Research in Plant Biology-1au

8/11/2019 Research in Plant Biology-1au

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NATURALPLANTRESOURCESINANTI-CANCER

THERAPY-AREVIEW

PURVI H. KAKRANI & Dr. HARISH KAKRANI

Cancer isoneof te!ost co!!on"e#astatin$"iseaseaffectin$!i%%ionsof&eo&%e&er

'ear.Canceras(eenesti!ate"as tesecon" %ea"in$ ca)seof"eat in)!ans.So tere

as(eenanintensesearcon#ario)s(io%o$ica%so)rcesto"e#e%o&ano#e%anti-cancer"r)$

toco!(attis"isease.P%antsa#e&ro#e" to(ean i!&ortantnat)ra%so)rceofanti*cancer

tera&'forse#era%'ears.A(o)t+,&%ant"eri#e"co!&o)n"sa#e(eeniso%ate"sofaran"

are c)rrent%' )n"er c%inica% tria%s. Tese anti*cancer co!&o)n"s a#e (een fo)n" to (e

c%inica%%'acti#ea$ainst#ario)s t'&esofcancerce%%s.-)rterresearcintisarea!a' %ea"

to(ettertreat!entofcancer.

Ke'.or"s/anti-cancer,apoptosis,clinicaltrials,plantderivative.

I!&ortanceof&%antsecon"ar'!eta(o%ites 0.Vincaa%1a%oi"s

Plant secondary metabolites have Vinca alkaloids belong to an

proved to be an excellent reservoir of new important class of anti-cancer drugs. The

medical compounds. Many anti-cancer mechanism of action of Vinca alkaloids is

agentshavebeenisolatedfromvariousplant that they inhibit the cell proliferation by

sources like Catharanthus roseus,Podophyllum affecting the microtubular dynamics during

species, Taxus brevifolia, Camptotheca mitosis, and this causes a characteristic

blockacuminate, Betula alba, Cephalotaxus species, during mitosis leading to apoptosis.

CertainErythroxylum pervillei, Curcuma longa, semi-synthetic analogues have

beenIpomoeca batatas, Centaurea schischkinii and developed to increasethetherapeutic

index.

manyothers.Scientistsarestillattemptingto

explore the bioavailability of anti-cancerous

compoundsinunexploredplantspecies.

Anti*cancero)s"r)$s)n"erc%inica%tria%s

There are four maor structural

classifications of plant-derived anti-

cancerous compounds viz., Vinca

alkaloids,!pipodophyllotoxin lignans,Taxane diterpenoids and Camptothecin

"uinoline alkaloid derivatives. #ifferent

anti-cancer compounds that have been

identified and reported by scientists have

been reviewed

under.

Vinblastine $V%&' and Vincristine

$VC(' are the two maor naturally occurring

active compounds obtained from the

Madagascar periwinkle, Catharanthus roseus

). #on. $*pocynaceae'+ These compounds

reported potential activity

againstlymphocytic leukemia in mice.

Vinorelbine$V(%&' and Vindesine $V#S'

are the twosemi synthetic analogsobtained from theactive compounds.

They showed potentialactivity against

leukemia,s, lymphomas,advanced

testicular cancer, breast cancer,

lung cancer and aposi,s sarcoma when

PURVI H. KAKRANI & Dr. HARISH KAKRANIPage 1


2/23

treated in combination with other action is that these active agentsbind to the

chemotherapeutic drugs $Cragg and polymeri.edmicrotubuleswhichpreventthe

/ewman, 0112'+ Vinflunine, a bifluorinated

derivative of vinorelbine exhibits a superior

anti-tumor activity compared to other vinca

alkaloids. This novel Vinca alkaloid is

currently under Phase 33 clinical trials. &othVinflunine and Vinorelbine exhibits reduced

toxicity in animal models $4kouneva et al.,

01056Simeonsetal.,0117'+

2.Po"o&'%%oto3in

normal mitosis to occur and thus they are

calledanti-mitoticdrugs$8aitetal.,0019'+

4.Ca!&totecin5CPT6

Camptothecin is a cytotoxic alkaloid isolatedmainly from the bark and stem of the

