone-induced apoptosis inhuman prostate cancer cells. Molecules 2013;18:9382–96.

137. Zhang Y, Bao YL,Wu Y, YuCL, Huang YX, Sun Y, et al. Alantolactoneinduces apoptosis in RKO cells through the generation of reactiveoxygen species and the mitochondrial pathway. Mol Med Rep2013;8:967–72.

138. Zang L, He H, Xu Q, Yu Y, Zheng N, Liu W, et al. Reactive oxygenspecies H2O2 and �OH, but not O2�(-) promote oridonin-inducedphagocytosis of apoptotic cells by human histocytic lymphomaU937cells. Int Immunopharmacol 2013;15:414–23.

139. Zhang YH, Wu YL, Tashiro S, Onodera S, Ikejima T. Reactive oxygenspecies contribute to oridonin-induced apoptosis and autophagy inhuman cervical carcinoma HeLa cells. Acta Pharmacol Sin 2011;32:1266–75.

140. Qi M, Fan S, Yao G, Li Z, Zhou H, Tashiro S, et al. Pseudolaric acid B-induced autophagy contributes to senescence via enhancement ofROS generation and mitochondrial dysfunction in murine fibrosar-coma L929 cells. J Pharmacol Sci 2013;121:200–11.

141. Zhao D, Lin F, Wu X, Zhao Q, Zhao B, Lin P, et al. Pseudolaric acid Binduces apoptosis via proteasome-mediated Bcl-2 degradation inhormone-refractory prostate cancer DU145 cells. Toxicol In Vitro2012;26:595–602.

142. Yang J, Wu LJ, Tashino S, Onodera S, Ikejima T. Critical roles ofreactive oxygen species in mitochondrial permeability transition inmediating evodiamine-induced humanmelanoma A375-S2 cell apo-ptosis. Free Radic Res 2007;41:1099–108.

143. Yang J, Wu LJ, Tashino S, Onodera S, Ikejima T. Reactive oxygenspecies and nitric oxide regulate mitochondria-dependent apoptosisand autophagy in evodiamine-treated human cervix carcinoma HeLacells. Free Radic Res 2008;42:492–504.

144. Hofmann DK, Fitt WK, Fleck J. Checkpoints in the life-cycle ofCassiopea spp.: control of metagenesis and metamorphosis in atropical jellyfish. Int J Dev Biol 1996;40:331–8.

145. Sanli T, Steinberg GR, Singh G, Tsakiridis T. AMP-activated proteinkinase (AMPK) beyond metabolism: a novel genomic stress sensorparticipating in theDNAdamage response pathway.Cancer Biol Ther2014;15:156–69.

146. Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB,Zerbini LF. GADD45 proteins: central players in tumorigenesis. CurrMol Med 2012;12:634–51.

147. Lawen A. Apoptosis-an introduction. Bioessays 2003;25:888–96.148. Reed JC. Apoptosis-based therapies. Nat Rev Drug Discov 2002;

1:111–21.149. Idris AI, LiboubanH, Nyangoga H, Landao-Bassonga E, Chappard D,

Ralston SH. Pharmacologic inhibitors of IkappaB kinase suppressgrowth and migration of mammary carcinosarcoma cells in vitro andprevent osteolytic bone metastasis in vivo. Mol Cancer Ther2009;8:2339–47.

150. Curry EA III,MurryDJ, YoderC, Fife K, ArmstrongV,Nakshatri H, et al.Phase I dose escalation trial of feverfew with standardized doses ofparthenolide in patients with cancer. Invest New Drugs 2004;22:299–305.

151. Sen S, Hassane DC, Corbett C, BeckerMW, Jordan CT, GuzmanML.Novel mTOR inhibitory activity of ciclopirox enhances parthenolideantileukemia activity. Exp Hematol 2013;41:799–807 e4.

152. Arora S, Bhardwaj A, Srivastava SK, Singh S, McClellan S, Wang B,et al. Honokiol arrests cell cycle, induces apoptosis, and potentiatesthe cytotoxic effect of gemcitabine in human pancreatic cancer cells.PLoS ONE 2011;6:e21573.

153. Arora S, Singh S, Piazza GA, Contreras CM, Panyam J, Singh AP.Honokiol: a novel natural agent for cancer prevention and therapy.Curr Mol Med 2012;12:1244–52.

