Review ArticleMedicinal Plants in the Prevention and Treatment ofColon Cancer

Paola Aiello,1,2 Maedeh Sharghi,3 Shabnam Malekpour Mansourkhani,4

Azam Pourabbasi Ardekan,5 Leila Jouybari,6 Nahid Daraei,7 Khadijeh Peiro,8

Sima Mohamadian,9 Mahdiyeh Rezaei,9 Mahdi Heidari,5 Ilaria Peluso ,1

Fereshteh Ghorat,10 Anupam Bishayee ,11 and Wesam Kooti 5

1Council for Agricultural Research and Economics, Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Rome, Italy2Department of Physiology and Pharmacology “V. Erspamer”, La Sapienza University of Rome, Rome, Italy3Nursing and Midwifery School, Guilan University of Medical Sciences, Rasht, Iran4Department of Biology, School of Science, Shiraz University, Shiraz, Iran5Lung Diseases and Allergy Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences,Sanandaj, Iran6Nursing Research Center, Golestan University of Medical Sciences, Gorgan, Iran7Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran8Department of Biology, Faculty of Sciences, Shahid Chamran University, Ahvaz, Iran9Faculty of Pharmacy and Pharmaceutical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran10Traditional and Complementary Medicine Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran11Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Boulevard, Bradenton, FL 34211, USA

Correspondence should be addressed to Anupam Bishayee; abishayee@gmail.com and Wesam Kooti; wesamkooti@gmail.com

Received 8 March 2019; Accepted 3 July 2019; Published 4 December 2019

Guest Editor: Ana S. Fernandes

Copyright © 2019 Paola Aiello et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The standard treatment for cancer is generally based on using cytotoxic drugs, radiotherapy, chemotherapy, and surgery. However,the use of traditional treatments has received attention in recent years. The aim of the present work was to provide an overview ofmedicinal plants effective on colon cancer with special emphasis on bioactive components and underlying mechanisms of action.Various literature databases, including Web of Science, PubMed, and Scopus, were used and English language articles wereconsidered. Based on literature search, 172 experimental studies and 71 clinical cases on 190 plants were included. The resultsindicate that grape, soybean, green tea, garlic, olive, and pomegranate are the most effective plants against colon cancer. In thesestudies, fruits, seeds, leaves, and plant roots were used for in vitro and in vivo models. Various anticolon cancer mechanisms ofthese medicinal plants include induction of superoxide dismutase, reduction of DNA oxidation, induction of apoptosis byinducing a cell cycle arrest in S phase, reducing the expression of PI3K, P-Akt protein, and MMP as well; reduction ofantiapoptotic Bcl-2 and Bcl-xL proteins, and decrease of proliferating cell nuclear antigen (PCNA), cyclin A, cyclin D1, cyclinB1 and cyclin E. Plant compounds also increase both the expression of the cell cycle inhibitors p53, p21, and p27, and the BAD,Bax, caspase 3, caspase 7, caspase 8, and caspase 9 proteins levels. In fact, purification of herbal compounds and demonstrationof their efficacy in appropriate in vivo models, as well as clinical studies, may lead to alternative and effective ways of controllingand treating colon cancer.

HindawiOxidative Medicine and Cellular LongevityVolume 2019, Article ID 2075614, 51 pageshttps://doi.org/10.1155/2019/2075614

1. Introduction

An uncontrolled growth of the body’s cells can lead tocancer. Cancer of the large intestine (colon) is one of themain cause of death due to cancer. While the numbersfor colon cancer are somewhat equal in women (47,820)and men (47,700), it will be diagnosed in (16,190) men(23,720) more than women. Multiple factors are involvedin the development of colorectal cancer, such as lack ofphysical activity [1], excessive alcohol consumption [2],old age [3], family history [4], high-fat diets with no fiberand red meat, diabetes [5], and inflammatory bowel dis-eases, including ulcerative colitis and Crohn’s disease [6].

Prevention of colorectal cancer usually depends onscreening methods to diagnose adenomatous polyps whichare precursor lesions to colon cancer [7]. The standardtreatment for cancer is generally based on using cyto-toxic drugs, radiotherapy, chemotherapy, and surgery[8]. Apart from these treatments, antiangiogenic agentsare also used for the treatment and control of cancerprogression [9].

