Natural compounds as inducers of cell death || Induction of Apoptosis by Polyphenolic Compounds in...

185M. Diederich and K. Noworyta (eds.), Natural Compounds as Inducers of Cell Death: Volume 1, DOI 10.1007/978-94-007-4575-9_8, © Springer Science+Business Media Dordrecht 2012

Abstract Apoptosis, one of the main types of programmed cell death, is a kind of defense mechanism that eliminates the cells that are abnormal or not needed and plays a critical role for the development and maintenance of tissue homeostasis. Apoptosis can be triggered by various physiological and pathological stimuli. Apoptotic path-ways require activation of caspases, a group destructive cystein proteases responsible for the cleavage of the key cellular proteins. Recent studies indicate that are two main apoptotic pathways, including extrinsic or death receptor pathway and intrinsic or mitochondrial pathway. Many natural compounds induce apoptosis in various cancer cells by acting through these pathways. These compounds are either antioxidants or inducers of antioxidant defense mechanism. Polyphenols (alone or in combination) are major constituents of plant-derived antioxidants that induce apoptosis by variety of mechanisms in cancer cells and reduce the risk of cancer. This chapter is focused on the effects of polyphenols such as resveratrol, quercetin and tannic acid on apoptosis in various cancers such as breast, colon and prostate cancers.

8.1 Introduction

Apoptosis or programmed cell death plays a major role in the control of normal development in multicellular organisms and tissue homeostasis. Defects in the mechanism of apoptosis might lead to various abnormalities ranging from autoim-mune diseases to cancer (Lorenzo and Susin 2004 ) . On the other hand, induction of apoptosis might act as a protective mechanism against cancer. This mechanism is responsible for the apoptosis-related degradation and death of cells and occurs via various activation signals (D’Archivio et al. 2008 ) . Apoptosis is mainly the result of

D. Turgut Cosan (*) • A. Soyocak Department of Medical Biology , Eskisehir Osmangazi University , 26480 Eskisehir , Turkeye-mail: [email protected]; [email protected]

Chapter 8 Induction of Apoptosis by Polyphenolic Compounds in Cancer Cells

Didem Turgut Cosan and Ahu Soyocak

186 D. Turgut Cosan and A. Soyocak

two pathways activated by intracellular and extracellular signals and is characterized with several morphological changes including cell shrinkage, nuclear DNA fragmen-tation and membrane blebbing (Debatin 2004 ) . The cytoplasmic (extrinsic) pathway of apoptosis activated by extracellular signals occurs via the death receptors that belong to a subgroup of TNF receptor super family. Activation of these receptors located on the cell membrane of target cell by related ligands induces the apoptotic pathway (Sprick and Walczak 2004 ; Bradshaw and Edward Dennis 2003 ) . Mitochondrial (intrinsic) pathway of apoptosis activated by intracellular signals is triggered by release of cytochrome-c to cytoplasm from intermembrane area of mitochondria and activation of the apoptosome complex consisting of cytosolic factor Apaf-1, ATP and active caspase 9. Caspases and members of the Bcl-2 protein family are involved in both of these apoptotic pathways. Caspases are members of a cystein protease family and are synthesized in the form of inactive zymogens activated by proteolytic cleavage. Overall caspases act as initiator (caspase 2,8,9,10) and effectors (caspase 3,6,7) in the apoptotic process. Members of the Bcl-2 family consist of proteins that either trigger (proapoptotic) or prevent (antiapoptotic) apoptosis. Among this family, while proteins including Bcl-2, Bcl-X

L and Mcl-1 prevent apoptosis, other proteins including Bax,

Bad, Bid, Bak, Bcl-xs trigger apoptosis (Bradshaw and Edward Dennis 2003 ; Burlacu 2003 ; Twomey and McCarthy 2005 ) . In addition, there are several other proteins that are involved in the apoptotic cell death whose names and functions have been sum-marized in Table 8.1 .

Many natural compounds including polyphenols induce apoptosis in various cancer cells by acting through these pathways. Polyphenols are major constituents of plant-derived antioxidants that induce apoptosis by a variety of mechanisms in cancer cells and reduce the risk of cancer.

Polyphenols in diet are extremely important for their favorable effects on health particularly due to their anti-cancer features (Ramos 2008 ) . These polyphenols are found in fruits, vegetables, seeds and beverages and are classi fi ed as stillbens (e.g. resveratrol), fl avonoids (e.g. quercetin), tannins (e.g. tannic acid), phenolic acids and analogues, lignans and others according to their chemical structures (Ramos 2008 ; Huang et al. 2010 ) .

Most dietary polyphenolic compounds including resveratrol, quercetin and tannic acid have an inhibitory role on carcinogenesis with the induction of apoptosis by several different mechanisms. The present chapter will focus the molecular basis of chemopreventive activity of some polyphenols (resveratrol, quercetin and tannic acid), addressing their effects on the induction of apoptosis in cancer cells (Fig. 8.1 ). Abbreviations are listed in Table 8.2 .

8.1.1 Induction of Apoptosis by Resveratrol

Apoptotic effects of resveratrol (3,5,4 ¢ trihydroxystilbene), a member of the stilben family, has been investigated in cancer cell lines in several studies. Other effects of resveratrol are summarized in Table 8.3 .

1878 Induction of Apoptosis by Polyphenolic Compounds in Cancer Cells

Tabl

e 8.

1 Pr

otei

ns in

volv

ed in

apo

ptos

is

Apo

ptot

ic p

rote

ins

Func

tion

Ref

eren

ces

Dea

th li

gand

s ( e

.g. F

asL

,TN

F a ,

TR

AIL

) T

hese

are

eff

ectiv

e in

the

cyto

plas

mic

(ex

trin

sic)

pat

hway

of

apop

tosi

s. T

he

extr

insi

c pa

thw

ay is

initi

ated

by

the

inte

ract

ion

betw

een

the

spec

i fi c

ligan

ds a

nd th

e su

rfac

e re

cept

ors

whi

ch a

re a

ble

to d

eliv

er a

dea

th s

igna

l fr

om th

e ex

trac

ellu

lar

mic

roen

viro

nmen

t to

the

cyto

plas

m. I

nduc

tion

of

apop

tosi

s th

roug

h ex

trin

sic

path

way

is th

eref

ore

very

rap

id

Bra

dsha

w a

nd E

dwar

d D

enni

s ( 2

003 )

and

Reu

ter

et a

l. ( 2

008 )

D

eath

rec

epto

r ( F

as ( C

D95

) ,T

NF

R1,

TR

AIL

R )

Cas

pase

fam

ily (

e.g.

Cap

ase

3,6,

7,2,

8,9,

10)

Cas

pase

s ar

e m

embe

rs o

f a

cyst

ein

prot

ease

fam

ily a

nd a

re s

ynth

esiz

ed in

the

form

of

inac

tive

zym

ogen

s ac

tivat

ed b

y pr

oteo

lytic

cle

avag

e. T

he

intr

acel

lula

r tr

ansm

issi

on o

f th

e ap

opto

tic s

igna

l is

regu

late

d by

cas

pase

fa

mily

Bra

dsha

w a

nd E

dwar

d D

enni

s ( 2

003 )

and

Hol

denr

iede

r an

d St

iebe

r ( 2

004 )

Bcl

-2 f

amily

(e.

g. B

cl-2

,Bcl

-xl,

Mcl

-1,B

ax, B

ad, B

id, B

ak,

Bcl

-xs,

Nox

a, P

UM

A)

Bcl

-2 f

amily

pro

tein

s ca

n ta

rget

the

mito

chon

dria

and

reg

ulat

ed m

embr

ane

perm

eabi

lizat

ion

Deb

atin

( 20

04 )

and

Bra

dsha

w

and

Edw

ard

Den

nis

( 200

3 )

Smac

/Dia

blo

Smac

/DIA

BL

O, a

mito

chon

dria

l pro

tein

, can

blo

ck I

AP

med

iate

d ca

spas

e in

hibi

tion

by b

indi

ng X

IAP

Bra

dsha

w a

nd E

dwar

d D

enni

s ( 2

003 )

Htr

A2/

Om

i O

mi/H

trA

2 is

a m

itoch

ondr

ial s

erin

e pr

otea

se th

at is

rel

ease

d in

to th

e cy

toso

l du

ring

apo

ptos

is to

ant

agon

ize

inhi

bito

rs o

f ap

opto

sis

(IA

Ps)

and

cont

ribu

te to

cel

l dea

th

Yan

g et

al.