154. Chen LC, Lee WS. P27/Kip1 is responsible for magnolol-inducedU373 apoptosis in vitro and in vivo. J Agric Food Chem 2013;61:2811–9.

155. Chen MC, Lee CF, Huang WH, Chou TC. Magnolol suppresseshypoxia-induced angiogenesis via inhibition of HIF-1alpha/VEGFsignaling pathway in human bladder cancer cells. Biochem Pharma-col 2013;85:1278–87.

156. Chen XR, Lu R, Dan HX, Liao G, Zhou M, Li XY, et al. Honokiol: apromising small molecular weight natural agent for the growth inhi-bition of oral squamous cell carcinoma cells. Int J Oral Sci 2011;3:34–42.

157. Dikalov S, Losik T, Arbiser JL. Honokiol is a potent scavengerof superoxide and peroxyl radicals. Biochem Pharmacol 2008;76:589–96.

158. Fang F, Gong C, Qian Z, Zhang X, Gou M, You C, et al. Honokiolnanoparticles in thermosensitive hydrogel: therapeutic effects onmalignant pleural effusion. ACS Nano 2009;3:4080–8.

159. Hou X, Yuan X, Zhang B, Wang S, Chen Q. Screening active anti-breast cancer compounds fromCortexMagnolia officinalis by 2DLC-MS. J Sep Sci 2013;36:706–12.

160. Hsu JL, Pan SL, Ho YF, Hwang TL, Kung FL, Guh JH. Costunolideinduces apoptosis through nuclear calcium2þ overload andDNA damage response in human prostate cancer. J Urol 2011;185:1967–74.

161. Kang YJ, Park HJ, Chung HJ, Min HY, Park EJ, Lee MA, et al. Wnt/beta-catenin signaling mediates the antitumor activity of magnolol incolorectal cancer cells. Mol Pharmacol 2012;82:168–77.

162. Ling Y, Zhu J, Fan M, Wu B, Qin L, Huang C. Metabolism studies ofcasticin in rats using HPLC-ESI-MS(n). Biomed Chromatogr 2012;26:1502–8.

Millimouno et al.





163. Shen JK, Du HP, YangM,Wang YG, Jin J. Casticin induces leukemiccell death through apoptosis and mitotic catastrophe. Ann Hematol2009;88:743–52.

164. Yang J, Yang Y, Tian L, Sheng XF, Liu F, Cao JG. Casticin-inducedapoptosis involves death receptor 5 upregulation in hepatocellularcarcinoma cells. World J Gastroenterol 2011;17:4298–307.

165. Ye Q, Zhang QY, Zheng CJ, Wang Y, Qin LP. Casticin, a flavonoidisolated fromVitex rotundifolia, inhibits prolactin release in vivo and invitro. Acta Pharmacol Sin 2010;31:1564–8.

166. Jeong JJ, Lee JH, Chang KC, Kim HJ. Honokiol exerts an anticancereffect in T98G human glioblastoma cells through the induction ofapoptosis and the regulation of adhesion molecules. Int J Oncol2012;41:1358–64.

167. Li X, Guo Q, Zheng X, Kong X, Shi S, Chen L, et al. Preparationof honokiol-loaded chitosan microparticles via spray-dryingmethod intended for pulmonary delivery. Drug Deliv 2009;16:160–6.

168. Li Z, Liu Y, Zhao X, Pan X, Yin R, Huang C, et al. Honokiol, a naturaltherapeutic candidate, induces apoptosis and inhibits angiogenesisof ovarian tumor cells. Eur J Obstet Gynecol Reprod Biol 2008;140:95–102.

169. LiangS, Fu A, ZhangQ, TangM, Zhou J,Wei Y, et al. Honokiol inhibitsHepG2migration via down-regulation of IQGAP1 expression discov-ered by a quantitative pharmaceutical proteomic analysis. Proteo-mics 2010;10:1474–83.

170. Liu H, Zang C, Emde A, Planas-Silva MD, Rosche M, Kuhnl A, et al.Anti-tumor effect of honokiol alone and in combination with otheranti-cancer agents in breast cancer. Eur J Pharmacol 2008;591:43–51.