Colon cancer has several stages: 0, I, II, III, and IV. Treat-ment for stages 0 to III typically involves surgery, while forstage IV and the recurrent colon cancer both surgeryand chemotherapy are the options [10]. Depending onthe cancer stage and the patient characteristics, severalchemotherapeutic drugs and diets have been recom-mended for the management of colorectal cancer. Drugssuch as 5-fluorouracil (5-FU), at the base of the neoadju-vant therapies folfox and folfiri, are used together withbevacizumab, panitumumab, or cetuximab [7].

Chemotherapy works on active cells (live cells), such ascancerous ones, which grow and divide more rapidly thanother cells. But some healthy cells are active too, includingblood, gastrointestinal tract, and hair follicle ones. Sideeffects of chemotherapy occur when healthy cells are dam-aged. Among these side effects, fatigue, headache, musclepain, stomach pain, diarrhea and vomiting, sore throat,blood abnormalities, constipation, damage to the nervoussystem, memory problems, loss of appetite, and hair losscan be mentioned [11].

Throughout the world, early diagnosis and treatmentof cancer usually increase the individual’s chances of sur-vival. But in developing countries, access to effective andmodern diagnostic methods and facilities is usually limitedfor most people, especially in rural areas [12]. Accordingly,the World Health Organization (WHO) has estimated thatabout 80% of the world population use traditional treat-ments [13]. One of these treatments is phytotherapy, alsoknown as phytomedicine, namely, the use of plants or amixture of plant extracts for the treatment of diseases.The use of medicinal plants can restore the body’s abilityto protect, regulate, and heal itself, promoting a physical,mental, and emotional well-being [14–16]. Various studieshave shown the therapeutic effects of plants on fertilityand infertility [17], hormonal disorders, hyperlipidemia[18], liver diseases [19], anemia [20], renal diseases [21],and neurological and psychiatric diseases [22]. Therefore,due to all the positive effects showed by medicinal plants,

their potential use in cancer prevention and therapy hasbeen widely suggested [23–25].

Since the current treatments usually have side effects,plants and their extracts can be useful in the treatmentof colon cancer with fewer side effects. The aims of thisreview are to present and analyse the evidence of medici-nal plants effective on colon cancer, to investigate andidentify the most important compounds present in theseplant extracts, and to decipher underlying molecular mecha-nisms of action.

2. Literature Search Methodology

This is a narrative review of all research (English full textor abstract) studies conducted on effective medicinalplants in the treatment or prevention of colon cancerthroughout the world. Keywords, including colon cancer,extract, herbs, plant extracts, and plants, were searchedseparately or combined in various literature databases,such as Web of Science, PubMed, and Scopus. OnlyEnglish language articles published until July 2018 wereconsidered.

In the current narrative review, studies (publishedpapers) were accepted on the basis of inclusion and exclusioncriteria. The inclusion criterion was English language studies,which demonstrated an effective use of whole plants orherbal ingredients, as well as studies which included standardlaboratory tests. In vivo and in vitro studies that were pub-lished as original articles or short communications werealso included. The exclusion criteria included irrelevancyof the studies to the subject matter, not sufficient data inthe study, studies on mushrooms or algae, and the lackof access to the full text. Reviews, case reports/case series,and letters to editors were also excluded but used to findappropriate primary literature.

The abstracts of the studies were reviewed indepen-dently by two reviewers (authors of this study) on the basisof the inclusion and exclusion criteria. In case of any incon-sistency, both authors reviewed the results together andsolved the discrepancy. Data extracted from various articleswere included in the study and entered into a check listafter the quality was confirmed. This check list includedsome information: authors’ name, year of publication,experimental model, type of extract and its concentrationor dose, main components, and mechanisms of action (ifreported).

3. Results

3.1. Medicinal Plants and Colon Cancer. Overall, 1,150 arti-cles were collected in the first step and unrelated articleswere excluded later on according to title and abstractevaluation. Moreover, articles that did not have completedata along with congress and conference proceedingswere excluded. Accordingly, a total of 1,012 articles wereexcluded in this step. Finally, 190 articles fulfilled the cri-teria and were included in this review. These papers werepublished within 2000-2017. A total of 190 plants were

2 Oxidative Medicine and Cellular Longevity

included in this study. Based on literature search, 172experimental studies and 71 clinical cases were included.

Overall, results indicate that grape, soybean, green tea,garlic, olive, and pomegranate are the most effective plantsagainst colon cancer. In these studies, fruits, seeds, leaves,and plant roots were used for in vitro and in vivo studies.