( 200

3 )

AIF

A

IF is

rel

ease

d fr

om m

itoch

ondr

ia in

apo

ptot

ic c

ondi

tions

, it t

rigg

ers

cell

deat

h ei

ther

dir

ectly

, thr

ough

inte

ract

ion

with

DN

A, o

r in

dire

ctly

, thr

ough

re

activ

e ox

ygen

spe

cies

pro

duct

ion

Lor

enzo

and

Sus

in (

2004

)

IAP

(e.g

. Sur

vivi

n, I

XA

P)

IAPs

are

blo

cks

activ

ity o

f ca

spas

es a

nd m

ay ta

rget

act

ive

casp

ases

for

de

grad

atio

n D

ebat

in (

2004

) an

d B

rads

haw

an

d E

dwar

d D

enni

s ( 2

003 )

c-FL

IP

FLIP

mol

ecul

es c

onst

itute

one

of

the

nega

tive

regu

lato

rs o

f de

ath

rece

ptor

in

duce

d ap

opto

sis

Los

and

Wal

czak

( 20

02 )

Cyt

ochr

ome

c T

he m

itoch

ondr

ial p

athw

ay is

initi

ated

by

the

rele

ase

of a

popt

ogen

ic f

acto

rs

such

as

cyto

chro

me

c, f

rom

the

mito

chon

dria

l int

erm

embr

ane

spac

e. T

he

rele

ase

of c

ytoc

hrom

e c

into

the

cyto

sol t

rigg

ers

casp

ase-

3 ac

tivat

ion

thro

ugh

form

atio

n of

the

cyto

chro

me-

c/A

paf-

1/ca

spas

e-9–

cont

aini

ng

apop

toso

me

com

plex

Deb

atin

( 20

04 )

(con

tinue

d)


Tabl

e 8.

1 (c

ontin

ued)

Apo

ptot

ic p

rote

ins

Func

tion

Ref

eren

ces

Apa

f-1

Apa

f1 p

lays

a c

entr

al r

ole

in th

e co

mm

on e

vent

s of

mito

chon

dria

-dep

ende

nt

apop

tosi

s in

mos

t dea

th p

athw

ays.

Apa

f-1

med

iate

d cl

uste

ring

of

casp

ase-

9 in

to in

apo

ptos

ome

requ

ires

the

pres

ence

of

cyto

chro

me

c

Los

and

Wal

czak

( 20

02 )

and

Yos

hida

et a

l. ( 1

998 )

P21

(WA

F-1/

CIP

-1)

p21

is a

pot

ent c

yclin

-dep

ende

nt k

inas

e in

hibi

tor

(CK

I). p

21 p

lays

an

esse

ntia

l rol

e in

gro

wth

arr

est a

fter

DN

A d

amag

e R

eute

r et

al.

( 200

8 ) , G

arte

l and

Ty

ner

( 200

2 ) , a

nd C

oque

ret

( 200

3 )

P27

(Kip

-1)

p27

is a

pot

ent c

yclin

-dep

ende

nt k

inas

e in

hibi

tor

(CK

I). F

ollo

win

g an

ti-m

ito-

geni

c si

gnal

s or

DN

A d

amag

e, p

27 b

ind

to c

yclin

-CD

K c

ompl

exes

to

inhi

bit t

heir

cat

alyt

ic a

ctiv

ity a

nd in

duce

cel

l-cy

cle

arre

st

Coq

uere

t ( 20

03 )

and

Agg

arw

al

and

Shis

hodi

a ( 2

006 )

P38

The

indu

ctio

n of

apo

ptos

is is

acc

ompa

nied

by

imm

edia

te a

nd s

usta

ined

ac

tivat

ion

of p

38 m

itoge

n-ac

tivat

ed p

rote

in k

inas

e (M

APK

) A

ctiv

atio

n of

th

e p3

8 si

gnal

ing

path

way

occ

urs

upst

ream

of

casp

ase

activ

atio

n

Kra

lova

et a

l. ( 2

008 )

P53

P53

is a

tum

or-s

uppr

esso

r an

d tr

ansc

ript

ion

fact

or. I

t is

a cr

itica

l reg

ulat

or in

m

any

cellu

lar

proc

esse

s in

clud

ing

cell

sign

al tr

ansd

uctio

n, c

ellu

lar

resp

onse

to D

NA

-dam

age,

gen

omic

sta

bilit

y, c

ell c

ycle

con

trol

, and

ap

opto

sis

Agg

arw

al a

nd S

hish

odia

( 20

06 )

PI3K

T

he p

hosp

hatid

ylin

osito

l-3-

kina

se (

PI3K

) si

gnal

ing

path

way

is c

ruci

al f

or

man

y as

pect

s of

cel

l gro

wth

and

sur

viva

l and

is f

requ

ently

dis

rupt

ed in

hu

man

can

cers

Reu

ter

et a

l. ( 2

008 )

Akt

A

ct in

activ

ates

pro

-apo

ptot

ic f

acto

rs li

ke B

ad, w

hich

con

trol

s th

e re

leas

e of

cy

toch

rom

e c,

pro

casp

ase-

9 an

d Fo

rkhe

ad tr

ansc

ript

ion

fact

ors.

Akt

als

o ac

tivat

es a

nti-

apop

totic

gen

es, i

nclu

ding

cyc

lic-A

MP

resp

onse

ele

men

t-bi

ndin

g pr

otei

n (C

RE

B)

and

IĸB

kin

ase

(IK

K)

lead

ing

to N

F-B

nuc

lear

lo

caliz

atio

n an

d th

e su

bseq

uent

tran

scri

ptio

n of

sur

viva

l gen

es, s

uch

as

Bcl

-xL

, cas

pase

inhi

bito

rs a

nd c

-Myb

Reu

ter

et a

l. ( 2

008 )

pRb

The

ret

inob

last

oma

prot

ein

(Rb)

has

bee

n re

cogn

ized

as

an im

port

ant c

ell

cycl

e re

gula

tor

activ

ely

invo

lved

in p

reve

ntin

g ce

lls f

rom

und

ergo

ing

apop

tosi

s. T

he a

ctiv

ity o

f R

b is

reg

ulat

ed th

roug

h its

pho

spho

ryla

tion

stat

e by

cel

l cyc

le-d

epen

dent

pro

tein

kin

ases

(C

DK

s) a

nd C

DK

inhi

bito

rs

(CD

KIs

)

Fan

and

Stee

r ( 1

999 )


8.1.1.1 Breast Cancer Cells and Resveratrol

Resveratrol induces apoptotic process in several breast cancer cell lines by up- or down-regulating certain pro- and anti-apoptotic proteins, respectively, that have a role in the intrinsic pathway (e.g., Bcl-2, Bcl-XL, Bak and Bax). For instance resveratrol inhibits expression of Bcl-XL anti-apoptotic protein and increases levels of bak and bax proapoptotic proteins(Nakagawa et al. 2001 ; Kim et al. 2004 ; Pozo-Guisado et al. 2005 ; Sakamoto et al. 2010 ) . Moreover, resveratrol induces apoptosis by increasing the activities of caspase 3 and 9 (Nakagawa et al. 2001 ; Kim et al. 2004 ; Alkhalaf et al. 2008 ; Sareen et al. 2007 ) . Analysis of the resveratrol-induced mechanisms in T47D breast cancer cells indicate that it induces apoptosis by activating death receptor pathway via FADD (CD95) in the extrinsic pathway (Clement et al. 1998 ) .

Alkhalaf et al. ( 2008 ) have shown that resveratrol induces PARP degradation with caspase 3 activation in MDA-MD-231 breast cancer cell line (Alkhalaf et al. 2008 ) . Furthermore, it has been reported that resveratrol induces apoptosis in T47D

Fig. 8.1 The effects of dietary polyphenolic compounds, including resveratrol, quercetin and tannic acid, in regulation of various molecules in intrinsic and extrinsic pathways of apoptosis. Apoptosis can be triggered in a cell through either the intrinsic or extrinsic pathways. Dietary polyphenols exert their effects by altering levels or activity of single or multiple apoptotic pathways depending on a cancer type or the structure of the compounds


Table 8.2 Abbreviations

AIF Apoptosis inducing factor AMPK 5 ¢ adenosine monophosphate (AMP)-activated protein kinase Apaf-1 Apoptosis protease activation factor-1 Bad BCL2-antagonist of cell death Bak BCL2-antagonist/killer Bax BCL2-associated X protein Bcl-2 B-cell leukemia/lymphoma 2 Bcl-X

L /BCL2L1 BCL2-like 1

Bid BH3 interacting domain death agonist Caspase Cysteine-aspartic-acid-protease Cdc Cell division cycle Cdk Cyclin-dependent kinase CIP1 Cdk-interacting protein 1 DD Death domain DR Death receptor EGCG Epigallocatechin gallate EGFR Epidermal growth factor ERK Extracellular signal regulated kinase ER Estrogen receptor FADD Fas-associated DD Kinase FasR (CD95/APO-1) Fas receptor FLICE FADD like interleukin-1 b converting enzyme FLIP FLICE like inhibitory protein HSP-70 Heat shock protein 70 Omi/HtrA2 High temperature requirement protein A2(Omi) IAP Inhibitor of apoptosis protein I B Inhibitor of K B JNK c-jun N-terminal kinase MAP Mitogen-activated protein Mcl-1 Myeloid cell leukemia sequence 1 NF- B Nuclear factor- Kappa B NO Nitric oxide NOS Nitric oxide synthase Noxa NADPH oxidase activator 1 P21 (Waf-1/Cip-1) Cyclin-dependent kinase inhibitor (CDKI) P27 (Kip-1) Cyclin-dependent kinase inhibitor 1B P38 Mitogen-activated protein kinase P53 Tumor suppressor protein PARP Poly (ADP-ribose) polymerase PI3K Phosphoinositide 3-kinase Stat 3 Signal transducer and activator of transcription 3 Akt Related to protein kinase A and C (RAC), Protein kinase B (PKB) pRb Retinoblastoma protein PUMA p53 up-regulated modulator of apoptosis ROS Reactive oxygen species Smac/Diablo Second mitochondria-derived activator of caspase/Direct IAP

binding protein (continued)


breast cancer cells that is associated with activation of p53 (Alkhalaf 2007 ) . Pozo-Guisado et al. ( 2002 ) showed that resveratrol induces CDK inhibitors, such as p27 and p21 in MCF-7 breast cancer cells, suggesting that resveratrol also inhibits cell cycle progression (Pozo-Guisado et al. 2002 ) .