171. Liu SH, Shen CC, Yi YC, Tsai JJ, Wang CC, Chueh JT, et al. Honokiolinhibits gastric tumourigenesis by activation of 15-lipoxygenase-1and consequent inhibition of peroxisome proliferator-activatedreceptor-gamma and COX-2-dependent signals. Br J Pharmacol2010;160:1963–72.

172. Mannal PW, Schneider J, Tangada A, McDonald D, McFadden DW.Honokiol produces anti-neoplastic effects onmelanoma cells in vitro.J Surg Oncol 2011;104:260–4.

173. Rajendran P, Li F, ShanmugamMK, Vali S, Abbasi T, Kapoor S, et al.Honokiol inhibits signal transducer and activator of transcription-3signaling, proliferation, and survival of hepatocellular carcinoma cellsvia the protein tyrosine phosphatase SHP-1. J Cell Physiol 2012;227:2184–95.

174. Singh T, Katiyar SK. Honokiol, a phytochemical from Magnolia spp.,inhibits breast cancer cell migration by targeting nitric oxide andcyclooxygenase-2. Int J Oncol 2011;38:769–76.

175. Tian W, Deng Y, Li L, He H, Sun J, Xu D. Honokiol synergizeschemotherapy drugs in multidrug resistant breast cancer cells viaenhanced apoptosis and additional programmed necrotic death. Int JOncol 2013;42:721–32.

176. Tian W, Xu D, Deng YC. Honokiol, a multifunctional tumor cell deathinducer. Pharmazie 2012;67:811–6.

177. Vaid M, Sharma SD, Katiyar SK. Honokiol, a phytochemical fromthe Magnolia plant, inhibits photocarcinogenesis by targetingUVB-induced inflammatory mediators and cell cycle regulators:development of topical formulation. Carcinogenesis 2010;31:2004–11.

178. Wu JP, Zhang W, Wu F, Zhao Y, Cheng LF, Xie JJ, et al. Honokiol: aneffective inhibitor of high-glucose-induced upregulation of inflam-matory cytokine production in human renal mesangial cells. InflammRes 2010;59:1073–9.

179. Ji HY, Kim SY, Kim DK, Jeong JH, Lee HS. Effects of eupatilin andjaceosidin on cytochrome p450 enzyme activities in human livermicrosomes. Molecules 2010;15:6466–75.

180. Lee JG, Kim JH, Ahn JH, Lee KT, Baek NI, Choi JH. Jaceosidin,isolated from dietary mugwort (Artemisia princeps), induces G2/Mcell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 acti-vation. Food Chem Toxicol 2013;55:214–21.

181. Lv W, Sheng X, Chen T, Xu Q, Xie X. Jaceosidin induces apoptosis inhuman ovary cancer cells through mitochondrial pathway. J BiomedBiotechnol 2008;2008:394802.

182. Choi JH, Lee KT. Costunolide-induced apoptosis in human leukemiacells: involvement of c-jun N-terminal kinase activation. Biol PharmBull 2009;32:1803–8.

183. Choi YK,SeoHS,ChoiHS,KimSR,ShinYC,KoSG. Induction of Fas-mediated extrinsic apoptosis, p21WAF1-related G2/M cell cyclearrest and ROS generation by costunolide in estrogen receptor-negative breast cancer cells, MDA-MB-231. Mol Cell Biochem2012;363:119–28.

184. KimSH, DanilenkoM, KimTS. Differential enhancement of leukaemiacell differentiation without elevation of intracellular calcium by plant-derived sesquiterpene lactone compounds. Br J Pharmacol 2008;155:814–25.

185. Kim TJ, Nam KW, Kim B, Lee SJ, Oh KB, Kim KH, et al. Inhibitoryeffects of costunolide isolated from laurus nobilis on IgE-induceddegranulation of mast cell-like RBL-2H3 cells and the growthof Y16 pro-B cells. Phytother Res 2011 Jun 14. [Epub ahead ofprint].

186. Liu CY, Chang HS, Chen IS, Chen CJ, Hsu ML, Fu SL, et al. Costu-nolide causes mitotic arrest and enhances radiosensitivity in humanhepatocellular carcinoma cells. Radiat Oncol 2011;6:56.