3.1.1. In Vitro Studies.Out of 172 studies, 75 were carried outon HT-29, 60 on HCT116, and 24 on Caco-2 cells (Table 1).On HT-29 cells, both Allium sativum root extracts andCamellia sinensis leaf extracts induced cell apoptosis by twodifferent mechanisms, respectively. In fact, the formershowed inhibition of the PI3K/Akt pathway, upregulationof PTEN, and downregulation of Akt and p-Akt expression,while the latter was involved in attenuation of COX-2 expres-sion and modulation of NFκB, AP-1, CREB, and/or NF-IL-6.Moreover, an antiproliferative activity has also been detectedin Olea europaea fruit extracts, which increased caspase3-like activity and were involved in the production of super-oxide anions in mitochondria. An antiproliferative activity,by means of a blockage in the G2/M phase, has also beenreported in Caco-2 cells by Vitis vinifera fruit extracts.Concerning HCT116 cells, several plants, such as Americanginseng and Hibiscus cannabinus, induced cell cycle arrestin different checkpoints.

3.1.2. Studies in Animal Models. The most used animal modelis the murine one (Tables 2(a) and 2(b)). In particular, stud-ies were carried out above all on HT-29 and HCT116 cells.The effects of the different medicinal plants and their extractsare essentially the same detected in in vitro studies. In partic-ular, plant extracts were able to induce apoptosis and inhibitproliferation and tumor angiogenesis by regulating p53 levelsand checkpoint proteins with consequent cell cycle arrest andantiproliferative and antiapoptotic effects on cancerous cells.

The main mechanisms of action of medicinal plants aresummarized in Figure 1.

In in vitro studies, it has been found that grapes, whichcontain substantial amounts of flavonoids and procyanidins,play a role in reducing the proliferation of cancer cells byincreasing dihydroceramides and p53 and p21 (cell cycle gatekeeper) protein levels. Additionally, grape extracts triggeredantioxidant response by activating the transcriptional factornuclear factor erythroid 2-related factor 2 (Nrf2) [27].

Grape seeds contain polyphenolic and procyanidin com-pounds, and their reducing effects on the activity of myelo-peroxidase have been shown in in vitro and in vivo studies.It has been suggested that grape seeds could inhibit thegrowth of colon cancer cells by altering the cell cycle, whichwould lead eventually to exert the caspase-dependentapoptosis [180].

Another plant that attracted researchers’ attention wassoybean, which contain saponins. After 72 h of exposure ofcolon cancer cells to the soy extract, it was found that thisextract inhibited the activity and expression of protein kinaseC and cyclooxygenase-2 (COX-2) [34]. The density of thecancer cells being exposed to the soy extract significantlydecreased. Soybeans can also reduce the number of cancer

cells and increase their mortality, which may be due toincreased levels of Rab6 protein [216].

Green tea leaves have also attracted the researchers’attention in these studies. Green tea leaves, with highlevels of catechins, increased apoptosis in colon cancercells and reduced the expression of the vascular endothe-lial growth factor (VEGF) and its promoter activity inin vitro and in vivo studies. The extract increased apopto-sis (programmed cell death) by 1.9 times in tumor cellsand 3 times in endothelial cells compared to the controlgroup [182]. In another in vitro study, the results showedthat green tea leaves can be effective in the inhibition ofmatrix metalloproteinase 9 (MMP-9) and in inhibitingthe secretion of VEGF [183].

Garlic was another effective plant in this study. Its rootshave allicin and organosulfur compounds. In an in vitrostudy, they inhibited cancer cell growth and inducedapoptosis through the inhibition of the phosphoinositide3-kinase/Akt pathway. They can also increase the expressionof phosphatase and tensin homolog (PTEN) and reduce theexpression of Akt and p-Akt [32]. Garlic roots containS-allylcysteine and S-allylmercaptocysteine, which areknown to exhibit anticancer properties. The results of a clin-ical trial on 51 patients, whose illness was diagnosed as coloncancer through colonoscopy, and who ranged in age from 40to 79 years, suggest that the garlic extract has an inhibitoryeffect on the size and number of cancer cells. Possible mech-anisms suggested for the anticancer effects of the garlicextract are both the increase of detoxifying enzyme solubleadenylyl cyclase (SAC) and an increased activity of glutathi-one S-transferase (GST). The results suggest that the garlicextract stimulates mouse spleen cells, causes the secretionof cytokines, such as interleukin-2 (IL2), tumor necrosisfactor-α (TNF-α), and interferon-γ, and increases theactivity of natural killer (NK) cells and phagocytic peritonealmacrophages [200].