Furthermore, resveratrol has been shown to induce activity of JNKs and p38 of the MAP kinase family as well as inhibiting NF-kB, PI3K and Akt (Pozo-Guisado et al. 2005 ; Sakamoto et al. 2010 ; Filomeni et al. 2007 ; Li et al. 2006 ) . At higher doses, resveratrol is also capable of inhibiting the proliferation of breast cancer cells and reducing their growth and viability (Nakagawa et al. 2001 ; Pozo-Guisado et al. 2002 ; Schmitt et al. 2002 ; Mgbonyebi et al. 1998 ; Scarlatti et al. 2003 ) . Studies have reported that resveratrol-induced growth inhibition is associated with changes in cell cycle at several levels including sub-G1, sub G0/G1, G1/S and G2/M (Nakagawa et al. 2001 ; Kim et al. 2004 ; Sakamoto et al. 2010 ; Pozo-Guisado et al. 2002 ; Scarlatti et al. 2003 ; Wang et al. 2009a ) .

Resveratrol can induce antiproliferative and apoptotic effects in highly metastatic and invasive breast cancer cell line, MDA-MB-231, by induction of ceramide, which is the mediator of various intracellular processes including proliferation, apoptosis, differentiation, and aging (Scarlatti et al. 2003 ) .

8.1.1.2 Colon Cancer Cells and Resveratrol

Several studies demonstrated that both the intrinsic and extrinsic apoptotic pathways contribute to cell death induced by resveratrol treatment (Kim et al. 2009 a; Cosan et al. 2009 ) . Studies in CaCo-2, HCT-116, SW620, and HT-29 colon cancer cells have demonstrated that resveratrol inhibits cell proliferation and commits cells to apoptosis (Szendel et al. 2000 ; Wolter et al. 2001 ; Juan et al. 2008 ; Zhang et al. 2009 ) . Delmas et al. ( 2003 ) have reported that resveratrol activates certain caspases in SW480 human colon cancer cells and might trigger apoptosis by inducing the redistribution of Fas receptor on cell membrane (Delmas et al. 2003 ) . Trincheri et al. ( 2007 ) have shown that resveratrol activates the intrinsic pathway in DLD1 and HT29 cell lines, whereas the study by Pohland et al. ( 2006 ) suggested that apoptosis occurred via the death receptor dependent pathway in HCT 116 cells with Bax and Bak de fi ciency (Trincheri et al. 2007 ; Pohland et al. 2006 ) . However, Mahyar et al. ( 2002 ) have shown that resveratrol triggers apoptosis through both Bax-dependent and independent mechanisms in HCT 116 cells (Mahyar-Roemer et al. 2002 ) . In study on HCT 116 cells,

Table 8.2 (continued)

AIF Apoptosis inducing factor TNF Tumor necrosis factor TNFR TNF receptor TRAIL Tumor necrosis factor related apoptosis inducing ligand TRAIL-R TRAIL receptor WAF1 Wild type p53 activated protein-1 XIAP X-linked Inhibitor of apoptosis protein


Tabl

e 8.

3 Po

lyph

enol

ic c

ompo

unds

and

thei

r kn

own

biol

ogic

al a

ctiv

ities

Poly

phen

olic

com

poun

ds (

repr

esen

tativ

e ph

eolic

s)

Sour

ces

Bio

logi

cal a

ctiv

ities

of

poly

phen

olic

com

poun

ds

Res

vera

trol

Ber

ries

(C

orre

et a

l. 20

05 ; A

zız

et a

l. 20

03 ; G

usm

an e

t al.

2001

) A

lter

atio

n of

eic

osan

oid

synt

hesi

s (C

orre

et a

l. 20

05 ; A

zız

et a

l. 20

03 ; G

usm

an e

t al.

2001

) G

rape

s (C

orre

et a

l. 20

05 ; A

zız

et a

l. 20

03 ; G

usm

an e

t al.

2001

) A

ntib

acte

rial

act

ivit

ies

(Gus

man

et a

l. 20

01 )

Gro

undn

uts

(Per

vaız

200

3 )

Ant

icar

cino

geni

c ac

tivi

ties

(C

orre

et a

l. 20

05 ;

Igna

tow

icz

and

Bae

r-D

ubow

ska

2001

) A

ntic

oagu

lant

pro

pert

ies

(Cor

re e

t al.

2005

; Ig

nato

wic

z an

d B

aer-

Dub

owsk

a 20

01 )

Pean

uts

(Cor

re e

t al.

2005

) ; A

zız

et a

l. 20

03 ; G

usm

an e

t al.

2001

) A

ntii

n fl am

mat

ory

acti

viti

es (

Cor

re e

t al.

2005

; A

zız

et a

l. 20

03 ; G

usm

an e

t al.

2001

; Ig

nato

wic

z an

d B

aer-

Dub

owsk

a 20

01 )

Poly

gonu

m c

uspi

datu

m (

Cor

re e

t al.

2005

; A

zız

et a

l. 20

03 ; P

erva

ız 2

003 )

A

ntim

utaj

en p

rope

rtie

s (A

zız

et a

l. 20

03 )

Red

win

e (A

zız

et a

l. 20

03 )

Ant

ioxi

dant

pro

pert

ies

(Cor

re e

t al.

2005

; Azı

z et

al.

2003

; Gus

man

et a

l. 20

01 ; I

gnat

owic

z an

d B

aer-

Dub

owsk

a 20

01 ; P

erva

ız 2

003 )

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ardi

opro

tect

ive

(Cor

re e

t al.

2005

; Per

vaız

20

03 )

Che

lati

on o

f cop

per

(Azı

z et

al.

2003

; Gus

man

et

al.

2001

) In

hibi

tion

of l

ipid

per

oxid

atio

n (C

orre

et a

l. 20

05 ; A

zız

et a

l. 20

03 ; G

usm

an e

t al.

2001

) In

hibi

tion

of p

late

let a

ggre

gati

on (

Cor

re e

t al.

2005

; Azı

z et

al.

2003

; Per

vaız

200

3 )

Neu

ropr

otec

tive

(Pe

rvaı

z 20

03 )

Oes

trog

enic

/ant

i-oe

stro

geni

c ac

tivi

ty (

Gus

man

et

al.

2001

) Va

sore

laxi

ng a

ctiv

itie

s (C

orre

et a

l. 20

05 ; A

zız

et a

l. 20

03 )

1938 Induction of Apoptosis by Polyphenolic Compounds in Cancer Cells Po

lyph

enol

ic c

ompo

unds

(re

pres

enta

tive

pheo

lics)

So

urce

s B

iolo

gica

l act

iviti

es o

f po

lyph

enol

ic c

ompo

unds

Que

rcet

in

A

pple

s (B

isch

off

2008

; Ahe

rne

and

O’B

rien

200

2 ; M

iddl

eton

et a

l. 20

00 )

Ant

iall

ergi

c ac

tivi

ty (

Bis

chof

f 20

08 )

Ber

ries

(B

isch

off

2008

; Ahe

rne

and

O’B

rien

200

2 )

Ant

icat

arac

t effe

cts

(Bis

chof

f 20

08 )

Bro

ccol

i (B

isch

off

2008

; Ahe

rne

and

O’B

rien

200

2 )

Ant

ihyp

erte

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e ac

tivi

ty (

Pere

z-V

izca

ino

et a

l. 20

09 )

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rrie

s (B

isch

off

2008

; Ahe

rne

and

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200

2 )

Ant

iin fl

amm

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y ac

tivi

ty (

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chof

f 20

08 )

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rus

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ts (

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f 20

08 )

Ant

imic

robi

al e

ffect

s (B

isch

off

2008

) G

rape

s (B

isch

off

2008

; Ahe

rne

and

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rien

200

2 )

Ant

ineu

rode

gene

rati

ve e

ffect

s (B

isch

off

2008

)

Oni

ons

(Bis

chof

f 20

08 ; A

hern

e an

d O

’Bri

en 2

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Mid

dlet

on e

t al.