187. Cheng G, Xie L. Parthenolide induces apoptosis and cell cycle arrestof human 5637 bladder cancer cells in vitro. Molecules 2011;16:6758–68.

188. Czyz M, Koprowska K, Sztiller-Sikorska M. Parthenolide reduces thefrequency of ABCB5-positive cells and clonogenic capacity of mel-anoma cells from anchorage independent melanospheres. CancerBiol Ther 2013;14:135–45.

189. Czyz M, Lesiak-Mieczkowska K, Koprowska K, Szulawska-MroczekA, Wozniak M. Cell context-dependent activities of parthenolide inprimary and metastatic melanoma cells. Br J Pharmacol 2010;160:1144–57.

190. Li Y, Zhang Y, FuM, Yao Q, Zhuo H, Lu Q, et al. Parthenolide inducesapoptosis and lytic cytotoxicity in Epstein-Barr virus-positive Burkittlymphoma. Mol Med Rep 2012;6:477–82.

191. Liu JW, Cai MX, Xin Y, Wu QS, Ma J, Yang P, et al. Parthenolideinduces proliferation inhibition and apoptosis of pancreatic cancercells in vitro. J Exp Clin Cancer Res 2010;29:108.

192. Nakabayashi H, Shimizu K. Involvement of Akt/NF-kappaB pathwayin antitumor effects of parthenolide on glioblastoma cells in vitro andin vivo. BMC Cancer 2012;12:453.

193. Shanmugam R, Kusumanchi P, Appaiah H, Cheng L, Crooks P,Neelakantan S, et al. A water soluble parthenolide analog suppressesin vivo tumor growth of two tobacco-associated cancers, lung andbladder cancer, by targeting NF-kappaB and generating reactiveoxygen species. Int J Cancer 2011;128:2481–94.

194. Sohma I, Fujiwara Y, Sugita Y, Yoshioka A, Shirakawa M, Moon JH,et al. Parthenolide, anNF-kappaB inhibitor, suppresses tumor growthand enhances response to chemotherapy in gastric cancer. CancerGenomics Proteomics 2011;8:39–47.

195. Sun Y, St Clair DK, Xu Y, Crooks PA, St Clair WH. A NADPH oxidase-dependent redox signaling pathway mediates the selective radio-sensitization effect of parthenolide in prostate cancer cells. CancerRes 2010;70:2880–90.

196. Watson C, Miller DA, Chin-Sinex H, Losch A, HughesW, Sweeney C,et al. Suppression of NF-kappaB activity by parthenolide induces X-ray sensitivity through inhibition of split-dose repair in TP53 nullprostate cancer cells. Radiat Res 2009;171:389–96.

197. Wyrebska A, Gach K, Szemraj J, Szewczyk K, Hrabec E, KoszukJ, et al. Comparison of anti-invasive activity of parthenolideand 3-isopropyl-2-methyl-4-methyleneisoxazolidin-5-one (MZ-6)–a new compound with alpha-methylene-gamma-lactonemotif–on two breast cancer cell lines. Chem Biol Drug Des 2012;79:112–20.

198. Wyrebska A, Szymanski J, Gach K, Piekielna J, Koszuk J, Janecki T,et al. Apoptosis-mediated cytotoxic effects of parthenolide and thenew synthetic analog MZ-6 on two breast cancer cell lines. Mol BiolRep 2013;40:1655–63.

199. ZhangD,Qiu L, Jin X, GuoZ,GuoC.Nuclear factor-kappaB inhibitionbyparthenolidepotentiates the efficacy of Taxol in non-small cell lungcancer in vitro and in vivo. Mol Cancer Res 2009;7:1139–49.






200. Zhao LJ, Xu YH, Li Y. Effect of parthenolide on proliferation andapoptosis in gastric cancer cell line SGC7901. J Dig Dis 2009;10:172–80.

201. Zunino SJ, Storms DH, Ducore JM. Parthenolide treatment activatesstress signaling proteins in high-risk acute lymphoblastic leukemiacells with chromosomal translocation t(4;11). Int J Oncol 2010;37:1307–13.

202. Hou L, Xu B, GuoW, Ran FX, Liu JT, Yuan X, et al. Pseudolaric acid Binhibits inducible cyclooxygenase-2 expression via downregulationof the NF-kappaB pathway in HT-29 cells. J Cancer Res Clin Oncol2012 Feb 8. [Epub ahead of print].