Chinese ornamental tree, Camptotheca

acuminate. 3t showed poor solubility and

severe toxicity, and, because of this reason,

certainanaloguesofCPTweresynthesi.edto

Podophyllotoxinisobtainedfromtherootsof overcome these disadvantages. They are

Podophyllum species, namely, Podophyllum topotecan, irinotecan $CPT-::';


3/23

S/-57 shows increased cytotoxic effects in

various cancer cell lines $Ehang et al.,010>'+

cells.TheyworkbyinhibitingTopoisomerase

3 and 33 $#e *lmeida, 011 cellsby the survivin-mediated

pathway$Dieetal.,001


4/23


5/23

00.Co!(retastatinA*4

Combretastatin *-> is a naturally occurring

stilbene compound obtained from the South

*fricanbush willow tree, Combretum caffrum

unt.e. This vascular targeting agent

disruptsthetubulinstructureandthechange

in morphology of endothelial cells causes

deprivation of nutrients to tumor cells by

impeding theblood flow through capillaries.

#ue to its poor solubility, a water-soluble

prodrug called Combretastatin *->disodium

phosphatehas been formulated for

experimental purpose which is currently

underphase 33 clinical trials $Thomsonetal.,

010@6%eyetal.,0119'+

02.C)c)r(itacin

Cucurbitacin, a tetracyclic triterpenoid

compound is predominantly obtained from

the Cucurbitaceae plants. They possess

antiproliferative behavior against various

cancer cell lines. (eports show that

Cucurbitacin-3and&selectivelyinhibitboth

Curcumin is involved in modulating the cell

cycle pathway and induces apoptosis of

variouscancercells.&uttheexactmechanism

of action is yet tobe studied clearly. Phase

3G33 trials are ongoing on the effects of

curcumin on colorectal cancer, multiple

myeloma and pancreatic cancer. Curcuminused at a high dosage level is reported tobe

safe by phase 3 clinical trials $Sa et al.,

00:16)oeletal.,0117'+

04.Da&noretin

#aphnoretin, a bis-coumarin derivative,

extractedingoodamountsfromtherootbark

of "ikstroemia indica $Thymelaeaceae' was

foundtohavegoodanti-canceractivity$%uet

al., 01::'+#aphnoretincausessuppressionof

protein and #/* synthesis in !hrlich ascitescarcinomas. 3t is also seen to suppress the

hepatitis & surface antigen expression on

human hepatoma 8ep5& cells $#iogo et al.,

010K, 9- #ihydroxyisoflavone' and

activity and activator of transcription 5 )enistein $>K, 2; 9-Trihydroxyisoflavone' are

$ST*T5' pathways. ST*T5 is activated in the two aglyconespresent abundantly in the

many cancer cell types likeprostate cancer, Soy 3soflavones. Maor sources include

breastcancerandalsocarcinomaofthehead, important legumes like lupine $%upinus

neck and nasopharynx. (eports show that spp+'; fava bean, $Vicia faba'; soybeans

inhibition of this oncogenic signaling $)lycine max'; kud.u $Pueraria lobata'; and

pathway, ST*T5; causes tumor cell growth psoralea $Psoralea corylifolia' $aufman et

inhibition and leads to apoptosis of cancer al., :


6/23

0+.C)rc)!in

Curcumin $diferuloylmethane', apolyphenolic compound is isolated from the 3ndian

plant spices, Curcuma longa $commonly called turmeric', now finds its

application as potential anti-cancercompound. *bout 5L2 of this yellow

pigment of turmeric contains curcuminoids.cancers. They also inhibit chemically induced cancers in stomach, bladder, lung, prostate,

colon and blood $#ixon and erreira et al.,0100'.