2000

) A

ntio

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ed w

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) Te

a (B

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; Ahe

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20

02 )

Ant

itum

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s (B

isch

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)

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ato

(Ahe

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2 )

Ant

ivir

al a

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ity

(Mid

dlet

on e

t al.

2000

) In

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tion

of l

ipid

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n (M

iddl

eton

et

al.

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) Ta

nnic

aci

d

B

eans

(N

aus

et a

l. 20

07 )

Ant

iang

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nic

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(C

hen

et a

l. 20

03 )

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fee

(Taf

feta

ni e

t al.

2005

) A

ntib

acte

rial

act

ivit

y (C

hung

et a

l. 19

98 )

Gra

pes

(Nau

s et

al.

2007

) A

ntic

arci

noge

nic

(Chu

ng e

t al.

1998

; Kha

n an

d H

adi 1

998 )

N

uts

(Nau

s et

al.

2007

; Taf

feta

ni e

t al.

2005

) A

ntim

icro

bial

act

ivit

y (C

hung

et a

l. 19

98 )

Red

win

e (T

affe

tani

et a

l. 20

05 )

Ant

imut

agen

ic a

ctiv

ity

(Kha

n an

d H

adi 1

998 )

Te

a (T

affe

tani

et a

l. 20

05 )

Ant

ioxi

dant

pro

pert

ies

(Chu

ng e

t al.

1998

; K

han

and

Had

i 199

8 ; K

han

et a

l. 20

00 )

Ant

ipro

life

rati

ve e

ffect

s (T

affe

tani

et a

l. 20

05 )

Che

mop

reve

ntiv

e ef

fect

s (C

hen

et a

l. 20

03 )

Pro

oxid

ant p

rope

rtie

s (K

han

et a

l. 20

00 )


Mahyar et al. ( 2001 ) , have reported that apoptosis induced through the mitochondrial pathway and that resveratrol up- regulated Bax independently of p53 (Mahyar-Roemer et al. 2001 ) . Studies on various colon cancer cell lines demonstrated that resveratrol induces the release of cytochrome c from mitochondria (Kim et al. 2009 a; Trincheri et al. 2007 ) .

The effects of resveratrol on caspases have been studied in colon cancer cells. Several studies have shown that resveratrol effects caspases 2, 3, 6, 8 and 9 (Kim et al. 2009 a; Wolter et al. 2001 ; Juan et al. 2008 ; Mahyar-Roemer et al. 2002 ; Lee et al. 2006 ; Mohan et al. 2006 ) . A study performed on DLD-1 and HT-29 colon cancer cells have shown the effects of resveratrol on cathepsin D, a lysosomal protease that emerges in the later stages of apoptosis. Thus, it might be suggested that lysosomes constitute one of the targets of resveratrol (Trincheri et al. 2007 ) . Resveratrol reduced mitotic activity by affecting cell cycle proteins in colon cancer cells. It has been reported that resveratrol inhibits the cell cycle. These effects of resveratrol on cell cycle have been shown to be associated with alterations in the expression of cyclins and CDKs (Wolter et al. 2001 ) . However, a study performed with CaCo-2 cell line has demonstrated that although resveratrol causes inhibition of cell growth and accumulation of cells in S/G2 phase, it has no effects on cytotoxicity or apoptosis (Schneider et al. 2000 ) . Caspase 6 activation has been reported to be an important factor in apoptosis triggered by resveratrol in HCT116 colon cancer cells with or without p53 (Lee et al. 2009a ) . Resveratrol also inhibits Wnt signaling markedly at low doses; an effect considered to be a consequence of regulation of intracellular beta-catenin localization (Hope et al. 2008 ) . Overall, studies suggest that resveratrol exerts its effects through multiple pathways leading to induction of apoptosis and inhibition of cell growth.

8.1.1.3 Prostate Cancer Cells and Resveratrol

Studies have shown that resveratrol induces apoptosis by up-regulating TRAILR1/DR4 and TRAILR2/DR5 in the death receptor pathway in LNCaP prostate cancer cell line (Shankar et al. 2007a, b ) . Aziz et al. ( 2006 ) have shown that resveratrol can induce apoptotic molecules including Bax, Bak, Bid and Bad in the intrinsic pathway, and commit cells to apoptosis in LNCaP cell line (Aziz et al. 2006 ) . In study on LNCap, PC3 and DU145 prostate cancer cell line, resveratrol alters release of Smac/Diablo, cytochrome c, AIF, Omi/HtrA2, PuMA and Noxa by causing loss of mito-chondrial membrane potential (Shankar et al. 2007a ; b ) . Studies have shown that resveratrol activates caspases in prostate cancer cells. In androgen responsive LNCaP and androgen insensitive PC3 prostate cancer cells, resveratrol induces apoptosis by activating both caspase 9 and caspase 3 (Shankar et al. 2007b ; Benitez et al. 2007a ) . Resveratrol increases expression of proapoptotic proteins in LNCaP cells, while down-regulating antiapoptotic molecules cIAP1-2, XIAP, Bcl-xl, survivin and Bcl-2 (Shankar et al. 2007b ) . It also has antiproliferative effects on prostate cancer cells and decreases cell viability (Aziz et al. 2006 ; Benitez et al. 2007a, b ; Hsieh and Wu 1999 ) . In a study performed with Du-145 prostate cancer cells, suppressive


effects of resveratrol on proliferation have been suggested to be mediated by HSPs70- (Cardile et al. 2003 ) .

Resveratrol might inhibit certain molecules in cell survival pathways including PI3K, Akt and NF- k B (Shankar et al. 2007b ; Aziz et al. 2006 ; Benitez et al. 2007b ; 2009 ) . Scarlatti et al. ( 2007 ) have shown that resveratrol induced cell cycle arrest and promoted apoptosis in prostate cancer cells (Benitez et al. 2009 ) . Kotha et al. ( 2006 ) have reported that resveratrol inhibits the activity of Src tyrosine kinase in malign cells and thus blocks the activation of Stat 3 proteins. As a result of the treatment of malign cells expressing active-Stat3 with resveratrol, human breast (MDA-MB-231) and prostate carcinoma (DU145) cell lines were inhibited at G0-G1 phase of cell cycle. However, resveratrol inhibited S phase of the cell cycle in human breast cancer (MDA-MB-468) and induced cell death via apoptosis (Kotha et al. 2006 ) .

Narayanan et al. ( 2003 ) showed that resveratrol alters the cell cycle regulation including cyclins, cdks, p53 and cdk inhibitors and expression of genes associated with apoptosis (Narayanan et al. 2003 ) . Joe et al. ( 2002 ) reported that resveratrol induces marked growth inhibition in MCF7 and SW480 cell lines (Joe et al. 2002 ) . Hsieh ( 2009 ) has been demonstrated that resveratrol achieves its anti-cancer activity in prostate cancer cells by suppressing cell proliferation, inhibiting proceeding of cell cycle and thus inducing apoptosis in androgen responsive LNCaP and androgen resistant (or insensitive) DU145 and PC-3 CaP cells (Hsieh 2009 ) .

Antiproliferative and proapoptotic effects of resveratrol in breast cancer cells might be due to accumulation of ceramide. However, Sala et al. ( 2003 ) have demonstrated that resveratrol might exhibit antiproliferative/proapoptotic effects secondary to endogen ceramide accumulation in androgen receptor (AR) negative prostate cancer cell line PC3 (Sala et al. 2003 ) .

8.1.2 Induction of Apoptosis by Quercetin

Quercetin (3,5,7,3 ¢ ,4 ¢ -pentahidroksi fl avon) is a fl avonoid commonly found in vegetables and fruits (Table 8.3 ). Its effects in the molecular mechanisms of apoptosis have been investigated in several cancer cell lines.