203. Khan M, Zheng B, Yi F, Rasul A, Gu Z, Li T, et al. Pseudolaric Acid Binduces caspase-dependent and caspase-independent apoptosis inu87 glioblastoma cells. Evid Based Complement Alternat Med2012;2012:957568.

204. Ma G, Chong L, Li XC, Khan IA, Walker LA, Khan SI. Selectiveinhibition of human leukemia cell growth and induction of cell cyclearrest and apoptosis by pseudolaric acid B. J Cancer Res Clin Oncol2010;136:1333–40.

205. Meng AG, Jiang LL. Induction of G2/M arrest by pseudolaric acid B ismediated by activation of the ATM signaling pathway. Acta Pharma-col Sin 2009;30:442–50.

206. Meng AG, Jiang LL. Pseudolaric acid B-induced apoptosis throughp53-dependent pathway in human gastric carcinoma cells. J AsianNat Prod Res 2009;11:142–52.

207. QiM,YaoG, FanS,ChengW,TashiroS,OnoderaS, et al. PseudolaricacidB inducesmitotic catastrophe followed by apoptotic cell death inmurine fibrosarcoma L929 cells. Eur J Pharmacol 2012;683:16–26.

208. Sarkar T, Nguyen TL, Su ZW, Hao J, Bai R, Gussio R, et al. Interactionof pseudolaric acid B with the colchicine site of tubulin. BiochemPharmacol 2012;84:444–50.

209. Tong J, Yin S, Dong Y, Guo X, Fan L, Ye M, et al. Pseudolaric acid Binduces caspase-dependent apoptosis and autophagic cell death inprostate cancer cells. Phytother Res 2012;27:885–91.

210. Yu JH, Cui Q, Jiang YY, Yang W, Tashiro S, Onodera S, et al.Pseudolaric acid B induces apoptosis, senescence, and mitoticarrest in human breast cancer MCF-7. Acta Pharmacol Sin 2007;28:1975–83.

211. Bu HQ, Luo J, Chen H, Zhang JH, Li HH, Guo HC, et al. Oridoninenhances antitumor activity of gemcitabine in pancreatic cancerthrough MAPK-p38 signaling pathway. Int J Oncol 2012;41:949–58.

212. Chen G, Wang K, Yang BY, Tang B, Chen JX, Hua ZC. Synergisticantitumor activity of oridonin and arsenic trioxide on hepatocellularcarcinoma cells. Int J Oncol 2012;40:139–47.

213. Chen JH, Wang SB, Li EM, Chen LM, Yuan SJ, Wang RL, et al.[Inhibitory effect of Oridonin injection on heterotransplanted gastricadenocarcinoma in nudemice and its mechanism]. Zhonghua ZhongLiu Za Zhi 2008;30:89–92.

214. Cheng Y, Qiu F, Ikejima T. Molecular mechanisms of oridonin-induced apoptosis and autophagy inmurine fibrosarcoma L929 cells.Autophagy 2009;5:430–1.

215. Cheng Y, Qiu F, Ye YC, Tashiro S, Onodera S, Ikejima T. Oridonininduces G2/M arrest and apoptosis via activating ERK-p53 apoptoticpathway and inhibiting PTK-Ras-Raf-JNK survival pathway inmurinefibrosarcoma L929 cells. Arch Biochem Biophys 2009;490:70–5.

216. GaoFH,HuXH, LiW, LiuH, ZhangYJ,GuoZY, et al. Oridonin inducesapoptosis and senescence in colorectal cancer cells by increasinghistone hyperacetylation and regulation of p16, p21, p27 and c-myc.BMC Cancer 2010;10:610.

217. Guo Y, Shan Q, Gong Y, Lin J, Yang X, Zhou R. Oridonin incombination with imatinib exerts synergetic anti-leukemia effectin Phþ acute lymphoblastic leukemia cells in vitro by inhibitingactivation of LYN/mTOR signaling pathway. Cancer Biol Ther2012;13:1244–54.