0:.E%%i&ticine

*plant alkaloid, !llipticine $2; ::-dimethyl-@8-pyrido I>; 5-bJ carba.ole' and

its

derivatives were isolated from *pocynaceae

plantspecies$eg.#chrosiaborbonica,Excavatia Topoisomerase 33 activity. 3t is also reported

coccinea, #chrosia elliptica'. They exhibit thatthisdrug,inhibitscellgrowthandcauses

significant anti-tumor properties against apoptosisofhumanhepatocellularcarcinoma

various cancer cell types. The primary 8ep)0cells$aoetal.,001@'+

function of this drug is that it intercalates

with #/* and also causes inhibition ofTa(%e0.Listof%ant"eri#ati#es)se"incancertera'

S. Se!is'ntetic

No ana%o$sof

%ant

"eri#ati#es

: Vindesineand

Vinorelbine

0 Vinflunine

5 !toposideand

Teniposide

> TaxolA

2 TaxotereA

@ Topotecan

9 3rinotecan

7 !xatecan

< %!-S/-57

:1 &erbamine

:: &erberine

:0 &eta-

lapac

hone

Seciesan">en)s

na!e

Catharanthusroseus

Catharanthusroseus

PodophyllumpeltatumandPodophyllumemodi

Taxusbrevifolia/utt,

Taxusbaccata

Taxusbrevifolia/utt,

Taxusbaccata

Camptothecaacuminate



Ca

mpto

the

caa

cumina

te

Berberisamarensis

Hvdrastiscanadensis%+;

BerberineerisspN

rcungelisiaflaw

Tabebuiaavellanedae

E3eri!entson

#ario)scancer

ce%%s

%eukemias;

lymphomas;

advancedtesticular

cancer; breastcancer;

lungcancerand

-aposi,ssarcoma.

(educedtoxicityin

animalmodels

%ymphomas,

bronchialand

testicularcancers.

Metastatic; breast;

ovarian; lung;

prostatecancerand

lymphoidmalignancies

Osedinpatients

resistantto

Paclitaxel

!pithelialovarian

cancerandsmallcell

lungcancer

Metastatic and

colorectalcancer

Potentialanti-tumor

activitybothinvitroand

invivo

Variouscancercelllines

Chronic myeloid

leukemia

4steosarc

oma;

lung;

liver; prostate and

breastcancer

breastcancer; prostate

cancer; lungcancer;

pancreatic cancerand

promyelocytic

leukemia.


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?ecanis!ofaction

mitoticblock

mitotic block

-

*nti-mitotic

*nti-mitotic

#/*

topoisomerase3

inhibition

#/*

topoisomerase3

inhibition

#/*

topoisomerase3inhibition

#/*

topoisomerase3

inhibition

Caspase-5-

dependent

apoptosis

/otknown

3nhibitionof

topoisomerase3and33

Reference

Craggand

/ewman,

0112

4kouneva etal+; 01156

Simeons et

al.,0117

Shoeb,011@

-ingston,0119

8aitetal+; 0119

Creemersetal+;

:


8/23

:5 &etulinic acid

:> Colchicine

:2 Combretastati

n*->

:@ Cucurbitacin

:9 Curcumin

:7 #aphnoretin

:< #iad.einand

)enistein

01 !llipticine

0: !modin

00 Clavopiridol

05 8arringtonineand

8omoharring-

tonine

0> 3ndirubin

Betulaalba

Colchicum

autumnaleand

!loriosasuperba

%+

Combretum

caffrum-unt.e

Cucurbitaceae

species

Curcumalonga

"ikstroemia

indica

$upinusspecies;

%iciafaba,

!lycinemax,

Psoralea

corylifolia

#chrosia

borbonica,

Excavatiacoccinea,

#chrosiaelliptica

(hi.omeof

rhubarb

moorarohituka

and&ysoxylum

binectariferum

Cephalotaxusharrintonia,C'

hainanensisand

C'(inensis

Chineseherb;

#anggui

%onghui=an

!xhibitsanti-cancer

activityinhumans

%eukemic andsolidtumors

Phase33clinicaltrials

Variouscancercelllines

colorectalcancer,multiple

myelomaandpancreatic

cancer.

a'!hrlichascites

carcinomasandb'humanhepatoma

8ep5&cells.

)enisteininhibitsovarian

andbreastcancersandalso

chemicallyinducedcancers

ofstomach; bladder; lung;

prostate; colonandblood.