8.1.2.1 Breast Cancer Cells and Quercetin

Several studies indicate that quercetin induces apoptosis in breast cancer cells (Chou et al. 2010 ; Choi et al. 2001 ; Hatipoglu et al. 2010 ) . Quercetin, induces apoptosis through modulation of various pathways in a manner similar to other phenolic com-pounds and causes reduction in Bcl-2, and elevation Bax and AIF levels in MCF-7, MDA-MB-231 and MDA-MB-453 breast cancer cells (Chou et al. 2010 ; Chien et al. 2009 ; Choi et al. 2008 ) . Chou et al. ( 2010 ) reported that quercetin decreased levels of Bcl-2 protein and increased the activation of caspase-6, -8 and −9 in MCF-7 cells (Chou et al. 2010 ) . Chien et al. ( 2009 ) showed that quercetin treatment promoted


activation of caspase-3, -8 and −9 in MDA-MB-231 cells (Chien et al. 2009 ) . Other studies showed that quercetin induces growth inhibition and decrease proliferation and cell viability in breast cancer cells (Chou et al. 2010 ; Choi et al. 2001 ; Hatipoglu et al. 2010 ; Chien et al. 2009 ; Choi et al. 2008 ; Jeong et al. 2009 ; Rodgers and Grant 1998 ; Lee et al. 2009b ; Hakimuddin et al. 2004 ) . Quercetin affects the cell cycle by increasing the levels of Cdk inhibitors including p53, p21 CIP1/waf1 and p27 Kip1 (Chou et al. 2010 ; Choi et al. 2001 ; Jeong et al. 2009 ) . In MDA-MB-231 cells, quercetin was shown to increase levels of cytosolic calcium, which is known to trigger apoptosis. (Chien et al. 2009 ) . In addition, Costillo-pichardo et al. ( 2009 ) have demon-strated that combination of various grape polyphenols induce apoptosis and are more effective than single use of resveratrol, quercetin, or catechin in inhibition of cell proliferation, cell cycle progression, and cell migration in the highly metastatic ER (−) MDA-MB-435 cell line (Castillo-Pichardo et al. 2009 ) .

8.1.2.2 Colon Cancer Cells and Quercetin

Studies have shown that quercetin induces TRAIL-mediated apoptosis in colon adenocarcinoma cells (Psahoulia et al. 2007 ) . Kim WK et al. ( 2005 ) have reported that Bcl-2 was reduced while Bax remained unchanged in HT9 and SW480 colon cancer cells after administration of quercetin (Kim et al. 2005 ) . Quercetin has been shown to decrease cell viability, increase differentiation, inhibit cell proliferation and induce apoptosis in colon cancer cells (Kim et al. 2005 ; Xavier et al. 2009 ; Wenzel et al. 2004 ; Kim et al. 2010 ; Van Erk et al. 2004 ; Shan et al. 2009 ) . Van Erk et al. ( 2005 ) showed that in CaCo-2 cell lines, quercetin down-regulates cell cycle genes (CDC6, CDK4, cyclin D1), reduces the number of cells in G1 phase, and increases the sub-G1 population (Van Erk et al. 2004 ) . Proapoptotic effector caspase 3 and PARP cleavage increases with the effect of quercetin (Kim et al. 2005 ; Wenzel et al. 2004 ) . Kim et al. ( 2010 ) shown that quercetin causes upregulation of proteins including AMPK, p53 and p21 in HT-29 colon cancer cell line (Kim et al. 2010 ) . Shan et al. ( 2009 ) have been reported that quercetin down-regulates survivin genes in SW480 colon cancer cells (Shan et al. 2009 ) . Kim et al. ( 2005 ) have demonstrated that in CO115 cells quercetin decreased Akt phosphorylation, but did not alter that of phospho-ERK (Xavier et al. 2009 ) . Overall available data suggest that quercetin exerts its effects by multiple mechanism in cells and not only induces apoptosis but also inhibits survival pathways and cell cycle progression.

8.1.2.3 Prostate Cancer Cells and Quercetin

Studies in prostate cancer cell lines demonstrated that quercetin induces TRAIL-mediated cytotoxicity in these cells (Kim et al. 2008 ; Jung et al. 2010 ) . However, one study has suggested that quercetin does not alter levels of TRAIL receptors including DR4, DR5, DcR2 in prostate adenocarcinoma cells (Kim and Lee 2007 ) . Another study has suggested that TRAIL-induced apoptosis was associated with the up-regulation


of DR5 receptor (Jung et al. 2010 ) . This discrepancy might be due to the utilization of different cell lines by different studies. It is also possible that the dose of the compounds, or the time of the treatment may cause different fi ndings by different investigators. Kim et al. ( 2008 ) , quercetin leads to TRAIL induced apoptosis with the inhibition of survivin, an antiapoptotic protein, expression. Although, survivin is down-regulated with quercetin, the expressions of apoptosis inhibitor proteins, FLIP and IAP, are not altered in prostate cancer cell line (Kim et al. 2008 ) . On the other hand, quercetin has been shown to inhibit activity (phosphorylation) of PI3K/Akt signaling pathway in DU-145, LNCaP, PC3 prostate cancer cell lines (Kim and Lee 2007 ; Senthilkumar et al. 2010 ; Lee et al. 2008 ) . Quercetin decreases levels of Bcl-2, Bcl-xl, while increases levels of Bax, Bad and caspases including 3, 8, 9, 10 and PARP cleavage in several prostate cell lines (Kim et al. 2008 ; Jung et al. 2010 ; Kim and Lee 2007 ; Senthilkumar et al. 2010 ; Lee et al. 2008 ; Vijayababu et al. 2005 ; Vijayababu et al. 2006a, b ) . In addition, quercetin inhibits proliferation and cell viability and induces cell cycle arrest (Vijayababu et al. 2005 ; Aalinkeel et al. 2008 ) . It has been demonstrated that cdc2/cdk1, cyclin B1 and D1 expressions were decreased and G2/M transition was blocked with quercetin (Senthilkumar et al. 2010 ; Vijayababu et al. 2005 ) . Some studies suggested that quercetin exerts its effects independent of p53. Quercetin induces p21/Cip1 CDK-inhibitor expression, suggesting that it blocks cell cycle progression (Vijayababu et al. 2005, 2006a ; b ) . Quercetin induced apoptosis and inhibition of migration and invasion are synergistically enhanced when combined with EGCG (Tang et al. 2010 ) . Overeall, studies indicate that quercetin is highly effective in inducing apoptosis and inhibition of cell growth in different prostate cancer cells regardless of androgen receptor status. The other important feature of quercetin is that this compound also have multiple effects in prostate cancer cells, ranging from inhibition of cell proliferation, cell cycle to induction of apoptosis.

8.1.3 Induction of Apoptosis by Tannic Acid

Tannins are polyphenolic compounds with molecular weights between 500 and 3000 Da. They are classi fi ed into two categories including hydrolyzed and condensed tannins. Hydrolyzed tannins are commonly termed as tannic acids and contain either gallotannin or ellagic tannin (Nam et al. 2001 ) (Table 8.3 ).

8.1.3.1 Breast Cancer Cells and Tannic Acid

Recent studies have shown that pomegranate extracts containing tannic acid inhibited the growth of breast, prostate, colon and lung cancer cells (Adhami et al. 2009 ) . In our study performed with MCF-7 breast cancer cell line, we demonstrated that treatment of cells with various doses of tannic acid induced apoptosis and increased the level of FADD and Bak proteins in extrinsic and intrinsic pathways, respectively


(data not published). In the study by Uchiumi et al, they examined the effects of biological activities of tannic acid on breast tumor, and found that tannic acid inhib-its promoter of mouse mammary tumor virus (Uchiumi et al. 1998 ) . In another study of our group, we observed that tannic acid reduces the overall activity of NOS that is responsible for the synthesis of NO in colon adenocarcinoma cells (CaCo-2) and breast adenocarcinoma cells (MCF-7) (Cosan et al. 2010 ) . Sirivastava et al, have reported that tannic acid might be a potential inhibitor of NOS activity due to its antioxidant features (Srivastava et al. 2000 ) .

8.1.3.2 Colon Cancer Cells and Tannic Acid

Our laboratory has investigated the effects of tannic acid on apoptosis in CaCo-2 colon cancer cell line, Bak in intrinsic pathway and FADD protein in extrinsic pathway by administration of tannic acid in various doses. We found that tannic acid led to an increased apoptotic index and dose and time independent increase in Bak and FADD proteins (Cosan et al. 2009 ) . In the study of Seeram et al. ( 2005 ) , antiproliferative effects of punicalagin, total pomegranate tannin and ellagic acid were demonstrated in human colon (HT-29, HCT116, SW480, SW620), oral (KB, CAL27) and prostate (RWPE-1, 22Rv1) cancer cells. In addition punicalagin, total pomegranate tannin and ellagic acid were reported to induce apoptosis in HT-29, HCT116 colon cancer cell lines (Seeram et al. 2005 ) . However, the mechanisms by which tannic acid induce apoptosis remains to be elucidated by further studies .

8.1.3.3 Prostate Cancer Cells and Tannic Acid

Various studies have been conducted in order to understand the effects and mecha-nisms of polyphenols in prostate cancer. In one of these studies, Romero et al. ( 2002 ) , have found that tannic acid inhibits growth of LNCaPs prostate cancer cells and induces apoptosis (Romero et al. 2002 ) . Bawadi et al. ( 2005 ) have demonstrated the anti-angiogenic activity of water-soluble condense tannins isolated from black bean in HEL 299 normal human fi broblast lung cells, Caco-2 colon, MCF-7 and Hs578T breast and DU 145 human prostate cancer cell lines. Furthermore, they found that the condense tannin at lower doses does not have an effect on growth of normal cells however induces death of cancer cells by means of apoptosis in a dose-dependent manner (Bawadi et al. 2005 ) .