218. Harris ES, Cao S, Schoville SD, Dong C, Wang W, Jian Z, et al.Selection for high oridonin yield in theChinesemedicinal plant Isodon(Lamiaceae) using a combined phylogenetics and population genet-ics approach. PLoS ONE 2012;7:e50753.

219. Huang J, Wu L, Tashiro S, Onodera S, Ikejima T. Reactive oxygenspecies mediate oridonin-induced HepG2 apoptosis through p53,

MAPK, and mitochondrial signaling pathways. J Pharmacol Sci2008;107:370–9.

220. Kwan HY, Yang Z, Fong WF, Hu YM, Yu ZL, Hsiao WL. Theanticancer effect of oridonin is mediated by fatty acid synthasesuppression in human colorectal cancer cells. J Gastroenterol2013;48:182–92.

221. Li CY, Wang EQ, Cheng Y, Bao JK. Oridonin: An active diterpenoidtargeting cell cycle arrest, apoptotic and autophagic pathways forcancer therapeutics. Int J Biochem Cell Biol 2011;43:701–4.

222. Li D,Wu LJ, Tashiro S, Onodera S, Ikejima T.Oridonin induces humanepidermoid carcinoma A431 cell apoptosis through tyrosine kinaseand mitochondrial pathway. J Asian Nat Prod Res 2008;10:77–87.

223. Li X,WangJ,YeZ, Li JC.Oridoninup-regulates expressionofP21andinduces autophagy and apoptosis in human prostate cancer cells. IntJ Biol Sci 2012;8:901–12.

224. Liu Z, Ouyang L, PengH, ZhangWZ.Oridonin: targeting programmedcell death pathways as an anti-tumour agent. Cell Prolif 2012;45:499–507.

225. Lou H, Gao L, Wei X, Zhang Z, Zheng D, Zhang D, et al. Oridoninnanosuspension enhances anti-tumor efficacy in SMMC-7721 cellsand H22 tumor bearing mice. Colloids Surf B Biointerfaces 2011;87:319–25.

226. Qi X, Zhang D, Xu X, Feng F, Ren G, Chu Q, et al. Oridonin nano-suspension was more effective than free oridonin on G2/M cell cyclearrest and apoptosis in the human pancreatic cancer PANC-1 cellline. Int J Nanomedicine 2012;7:1793–804.

227. Sun KW,Ma YY, Guan TP, Xia YJ, Shao CM, Chen LG, et al. Oridonininduces apoptosis in gastric cancer through Apaf-1, cytochrome cand caspase-3 signaling pathway. World J Gastroenterol 2012;18:7166–74.

228. Wang S, Zhong Z, Wan J, Tan W, Wu G, Chen M, et al. Oridonininduces apoptosis, inhibits migration and invasion on highly-met-astatic human breast cancer cells. Am J Chin Med 2013;41:177–96.

229. Benes P, Alexova P, Knopfova L, Spanova A, Smarda J. Redox statealters anti-cancer effects of wedelolactone. Environ Mol Mutagen2012;53:515–24.

230. Benes P, Knopfova L, Trcka F, Nemajerova A, Pinheiro D, Soucek K,et al. Inhibition of topoisomerase IIalpha: novel function of wedelo-lactone. Cancer Lett 2011;303:29–38.

231. Bharadwaj U, Marin-Muller C, Li M, Chen C, Yao Q. Mesothelinconfers pancreatic cancer cell resistance to TNF-alpha-inducedapoptosis through Akt/PI3K/NF-kappaB activation and IL-6/Mcl-1overexpression. Mol Cancer 2011;10:106.

232. Bharadwaj U, Marin-Muller C, Li M, Chen C, Yao Q. Mesothelinoverexpression promotes autocrine IL-6/sIL-6R trans-signaling tostimulate pancreatic cancer cell proliferation. Carcinogenesis 2011;32:1013–24.

233. Hammadi A, Billard C, Faussat AM, Kolb JP. Stimulation of iNOSexpression and apoptosis resistance in B-cell chronic lympho-cytic leukemia (B-CLL) cells through engagement of Toll-likereceptor 7 (TLR-7) and NF-kappaB activation. Nitric Oxide2008;19:138–45.

234. Kobori M, Yang Z, Gong D, Heissmeyer V, Zhu H, Jung YK, et al.Wedelolactone suppresses LPS-induced caspase-11 expressionby directly inhibiting the IKK complex. Cell Death Differ 2004;11:123–30.