The results of in vitro studies on olive fruit showed that itcan increase peroxide anions in the mitochondria of HT-29cancer cells due to the presence of 73.25% of maslinic acidand 25.75% of oleanolic acid. It also increases caspase 3-likeactivity up to 6 times and induces programmed cell deaththrough the internal pathway [217]. Furthermore, the oliveextract induces the production of reactive oxygen species(ROS) and causes a quick release of cytochrome c from mito-chondria to cytosol.

The pomegranate fruit contains numerous phytochemi-cals, such as punicalagins, ellagitannins, ellagic acid, andother flavonoids, including quercetin, kaempferol, and luteo-lin glycosides. The results of an in vitro study indicate theanticancer activity of this extract through reduction of phos-phorylation of the p65 subunit and subsequent inhibition ofnuclear factor-κB (NFκB). It also inhibits the activity ofTNF receptor induced by Akt, which is needed for theactivity of NFκB. The fruit juice can considerably inhibitthe expression of TNF-α-inducing proteins (Tipα) in theCOX-2 pathway in cancer cells [43]. The effective and impor-tant compounds in pomegranate identified in these 104 stud-ies are flavonoids, polyphenol compounds, such as caffeicacid, catechins, saponins, polysaccharides, triterpenoids,

3Oxidative Medicine and Cellular Longevity

Table1:Cytotoxiceffectsof

medicinalplantson

coloncancer

inin

vitromod

els.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Vitisvinifera

Fruit

HCT116

NM

Lyophilized

Hydroxycinn

amicacids,

proantho

cyanidins,stilb

enoids

Increase

ofdihydroceram

ides,

sphingolipid

mediators

involved

incellcycle

arrest,and

redu

ctionof

theproliferation

rate

(i)Increase

ofp53andp21cellcycle

gatekeepers

(ii)Activationof

thetranscriptional

factor

Nrf2

[26,27]

Fruit

Caco-2

365mg/g

Methanolic

Catechin,

epicatechin,

quercetin,

gallic

acid

Antiproliferativeactivity

anddirectinitiation

ofcelldeath

Blockagein

theG2/M

phase

[28,29]

Seed

Caco-2

10–25μg/mL

Aqu

eous

Procyanidins

(i)Increasedcrypt

depth

(ii)Inhibitedcell

viability

and

decreased

histologicaldamage

score

Reduced

MPO

(myeloperoxidase)

activity

[29]

Skin

NM

7.5,30,60μg/mL

Methanolic

4′-G

eranyloxyferulicacid

NM

NM

[30]

Seed

Colon

cancer

stem

cells

6.25,12.5,

25μg/mL

NM

(+)-catechin,(−)-epicatechin

NM

(i)Increm

entof

p53,Bax/Bcl-2

ratio,

andcleavedPARP

(ii)Inhibition

ofWnt/β-catenin

signaling

[31]

Allium

sativum

Root

HT-29

20,50,100mg/mL

Ethanolic

NM

Indu

ctionof

apop

tosis

andcellcyclearrest

(i)Inhibition

ofthePI3K̸Akt

pathway

(ii)Upregulationof

PTEN

and

downregulationof

Akt

andp-Akt

expression

[32]

Glycine

max

Seed

Caco-2,

SW620,HT-

2912.5μg/mL

Aqu

eous

Antho

xanthin

Celld

eath

and

significant

redu

ctionof

celldensity

Enh

ancementof

Rab6proteinlevels

[33]

Seed

HT-29

240,600pp

mCrude

Sapo

nin

Supp

ressionof

PKCactivation

and

increase

ofalkalin

eph

osph

ataseactivity

[33]

Seed

HT-29

NM

Crude

Sapo

nin

NM

(i)Supp

ressionof

thedegradationof

IκBαin

PMA-stimulated

cells

(ii)Dow

nregulationof

COX-2

andPKCexpression

s

[34]

4 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Cam

ellia

sinensis

Leaf

HT-29

0,10,30,50

μM

Aqu

eous

Catechin,

epigallocatechin

gallate

1.9-fold

increase

intumor

cellapop

tosisand

a3-fold

increase

inendo

thelialcellapo

ptosis

(i)Supp

ressionof

ERK-1

andERK-2

activation

(ii)Supp

ressionof

VEGFexpression

[35]