Chemopreventive effects of tannic acid might be due to suppression the growth of cancer cells. Currently, there are only very few studies with tannic acid with regard to its role in cancer chemoprevention. However in vitro studies showed that tannic acid inhibits cell proliferation and induces apoptosis in several cancer cell lines. In one of the these studies, Devi et al. ( 1993 ) have demonstrated that tannic acid has the highest effect on proliferation in several natural plant polyphenols tested in normal and abnormal human lymphocytes (Devi and Das 1993 ) . Ramanathan et al. ( 1992 ) , has demonstrated that together with various fl avonoids, tannic acid


inhibits growth of HeLa and Raji lymphoma cells (Ramanathan et al. 1992 ) . Pan et al. ( 1999 ) have shown that penta-O-galloyl-beta-D-glucose is structurally related to (−)-epigallocatechin gallate and is isolated from hydrolyzed tannin, induces apoptosis in HL-60 human acute leukemia (AML) cells by activation of caspase 3 (Pan et al. 1999 ) . Wang et al. ( 2000 ) , have found that the anti tumor effect of Cuphiin D1 (CD1) which is a macrocyclic hydrolysable tannin induces apoptosis by inhibiting Bcl-2 expression in HL60 leukemia cells, and G1-arrest (accumulation of cells in G1 phase of cell cycle) and decreasing number of cells in G2/M phase (Wang et al. 2000 ) . Chen et al. ( 2009 ) have demonstrated tannic acid induced apoptotic death has been observed in HL-60 AML cells in a dose- and time-dependent manner and that this effects were associated with an increase in sub-G1 fraction, chromosome condensation, and DNA fragmentation. Furthermore, it has been stated that tannic acid leads to apoptosis by activation of caspase cascade and cleavage of PARP followed by the disruption of mitochondrial membrane potential, and release of cytochrome c (Chen et al. 2009 ) . Sakagami et al. ( 2000 ) , have indicated that hydro-lyzable tannins lead to induction of apoptotic cell death in human oral squamous cell carcinoma and salivary gland tumor as indicated by the activation of caspases, cytokeratin 18 cleavage and DNA fragmentation (Sakagami et al. 2000 ) . Marienfeld et al. ( 2003 ) , have found out that tannic acid inhibits in vitro proliferation and cell cycle progression and increases expression of cyclin-dependent kinase inhibitor p27 KIP1 in malignant human cholangiocytes (Marienfeld et al. 2003 ) .

More interestingly, administration of tannic acid with a diet in C3H mice was shown to be highly effective in prevention of self developing liver tumors depending on dosage. These data clearly suggested that tannic acid can be used as a chemical prevention method against certain tumors (Nam et al. 2001 ) . However, more studies need to be performed to demonstrate the role of tannic acid as a chemopreventive agent in different carcinogenesis models.

Ubiquitin proteasome system plays a critical role in speci fi c degradation of cellular proteins. The most signi fi cant functions of proteasomes are to promote tumor cell proliferation and protect tumor cells against apoptosis. Tannic acids effective in the ubiquitin-proteasome system, which plays an important role in destruction of cell proteins. The ubiquitin-proteasome system can modulate levels of proteins such as p53, pRb, p21, p27 Kip1 , IKB- a and Bax that are involved in regulation of cell prolif-eration and cell death. Inhibition of proteasomes by tannic acid in Jurkat T cancer cells, stimulates apoptosis by accumulation of kinase inhibitor p27 Kip1 , proapoptotic protein Bax and suppression of cell cycle in G1 phase (Nam et al. 2001 ) .

8.1.4 Induction of Apoptosis by Other Polyphenols

Dietary polyphenols are the compounds found in fruits, vegetables and seeds. There are approximately 8.000 different polyphenols that are classi fi ed according to their chemical and structural features. The idea that these polyphenols might have a role in the prevention of cancer and can be used as chemical inhibitors of cancer justi fi ed

200 D. Turgut Cosan and A. Soyocak Ta

ble

8.4

Eff

ects

of

othe

r di

etar

y po

lyph

enol

s on

apo

ptot

ic p

athw

ays

in b

reas

t, pr

osta

te a

nd c

olon

can

cer

cells

Oth

er d

ieta

ry

poly

phen

ols

Sour

ces

Can

cer

cells

type

A

popt

osis

eff

ects

Api

geni

n Pl

ant s

eeds

fru

its a

nd

vege

tabl

es (

Agg

arw

al

and

Shis

hodi

a 20

06 )

Bre

ast c

ance

r ce

lls (

MD

A-M

B-

453,

SK-B

R-3

) (C

hoi

and

Kim

200

9a, b

)

Indu

ced

apop

tosi

s (C

hoi a

nd K

im 2

009a

, b ; C

hung

et a

l. 20

07 ; K

aur

et a

l. 20

08 )

Tri

gger

ed c

aspa

se a

ctiv

atio

n (C

hoi a

nd K

im 2

009a

; Shu

kla

and

Gup

ta

2008

) C

olon

can

cer

cells

(H

T29

-A

PC, H

T29

-GA

L)

(Chu

ng e

t al.

2007

)

Rel

ease

d cy

toch

rom

e c

(Cho

i and

Kim

200

9a )

Exp

ress

ion

of B

ax (

Cho

i and

Kim

200

9b ; S

hukl

a an

d G

upta

200

8 )

Pros

tate

can

cer

cells

(22

Rv1

, PC

-3)

(Shu

kla

and

Gup

ta 2

008 ;

Kau

r et

al.

2008

)

Dec

reas

ed le

vels

of

Bcl

-XL

,Bcl

-2 (

Shuk

la a

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upta

200

8 )

Inhi

bite

d ce

ll pr

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(Cho

i and

Kim

200

9b )

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ced

cell

cycl

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rest

(C

hoi a

nd K

im 2

009b

; Chu

ng e

t al.

2007

) R

egul

atio

n of

CD

K1

and

p21(

Cip

1) (

Cho

i and

Kim

200

9b )

Incr

ease

d ac

cum

ulat

ion

of p

53 (

Cho

i and

Kim

200

9b )

Inac

tivat

ion

of A

kt (

Kau

r et

al.

2008

)

Cap

saic

in

Red

pep

pers

(C

hou

et a

l. 20

09 )

Bre

ast c

ance

r ce

lls (

MC

F-7,

T

47D

, BT-

474,

SK

BR

-3,

MD

A-M

B23

1) (

Cho

u et

al.

200

9 ; T

hoen

niss

en

et a

l. 20

10 )

Indu

ced

apop

tosi

s (T

hoen

niss

en e

t al.

2010

; Kim

et a

l. 20

09 b;

Yan

g et

al.

2009

; Kim

et a

l. 20

07 )

Indu

ced

cellu

lar

apop

tosi

s th

roug

h a

casp

ase

inde

pend

ent p

athw

ay

(Cho

u et

al.

2009

) In

duce

d ap

opto

sis

thro

ugh

mito

chon

dria

l and

dea

th r

ecep

tor

path

way

s C

olon

can

cer

cells

(H

CT

116,

C

olo3

20D

M, L

oVo,

HT-

29)

(Kim

et a

l. 20

07, 2

009 b

; Y

ang

et a

l. 20

09 )

Indu

ced

apop

tosi

s vi

a R

OS

gene

ratio

n (S

ánch

ez e

t al.

2007

) A

ctiv

atio

n of

cas

pase

3 (

Yan

g et

al.

2009

)

Pros

tate

can

cer

cells

(PC

-3)

(Sán

chez

et a

l. 20

07 )

Inhi

bite

d ce

ll gr

owth

(C

hou

et a

l. 20

09 ; T

hoen

niss

en e

t al.

2010

; Kim

et

al.

2009

b)

Dec

reas

ed c

ell v

iabi

lity

(Yan

g et

al.

2009

) In

duce

d ce

ll cy

cle

arre

st (

Tho

enni

ssen

et a

l. 20

10 )

AM

PK a

ctiv

atio

n (K

im e

t al.

2007

) JN

K a

ctiv

atio

n (S

ánch

ez e

t al.

2007

) E

RK

act

ivat

ion

(Sán

chez

et a

l. 20

07 )

2018 Induction of Apoptosis by Polyphenolic Compounds in Cancer Cells O

ther

die

tary

po

lyph

enol

s So

urce

s C

ance

r ce

lls ty

pe

Apo

ptos

is e

ffec

ts

Cur

cum

in

Cur

cum

a lo

nga

(Tei

ten

et a

l. 20

10 )

Bre

ast c

ance

r ce

lls (

MD

A-

MB

-231

, BT-

483,

MC

F-7)

(L

iu e

t al.

2009

; Chi

u an

d Su

200

9 ; D

uvoi

x et

al.

2005

)

Indu

ced

apop

tosi

s (C

hiu

and

Su 2

009 ;

Duv

oix

et a

l. 20

05 ; T

eite

n et

al.

2010

; Lee

et a

l. 20

09c ;

Wat

son

et a

l. 20

08 ; H

ilchi

e et

al.