235. Lim S, Jang HJ, Park EH, Kim JK, Kim JM, Kim EK, et al. Wedelo-lactone inhibits adipogenesis through the ERK pathway in humanadipose tissue-derived mesenchymal stem cells. J Cell Biochem2012;113:3436–45.

236. Tanabe K, Nishimura K, Dohi S, Kozawa O. Mechanisms of interleu-kin-1beta-induced GDNF release from rat glioma cells. Brain Res2009;1274:11–20.

237. Tsai CH, Lin FM, Yang YC, Lee MT, Cha TL, Wu GJ, et al. Herbalextract of Wedelia chinensis attenuates androgen receptor activityand orthotopic growth of prostate cancer in nude mice. Clin CancerRes 2009;15:5435–44.

238. ChaoDC, Lin LJ,HsiangCY, LiCC, LoHY, Liang JA, et al. Evodiamineinhibits 12-O-tetradecanoylphorbol-13-acetate-induced activator

Millimouno et al.





protein 1 transactivation and cell transformation in human hepato-cytes. Phytother Res 2011;25:1018–23.

239. Chen MC, Yu CH, Wang SW, Pu HF, Kan SF, Lin LC, et al. Anti-proliferative effects of evodiamine on human thyroid cancer cell lineARO. J Cell Biochem 2010;110:1495–503.

240. Jiang J, Hu C. Evodiamine: a novel anti-cancer alkaloid from Evodiarutaecarpa. Molecules 2009;14:1852–9.

241. Pan X, Hartley JM, Hartley JA, White KN, Wang Z, Bligh SW. Evo-diamine, a dual catalytic inhibitor of type I and II topoisomerases,exhibits enhanced inhibition against camptothecin resistant cells.Phytomedicine 2012;19:618–24.

242. Rasul A, Yu B, Zhong L, Khan M, Yang H, Ma T. Cytotoxic effect ofevodiamine in SGC-7901 human gastric adenocarcinoma cells viasimultaneous induction of apoptosis and autophagy. Oncol Rep2012;27:1481–7.

243. Yang J, Cai X, Lu W, Hu C, Xu X, Yu Q, et al. Evodiamineinhibits STAT3 signaling by inducing phosphatase shatterproof1 in hepatocellular carcinoma cells. Cancer Lett 2013;328:243–51.

244. ZhangC, FanX, XuX,YangX,WangX, LiangHP. Evodiamine inducescaspase-dependent apoptosis and S phase arrest in human colonlovo cells. Anticancer Drugs 2010;21:766–76.






2014;7:1081-1107. Published OnlineFirst August 26, 2014.Cancer Prev Res Faya M. Millimouno, Jia Dong, Liu Yang, et al. Natural Compounds from Mother NatureTargeting Apoptosis Pathways in Cancer and Perspectives with

Updated version

10.1158/1940-6207.CAPR-14-0136doi:

Access the most recent version of this article at:

Cited articles

http://cancerpreventionresearch.aacrjournals.org/content/7/11/1081.full#ref-list-1

This article cites 242 articles, 19 of which you can access for free at:

Citing articles

http://cancerpreventionresearch.aacrjournals.org/content/7/11/1081.full#related-urls

This article has been cited by 1 HighWire-hosted articles. Access the articles at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected]

To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerpreventionresearch.aacrjournals.org/content/7/11/1081To request permission to re-use all or part of this article, use this link



http://cancerpreventionresearch.aacrjournals.org/lookup/doi/10.1158/1940-6207.CAPR-14-0136

http://cancerpreventionresearch.aacrjournals.org/content/7/11/1081.full#ref-list-1

http://cancerpreventionresearch.aacrjournals.org/content/7/11/1081.full#related-urls

http://cancerpreventionresearch.aacrjournals.org/cgi/alerts

mailto:[email protected]

http://cancerpreventionresearch.aacrjournals.org/content/7/11/1081


Targeting Apoptosis Pathways in Cancer and Perspectives ......Review Targeting Apoptosis Pathways in...

Documents

Transcript of Targeting Apoptosis Pathways in Cancer and Perspectives ......Review Targeting Apoptosis Pathways in...