Variouscancercelltypes

lung; liver; ovarianand

bloodcancer

colorectal; non-smallcell

lungcancer,renalcell

carcinoma,non-8odgkin,s

lymphoma; chronic

lymphocytic leukemia,and

alsosolidtumors

*cutemyeloidleukemiaandchronic myeloid

leukemia.

Chronic myeloidleukemia

Triggers

mitochondrial

pathwayofapoptosis

*nti-mitotic

Tubulinstructure

disruption

3nhibitssignal

transducerGF*- 0

activityandactivates

ST*T5 pathway

!xactmechanismof

actionisstill

unknown

a'suppressionof

proteinand#/*synthesis

b'suppresses

8epatitis&surface

antigenexpression

3nhibits5*>-

mediatedmetabolism

andoxidative

metabolism

#/*intercalation

andinhibitionof

topoisomerase33

*poptosisofcancer

cellsbyseveral

pathways

3nhibitscellcycle

progressionat): or

)0 phase

3nhibitionofproteinsynthesisandchain

elongationduring

translation

3nhibitscyclin-

dependentkinases

Culda,0117

#ubeyetal+; 0117

Thomsonetal+;

011@6%eyetal+;

0119

Molavietal.,

01176&ernardand

4layinkaetal+;

01:1

Saetal.,00:06

)oeletal.,0117

%uetal+ 01::6

#iogoetal+; 001-3pomeanol

09 3ris"uinone

07 Phenoxodiol

0< PandimexTM

51 Perillylalcohol

5: Pervilleines

50 Salvicine

55 Schischkinnin

5> Montamine

52 Silvestrol

5@ P)>21-

mediatedconversion

into#/*-binding

metabolites

*ctsasa

chemosensiti.er

inhibitplasma

membraneelectron

transportandcell

proliferation

Cellcyclearrestand

actsasP-glycoprotein

blocker

!xactmechanismisyettobeidentified

3nhibitorsofP-

glycoprotein

3nhibitionof

topoisomerase33

/otknown

/otknown

apoptosomeGmitocho

ndrialpathwaywas

involvedintriggering

extrinsic pathwayof

programmedcell

deathoftumorcells

!nhancestheanti-

tumoreffectsof

cytotoxic and

chemotherapeutic

agents; thereby

inducesapoptosis.

8ampsonetal+;

0112

*ncuceanuand

3studor,011>

8a.raetal+; 011>

8erstetal+; 011'.

phaseandcausesinhibitionofcancerouscell

growth.&uttheexactmechanismofactionis

2+.Iris@)inone

3ris"uinone, aben.o"uinonewith anti-tumor

activity is obtained from plant species like

Iridaceaelatea pallasii and Iris k umaoensis$3ridaceae'+ 3ris"uinoneshowed goodactivity

against transplantable rodent tumors and

also acts as a chemosensiti.er $8a.ra et al.,

010>'.

24.Peno3o"io%an"Proto&ana3a"io%

Phenoxodiol $08-:-ben.opyran-9-0, :; 5-

I>-hydroxyphenylJ; PD#' is a synthetic

analogof naturally occurring plant

isoflavone,genistein. (eports of

phenoxodioldemonstrated that theyinhibit plasma membrane electron

transport and cell proliferation and

leads to apoptosis of many cancer cell

lines. This anti-cancer drug is being

developed as a Pchemosensiti.erQ and is

currently under Phase 333 clinical trials for

treatingovariancancerandalso intheinitial

yettobeidentified.3nvestigationisstillbeing

done on the effectiveness of

chemotherapeutic activity against human

cancers like non small cell lung cancer,

prostate cancer and colon cancer.Combination therapies were used in treating

breast cancer cells $Pan et al., 01:16&ardona

etal.,01106Beruvaetal.,0019'+

2:.Per#i%%eines

Pervilleines*,&,C,andareobtainedfrom

therootsofErythroxylumpervillei.Theyactas

good inhibitors of P-glycoprotein which

causes a multidrug resistance related to low

response for cancer therapy. urther

investigation on clinical trials is yet to bedone $Mi et al., 011:6 Mi et al., 01106 Mi et

al.,0105'.