2010

; Sr

ivas

tava

et a

l. 20

07 )

Inhi

bite

d ex

pres

sion

s of

Bcl

-2, B

cl-X

L, s

urvi

vin

and

XIA

P (S

hank

ar

et a

l. 20

07c )

In

duce

d ex

pres

sion

s of

Bax

, Bak

, PU

MA

, Bim

, and

Nox

a an

d de

ath

Rec

epto

rs (

TR

AIL

R1/

DR

4 an

d T

RA

IL-R

2/D

R5)

(Sh

anka

r et

al.

2007

c )

Dow

n-re

gula

tion

of N

Fkap

paB

indu

cing

gene

s (L

iu e

t al.

2009

) A

ctiv

atio

n of

cas

pase

-3, -

8,-9

(Sh

anka

r et

al.

2007

) C

olon

can

cer

cells

(H

T-29

, H

CT-

116)

(L

ee e

t al.

2009

c ;

Wat

son

et a

l. 20

08 )

Dec

reas

ed p

rote

in e

xpre

ssio

n of

p53

and

Bcl

-2 (

Chi

u an

d Su

200

9 )

Act

ivat

ion

of p

38 m

itoge

n-ac

tivat

ed p

rote

in k

inas

e (M

APK

) (H

ilchi

e et

al.

2010

) A

ctiv

atio

n of

c-j

un N

-ter

min

al k

inas

e (J

NK

) (H

ilchi

e et

al.

2010

) Pr

osta

te c

ance

r ce

lls (

PC3,

L

NC

aP)

(Tei

ten

et a

l. 2

010 ;

Hilc

hie

et a

l. 20

10 ;

Sriv

asta

va e

t al.

2007

; Sh

anka

r et

al.

2007

c )

Inhi

bite

d ce

ll pr

olif

erat

ion

(Liu

et a

l. 20

09 ; C

hiu

and

Su 2

009 )

In

duce

d ce

ll cy

cle

arre

st (

Liu

et a

l. 20

09 ; C

hiu

and

Su 2

009 ;

Sri

vast

ava

et a

l. 20

07 )

Indu

ced

expr

essi

on o

f cy

clin

-dep

ende

nt k

inas

e (C

DK

) in

hibi

tors

p16

(/IN

K4a

), p

21(/

WA

F1/C

IP1)

and

p27

(/K

IP1)

(Sr

ivas

tava

et a

l. 20

07 )

Inhi

bite

d ex

pres

sion

of

cycl

in E

and

cyc

lin D

1 (S

riva

stav

a et

al.

2007

) D

ecre

ased

pA

kt a

nd C

OX

-2 (

Lee

et a

l. 20

09c )

In

crea

sed

p-A

MPK

(L

ee e

t al.

2009

c )

Act

ivat

ion

of p

38 m

itoge

n-ac

tivat

ed p

rote

in k

inas

e (M

APK

) (H

ilchi

e et

al.

2010

)

(con

tinue

d)


Oth

er d

ieta

ry

poly

phen

ols

Sour

ces

Can

cer

cells

type

A

popt

osis

eff

ects

Dai

dzei

n So

ybea

n (H

su e

t al.

2010

) B

reas

t can

cer

cells

(M

CF-

7,

MD

A-M

B-4

53)

(Jin

et a

l. 20

10 ;

Cho

i and

Kim

200

8 )

Indu

ced

apop

tosi

s (J

in e

t al.

2010

; Hsu

et a

l. 20

10 )

Act

ivat

ion

of c

aspa

se-3

,-9,

-7 (

Jin

et a

l. 20

10 ; C

hoi a

nd K

im 2

008 ;

Guo

et

al.

2004

) D

own-

regu

latio

n of

bcl

-2 (

Jin

et a

l. 20

10 )

Up-

regu

latio

n of

bax

(Ji

n et

al.

2010

; Hsu

et a

l. 20

10 )

Col

on c

ance

r ce

lls (

LoV

o) (

Guo

et a

l. 20

04 )

Rel

ease

d cy

toch

rom

e c

(Jin

et a

l. 20

10 )

Inhi

bite

d ce

ll pr

olif

erat

ion

(Jin

et a

l. 20

10 ; C

hoi a

nd K

im 2

008 )

Pr

osta

te c

ance

r ce

lls (

LnC

ap, P

C3)

(H

su e

t al.

2010

; Wan

g et

al.

2009

b )

Arr

este

d ce

ll cy

cle

(Cho

i and

Kim

200

8 ; G

uo e

t al.

2004

) In

crea

sed

expr

essi

on o

f th

e C

DK

inhi

bito

rs p

21(C

ip1)

, p57

(Kip

2) (

Cho

i an

d K

im 2

008 )

D

NA

fra

gmen

tatio

n (G

uo e

t al.

2004

) In

crea

sed

p53

prot

ein

expr

essi

on (

Wan

g et

al.

2009

b )

Del

phin

idin

Pi

gmen

ted

frui

ts a

nd

vege

tabl

es (

berr

ies,

po

men

gran

ates

etc

.)

(Afa

q et

al.

2008

; Yun

et

al.

2009

)

Bre

ast c

ance

r ce

lls (

AU

-565

, M

CF-

10A

) (A

faq

et a

l. 20

08 )

Indu

ced

apop

tosi

s (A

faq

et a

l. 20

08 ; Y

un e

t al.

2009

; Bin

Haf

eez

et a

l. 20

08 )

Act

ivat

ion

of c

aspa

se-3

,-8,

-9 (

Afa

q et

al.

2008

; Yun

et a

l. 20

09

Incr

ease

d B

ax (

Afa

q et

al.

2008

; Yun

et a

l. 20

09 )

Dec

reas

ed B

cl-2

pro

tein

(A

faq

et a

l. 20

08 ; Y

un e

t al.

2009

; Bin

Haf

eez

et a

l. 20

08 )

Col

on c

ance

r ce

lls (

HC

T11

6) (

Yun

et

al.

2009

) C

leav

age

of P

AR

P pr

otei

n (A

faq

et a

l. 20

08 ; Y

un e

t al.

2009

) Su

ppre

ssed

NF-

B p

athw

ay (

Yun

et a

l. 20

09 )

Dec

reas

ed c

ell v

iabi

lity

(Yun

et a

l. 20

09 )

Arr

este

d ce

ll cy

cle

in th

e G

2/M

pha

se (

Yun

et a

l. 20

09 )

Pros

tate

can

cer

cells

(PC

3, L

NC

aP,

C4-

2, 2

2Rnu

1) (

Bin

Haf

eez

et a

l. 20

08 ; H

afee

z et

al.

2008

)

Act

ivat

ion

of P

I3K

(A

faq

et a

l. 20

08 )

Inhi

bite

d E

GF-

indu

ced

auto

phos

phor

ylat

ion

of E

GFR

, AK

T a

nd M

APK

(A

faq

et a

l. 20

08 )

Inhi

bitio

n of

NFk

appa

B s

igna

ling

(Yun

et a

l. 20

09 ; B

in H

afee

z et

al.

2008

) D

ecre

ased

exp

ress

ion

of N

Fkap

paB

/p65

and

PC

NA

(H

afee

z et

al.

2008

)

Tabl

e 8.

4 (c

ontin

ued)


ther

die

tary

po

lyph

enol

s So

urce

s C

ance

r ce

lls ty

pe

Apo

ptos

is e

ffec

ts

Dia

llylp

olys

ul fi d

es

Gar

lic (

Bus

ch e

t al.

2010

) H

CT

116

hum

an c

olon

can

cer

cells

(B

usch

et a

l. 20

10 )

Indu

ced

apop

tosi

s (B

usch

et a

l. 20

10 )

Arr

este

d ce

ll cy

cle

(Bus

ch e

t al.

2010

) D

ecre

ased

cel

l via

bilit

y (B

usch

et a

l. 20

10 )

Ella

gic

acid

A

vaca

do

Bre

ast c

ance

r ce

lls (

MC

F-7,

Hs5

78T,

W

A-4

) (L

osso

et a

l. 20

04 ; D

ai

et a

l. 20

10 )

Indu

ced

apop

tosi

s (L

osso

et a

l. 20

04 )

Red

ber

ries

D

ecre

ased

AT

P pr

oduc

tion

(Los

so e

t al.

2004

)

Gra

pes

Col

on c

ance

r ce

lls (

CaC

o-2)

(L

osso

et

al.

2004

) A

rres

ted

cell

cycl

e pr

ogre

ssio

n in

the

G0/

G1

phas

e (D

ai e

t al.

2010

) St

raw

berr

ies

Dec

reas

ed le

vels

of

pro-

MM

P-2,

-9 (

Los

so e

t al.

2004

) R

aspb

erri

es

Pros

tate

can

cer

cells

(D

u-14

5) (

Los

so

et a

l. 20

04 )

Dec

reas

ed le

vels

of

VE

GF

(Los

so e

t al.

2004

) N

uts

(Agg

arw

al a

nd

Shis

hodi

a 20

06 ; L

osso

et

al.