Leaf

Caco-2,

HT-29

300μM

Aqu

eous

Theaflavins(TF-2T

,F-3,T

F-1)

Hum

ancoloncancer

cell

apop

tosisindu

ction

Mod

ulationof

NFκ

B,A

P-1,C

REB,

and/or

IL-6

[36]

Leaf

HT-29

68-80

0.73

μg/mL

Hot

water

extract

Flavan-3-ol(catechin

&tann

in)

&po

lyph

enols(teadeno

lB)

Inhibition

ofproliferation

ofHT-29cells

Increasedexpression

levelsof

caspases

3/7,8,and9

[35]

Oleaeuropaea

Fruit

HT-29

150,55.5

200and

74μmol/L

Methanolic

and

chloroform

Maslin

icacid,oleanolicacid

Antiproliferativeactivity

(i)Increasedcaspase3-likeactivity

to6-

fold

(ii)Produ

ctionof

superoxide

anions

inthemitocho

ndria

[37]

Fruit,leaf

SW480and

HT-29

100–400m/z

Methanolic

&hexane

Oleicacid,linoleicacid,gam

ma-

linolenicacid,lignans,fl

avon

oids,

secoiridoids

Reduced

cellgrow

thin

both

celllin

es

(i)Limited

G2M

cellcycle

(ii)Depressed

cyclooxygenase-2

expression

inHT-29cells

(iii)

Supp

ressionof

β-catenin/TCF

signalingin

SW480cells

(iv)

Promotionof

theentryinto

subG

1ph

ase

[38]

Fruit

Caco-2

50μM

Aqu

eous

Pheno

liccompo

unds,authentic

hydroxyltyrosol(HT)

Reduced

proliferation

ofCaco-2cells

Reduction

ofthemethylation

levelsof

CNR1prom

oter

[39]

Fruit

HT115

25μg/mL

Hydroethanolic

Pheno

liccompo

unds

(p-hydroxyph

enylethano

l,pino

resino

l&dihydroxyphenylethanol)

NM

Inhibition

byredu

cedexpression

ofa

rangeof

α5&β1

[40]

Olivemill

wastewater

HT-29,

HCT116,

CT26

NM

Methanolic

Hydroxytyrosol

(i)Inhibited

proliferation

(ii)Inhibitedmigration

andinvasion

(i)Reduced

sprout

form

ation

(ii)InhibitedVEGFandIL-8

levels

[41]

Fruit

Caco-2

0-2,000μg/mL

Ethanolic

Tyrosol,h

ydroxytyrosol,oleuropein,

rutin,

quercetinandglucosideform

sof

luteolin

andapigenin

NM

(i)Indu

ctionof

thecellcyclearrest

inS-ph

ase

[42]

Punica

gran

atum

Juice

HT-29

50mg/L

Aqu

eous

Ellagitann

ins,pu

nicalagin

Inhibition

ofcancer

cell

proliferation

(i)Supp

ressed

TNFR

-ind

uced

COX-2

proteinexpression

(ii)Reduced

phosph

orylationof

thep65

subu

nitandbind

ingto

theNFκ

Brespon

seelem

ent

[43]

Seed

LS174

63.2μg/mL

Supercriticalfl

uid

Pun

icicacid,γ-tocop

herol,

α-tocop

herol

Cytotoxicactivity

(i)Slightlydecreaseddevelopm

entof

tubu

lesfrom

elon

gatedcellbodies

(ii)Reduction

ofthenu

mberof

cell

conn

ection

s

[44]

5Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Glycyrrhiza

glabra

Root

HT-29

12.2and31

μg/mL

Ethanolic

Licochalcone

NM

Increase

oftheproteinlevelsof

proapo

ptoticBax

[37]

Opu

ntia

ficus-indica

Fruit

Caco-2

115μM

Aqu

eous

Betalainpigm

entindicaxanthin

Apo

ptosisof

proliferating

cells

(i)Dem

ethylation

ofthetumor

supp

ressor

p16INK4a

gene

prom

oter

(ii)Reactivationof

thesilenced

mRNA

expression

andaccumulationof

p16INK4a

[38]

Fruit

HT-29&

Caco-2&NIH

3T3(as

control)