2;.Sa%#icine

Salvicine, a diterpenoid "uinone is obtained

asaderivativeofthenaturallyoccurringlead

stages of clinical trial for treating prostate saprortho"uinone compound. This lead

andcervicalcancer$8erstetal.,011


13/23


14/23

potential against CaCo0 colon cancer cells 8omoharringtonine showed potential

$Shoebetal.,011@'+ activity against various leukemic cells6

2'+ Pharmacologically

active naturalcompounds

for lung cancer. ltern )ed,ev.,10-

>:


15/23

Cao, E., o.ielski, *., %iu, D., =ang,B.,

Vardeman, #., )iovanella, &., $010


16/23

Crystalline camptothecin-01$s'-o- uchs, C., Mitchell, !.P., 8off, P.M.,

$010@'+propionate hydrate a novel anticancer 3rinotecan in the treatment of

colorectalagent with strong activity against :0->9

#eng, +; %u,F.F., %iu, 8.B., %in, %+P., #ing,

F.,Ehang, F.S., $00::'+

Synthesis and antitumor

activity of novel salvicine analogues.

ChinChem$ett.,22/02-07+

#iogo,C.V+;elix,%+;Vilela,S.,&urgeiro,

*.,&arbosa,3.*.,Carvalho,M.F.M.,

4liveira,P.F., Peixoto, .P., $011'+Separation methods

of "uinonoid

constituents of plants used in oriental

traditional medicines. -

ChromatogrB.,902/02


17/23

aina, &., $0109'+ rom traditional

Chinese medicine to rational cancer

therapy.Trends)ol)ed.,0+/525-@:+

aufman, P.&., #uke, F.*., &rielmann,

8., &oik, F., 8oyt, F.!., $:


18/23

of the isoflavones, genistein and proteinsynthesis.)olPharmacol.,02/:@9-

daid.ein implications for human :9@+

nutritionandhealth.-lternComplement

)edSpring.,+/9-:0+

im, S., 8wang, &.B., Su, &/., Chai, 8.,

Mi, U., inghorn, *.#., =ild, (.,

Swanson,S.M., $0119'+ Silvestrol, a

potentialanticancer rocaglate

derivative from glaia

foveolata, induces apoptosis in%/CaP

cells through the

mitochondrialGapoptosome pathway

without activation of

executioner caspase-5 or -9+ nticancer

,es.,2;/ 0:92-0:75+

inghorn, #., de &lanco, !.F.C., Chai,

8.&.,4rala, F., arnsworth, /+(+;Soearto,#.#., 4berlies,/,8., =ani,

M.C., roll,#.F., Pearce, C.F., et al.

$000>-:72>.

uo, BC., uo, P%+; 8su, B%., Cho, CB.,

%in, CC., $011@'+ !llipticine induces

apoptosisthrough p25-

dependent pathway in

human hepatocellular carcinoma 8ep)0

cells.$ifeSciences.,;9/0220-0229+

%iu, U., $01::'+ Triptolide and its expanding

multiple pharmacological functions. Int

Immunopharmacol.,00/599-575.

%iu,D.M.,=ung,%+).,%i,8.B.,Fi,D.F.,

$:


19/23

8ollingshead,compound bruceantin, an inhibitor of M.)., Mayo, F.)., inghorn,

*.#., et al.$010:'+ Pervilleine *, a novel tropane

:0


20/23

alkaloid that reverses the multidrug- Christensen, T.&., Pink, #., #augaard,

S.,resistance phenotype. Cancer ,es.,:0/ Marreaud,

S., )labbeke, V.M., et al.>050-9+ $0119'+

!xatecan in pretreated adult

Mineko, 3., Michio, 3., 3kuo, M., Megumi,

M., Setsuko, 3., *kiko, T+; *kio, !+;

$0111'+ )rowth inhibitory effect of

a newcamptothecin analog,

#D-7


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important leads. Bioorg )ed Chem.,0+/ compounds for anti-leukemia activity.

27'.Ehang, %+; Du, (+; Bu, B., $011


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