2004

)

Epi

gallo

cate

chin

G

alla

te

(EG

CG

)

Gre

en te

a (T

hang

apaz

ham

et

al.

2007

; Has

tak

et a

l. 20

05 )

Bre

ast c

ance

r ce

lls (

MD

A-M

B-2

31,

MC

F-7)

(T

hang

apaz

ham

et a

l. 20

07 ; T

ang

et a

l. 20

07 )

Indu

ced

apop

tosi

s (T

hang

apaz

ham

et a

l. 20

07 ; H

asta

k et

al.

2005

) In

crea

sed

casp

ase-

9 ac

tivity

(Ta

ng e

t al.

2007

) In

crea

sed

Bax

(T

hang

apaz

ham

et a

l. 20

07 )

Red

uced

Bcl

-2 (

Tha

ngap

azha

m e

t al.

2007

) C

olon

Can

cer

Cel

ls (

HC

T11

6, H

T-29

) (T

haku

r et

al.

2010

; Hw

ang

et a

l. 20

07 )

Incr

ease

d le

vels

of

Bax

(H

asta

k et

al.

2005

) PA

RP

clea

vage

(T

hang

apaz

ham

et a

l. 20

07 )

Arr

este

d ce

ll gr

owth

(H

asta

k et

al.

2005

) Pr

osta

te c

ance

r ce

lls (

LnC

aP)

(Has

tak

et a

l. 20

05 )

Inhi

bite

d ce

ll pr

olif

erat

ion

(Tha

ngap

azha

m e

t al.

2007

; Tan

g et

al.

2007

) A

rres

ted

cell

cycl

e in

the

G1

phas

e (H

asta

k et

al.

2005

) In

duce

d p5

3, p

21 a

nd P

UM

A (

Tha

kur

et a

l. 20

10 ; H

asta

k et

al.

2005

) D

ecre

ased

AK

T p

hosp

hory

latio

n (T

hang

apaz

ham

et a

l. 20

07 ; T

ang

et a

l. 20

07 )

Supp

ress

ion

of s

urvi

vin

(Tan

g et

al.

2007

) D

ecre

ased

CO

X-2

exp

ress

ion

(Hw

ang

et a

l. 20

07 )

Act

ivat

ion

of A

MPK

(H

wan

g et

al.

2007

)

(con

tinue

d)


Oth

er d

ieta

ry

poly

phen

ols

Sour

ces

Can

cer

cells

type

A

popt

osis

eff

ects

Gen

iste

in

Soy

bean

s B

reas

t can

cer

cells

(M

DA

-MB

-231

, M

CF-

7) (

Fere

nc e

t al.

2010

; Li

et a

l. 20

08 ; T

ophk

hane

et a

l. 20

07 )

Indu

ced

apop

tosi

s (H

su e

t al.

2010

; Li e

t al.

2008

; Fan

et a

l. 20

10 ; L

u an

d Y

u 20

05 )

Indu

ced

casp

ase-

3 ac

tivity

(L

i et a

l. 20

08 )

Dow

n-re

gula

tion

of B

cl-2

(Fe

renc

et a

l. 20

10 ; L

i et a

l. 20

08 )

Up-

regu

latio

n of

Bax

(Fe

renc

et a

l. 20

10 ; L

i et a

l. 20

08 ; F

an e

t al.

2010

; L

u an

d Y

u 20

05 )

Chi

ckpe

a C

olon

can

cer

cells

(SW

480,

HT-

29)

(Fan

et a

l. 20

10 ; L

u an

d Y

u 20

05 )

Incr

ease

d cy

toch

rom

e c

rele

ase

(Top

hkha

ne e

t al.

2007

) In

hibi

ted

cell

grow

th (

Li e

t al.

2008

; Fan

et a

l. 20

10 )

Inhi

bite

d pr

olif

erat

ion

(Lu

and

Yu

2005

) Pr

osta

te c

ance

r ce

lls (

LnC

ap, P

C3)

(H

su e

t al.

2010

; Wan

g et

al.

2009

b )

Arr

este

d ce

ll cy

cle

(Hsu

et a

l. 20

10 ; W

ang

et a

l. 20

09b ;

Top

hkha

ne e

t al.

2007

; Fan

et a

l. 20

10 ; L

u an

d Y

u 20

05 )

Kud

zu r

oot (

Agg

arw

al a

nd

Shis

hodi

a 20

06 ; L

i et

al.

2008

)

Inhi

bite

d N

F-ka

ppaB

act

ivity

via

the

ME

K5/

ER

K5

path

way

(L

i et a

l. 20

08 )

Dow

n-re

gula

tion

of e

xpre

ssio

n of

VE

GFa

nd P

CN

A (

Fan

et a

l. 20

10 ; L

u an

d Y

u 20

05 )

Up-

regu

latio

n of

exp

ress

ion

of p

21 (

Fan

et a

l. 20

10 )

Lut

eolin

Te

a C

olon

can

cer

cells

(H

T-29

, CO

LO

205,

H

CT

116)

(do

Lim

et a

l. 20

07 ; S

hi

et a

l. 20

04 )

Indu

ced

apop

tosi

s (d

o L

im e

t al.

2007

; Chi

u an

d L

in 2

008 )

Fr

uits

R

epre

ssed

cel

l pro

lifer

atio

n (C

hiu

and

Lin

200

8 )

Veg

etab

les

Inhi

bite

d ce

ll gr

owth

(C

hiu

and

Lin

200

8 )

Cel

ery

Pros

tate

can

cer

cells

(L

NC

aP, D

U14

5,

PC-3

) (C

hiu

and

Lin

200

8 )

Arr

este

d ce

ll cy

cle

(do

Lim

et a

l. 20

07 )

Gre

en p

eppe

r pe

rilla

leaf

(A

ggar

wal

and

Sh

isho

dia

2006

; do

Lim

et a

l. 20

07 )

Supp

ress

ed e

xpre

ssio

n of

NF-

kapp

aB (

Shi e

t al.

2004

)

Tabl

e 8.

4 (c

ontin

ued)


ther

die

tary

po

lyph

enol

s So

urce

s C

ance

r ce

lls ty

pe

Apo

ptos

is e

ffec

ts

Lyco

pene

To

mat

o (A

ggar

wal

and

Sh

isho

dia

2006

) B

reas

t can

cer

cells

(M

CF-

7 an

d M

DA

-MB

-231

) (W

ang

and

Zha

ng

2007

a ; C

hala

bi e

t al.

2006

)

Indu

ced

apop

tosi

s (W

ang

and

Zha

ng 2

007a

; Cha

labi

et a

l. 20

06 ; P

aloz

za

et a

l. 20

10 ; W

ang

and

Zha

ng 2

007b

) D

own-

regu

latio

n of

bcl

-2 (

Wan

g an

d Z

hang

200

7b )

Up-

regu

latio

n of

bax

(W

ang

and

Zha

ng 2

007b

) C

olon

can

cer

cells

(H

uCC

) (S

alm

an

et a

l. 20

07 )

Inhi

bite

d ce

ll gr

owth

(W

ang

and

Zha

ng 2

007a

) A

ntip

rolif

erat

ive

effe

ct (

Salm

an e

t al.

2007

; Wan

g an

d Z

hang

200

7b )

Pros

tate

can

cer

cells

(L

NC

aP, P

C3)

(P

aloz

za e

t al.

2010

; Wan

g an

d Z

hang

200

7b )

Arr

este

d ce

ll cy

cle

prog

ress

ion

(Wan

g an

d Z

hang

200

7a ; C

hala

bi e

t al.

2006

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the need to investigate their mechanisms (Saunders and Wallace 2010 ; Han et al. 2007 ; Ramos 2007 ) . Other polyphenols, their effects and the mechanisms by which they induce apoptosis in breast, colon and prostate cancer cell line are summarized in Table 8.4 .

8.2 Conclusions and Future Directions

In this chapter, we summarized the fi ndings of recent studies and the effects of resveratrol, quercetin and tannic acid on apoptosis in cancer cells. Experimental data obtained from recent studies have indicated that polyphenols have antiproliferative effects through different mechanisms, including inhibition of cell signaling and survival pathways in addition to their effects on different apoptotic pathways. However, the exact mechanisms by which these compounds exert their effects have not been well understood. Considering their bene fi cial effects in prevention of cancer or as novel potential therapeutic agents more research are needed to determine their mechanism of action in normal and cancer cells. Furthermore, more in vivo studies are also required to evaluate the ef fi cacy of these polyphenols alone and in combination with standard therapies in various human tumor models. It is also critical to elucidate mechanisms of induction of apoptosis and antiproliferative effects as well as deter-mining the in vivo effective doses and administration schedules of these compound for using them as potential chemopreventive and novel potential anticancer agents.

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http://dx.doi.org/10.5174/tutfd.2010.03372.3

http://dx.doi.org/10.5174/tutfd.2010.03372.3


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