AgainstHT-29

(4.9μg/mL)

againstCaco-2

(8.2μg/mL)

Alkalinehydrolysis

withNaO

HIsorhamnetinglycosides

(IG5andIG

6)-pheno

lCelld

eath

through

apop

tosisandnecrosis

Increasedactivity

ofcaspase3/7

[45]

Piperbetle

Leaf

HT-29and

HCT116

200.0μg/mL

Aqu

eous

Hydroxychavicol

Antioxidant

capacity

andindu

ctionof

agreaterapop

toticeffect

(i)Scavenging

activity

(ii)Fo

rmationof

electrop

hilic

metabolites

[41,46]

Fragaria×an

anassa

Fruit

HT-29

0.025,0.05,0.25,

0.5%

Ethanolic

Ascorbate,ellagicacid

Decreased

proliferation

ofHT-29cells

Increase

inthelevelsof

8OHAand

decrease

inthelevelsof

8OHG

[40]

Sasa

quelpaertensis

Leaf

HT-29

HCT116

0,100,200,

300mg/L

Ethanolic

p-Cou

maricacid,tricin

Inhibitedcolony

form

ation

Non

adherent

sphere

form

ation

supp

ressed

CD133+

&CD44+

popu

lation

[41]

Salvia

chinensis

Stem

HCT116,

COLO

205

10,20,40,60,80,

100mg/L

Polyphenolic

Terpeno

ids,ph

enolicacid,fl

avon

oids,

dibenzylcyclooctadiene

Apo

ptosis&loss

ofmitocho

ndrial

mem

brane

Indu

cedG0/G1cellcycle

[42]

Rub

usidaeus

L.Fruit

HT-29,

HT-115,

Caco-2

3.125,6.25,12.5,

25,50mg/L

Acetate

Polypheno

l,anthocyanin,

ellagitann

inNM

Decreased

popu

lation

ofcells

inG1

phase

[47]

LoVo

50μL

Aqu

eous

NM

Inhibitedproliferation

ofLo

Vo

Supp

ressionof

theNFκ

Bpathway

[48]

Curcumalonga

Root

HT-29,

HCT15,

DLD

1,HCT116

(i)Short-term

assay:four

10-fold

dilution

s(100

to0.1mg/L)

(ii)Lo

ng-term

assay:5,10,

20mg/L

Ethanolic

Curcumin

(diferuloylmethane)

Inhibitedform

ationof

HCT116spheroids

NM

[49]

6 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Eleutherococcus

senticosus

Root

HCT116

12.5,25,50,100

Methanolic

Eleutherosides,triterpeno

idsapo

nins,

glycans

NM

Activationof

naturalk

iller

cells

andthus

enhancem

entof

immun

efunction

[50]

Taberna

emontana

divaricata

L.Leaf

HT-29,

HCT15

10,30,100mg/L

Ethyla

cetate,

chloroform

,methanolic

Alkaloids

NM

Inhibitedtheun

winding

ofsupercoiled

DNA

[45]

Millingtonia

hortensis

Root,flow

er,

leaf

RKO

50,100,200,400,

800mg/L

Aqu

eous

Phenylethanoidglycoside,squalene,

salid

roside,2-phenylrutinoside

Apo

ptosisindu

ction

(i)Increase

offragmentedDNA

(ii)Decreaseof

theexpression

ofantiapop

toticproteins,B

cl-xLand

p-BAD

[46]

Pow

der

RKO

200,400,

800μg/mL

Aqu

eous

Water

solublecompo

unds

Antiproliferativeeffect

NM

[51]

Thaip

urplerice

Seed

Caco-2,Cat.

No.HTB-37

16.11μg/mL

Methanola

cidified

Cyanidin-3-glucosideandpeon

idin-3-

glucoside,anthocyanins,p

heno

liccompo

unds

(i)Antioxidation

ofanthocyanins

and

phenols

(ii)Antiproliferationof

coloncancer

cells

NM

[52]

Ann

onamuricata

Leaf

HCT116,

HT-29

11:43±

1:87μ

g/ml

and

8:98±

1:24μ

g/ml

Ethanolic

Alkaloids,acetogenins,essentialoils

Block

ofthemigration

andinvasion

ofHT-29

andHCT116cells

(i)Cellcyclearrestat

G1ph

ase

(ii)Disruptionof

MMP,cytochrom

ec

leakageandactivation

[53]

NM

HT-29,

HCT116

<4,<

20μg/mL

EtOAc

Ann

opentocinA,ann

opentocinB,

anno

pentocin

C,cis-andtrans-

anno

muricin-D

-ones,anno

muricin

ENM

Supp

ressionof

ATPprod

uction

and

NADH

oxidasein

cancer

cells

[54]

Pistacia

lentiscusL.

var.chia

Leaf

HCT116

NM

Ethanolic

Resin,kno

wnas

Chios

masticgum

(CMG)

Causesseveral

morph

ologicalchanges

typicalo

fapop

tosisin

cellorganelles

(i)Indu

ctionof

cellcyclearrestat

G1

phase

(ii)Activationof

pro-caspases

8,9,3

[55]

Resin

HCT116

100μg/mL

Hexan

eCaryoph

yllene

Indu

ctionof

theanoikis

form

ofapop

tosisin

human

coloncancer

HCT116cells

(i)Indu

ctionof

G1ph

asearrest

(ii)Lo

ssof

adhesion

tothesubstrate

[56]

American

ginseng

(Pan

axqu

inqu

efolius)

Biological

constituents

HCT116

0-2.0mg/mL

Aqu

eous

Ginseng

(GE)or

itsginsenoside(G

F)andpo

lysaccharide

(PS)

Proliferationwas

inhibitedby

GE,G

F,and

PSin

wild

-typeandp21

cells

(i)Cellsarrestin

G0/G1ph

aseand

increm

entof

p53andp21proteins

(ii)Increm

entof

Bax

andcaspase3

proteins

expression

[57]

7Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Purple-fleshed

potatoes

Fruit

Colon

cancer

stem

cells

5.0μg/mL

Ethanol,methanol,

ethylacetate

Antho

cyanin,β

-catenin,cytochrom

ec

Criticalregulator

ofCSC

proliferation

andits

downstream

proteins

(c-M

ycandcyclin

D1)

andelevated

Bax

and

cytochromec

(i)Cytochrom

eclevelswereelevated

regardless

ofp53status

(ii)Mitocho

ndria-mediatedapop

totic

pathway

(iii)

Supp

ressed

levelsof

cytoplasmicand

nuclearβ-catenin

[58]

Phaseolusvulgaris

Leaf

HT-29

NM

Ethanolic

Polysaccharides,o

ligosaccharides

Changes

ingenes

involved

orlin

kedto

cell

cyclearrest

(i)Inactivation

oftheretino

blastoma

phosph

oprotein

(ii)Indu

ctionof

G1arrest

(iii)

Supp

ressionof

NF-jB1

(iv)

Increase

inEGR1expression

[59]

Opu

ntia

spp.

Fruit

HT-29

5:8±1:0

,7:5±2:0

,12±

1%(V

/V)

Hydroalcoholic

Betacyanins,fl

avon

oids

(isorham

netin

derivatives)andph

enolicacids(ferulic

acid)

NM

Indu

cedcellcyclearrestat

different

checkp

oints—

G1,G2/M,and

S[60]

Suillus

luteus

NM

HCT15

400μg/mL

Methanolic

Protocatechuicacid,cinnamicacid,

α-tocop

herol,β-tocop

herol,mannitol,

trehalose,po

lyun

saturatedfattyacids,

mon

ounsaturated

fattyacids,saturated

fattyacids

(i)Increase

inthe

cellu

larlevelsof

p-H2A

.X,w

hich

issuggestive

ofDNA

damage

(i)Inhibition

ofcellproliferation

inG1

phase

(ii)Increase

inthecellu

larlevelsof

p-H2A

.X

[61]

Poncirus

trifo

liata

Leaf

HT-29

0.63

μM

Aqu

eous

(inacetone)

β-Sitosterol,2-hydroxy-1,2,3-

prop

anetricarboxylicacid

2-methylester

Arrestof

cellgrow

thwas

observed

with

β-sitosterol

NM

[62]

Rosmarinus

officina

lisL.

Leaf

SW620,

DLD

-10-120μg/mL

Methanolic

Polypheno

lsAntiproliferativeeffectof

5-FU

Dow

nregulationof

TYMSandTK1,

enzymes

relatedto

5-FU

resistance

[63]

Leaf

HT-29

SC-RE30

μg/mL

andCA

12.5μg/mL

Ethanolic

Polypheno

ls(carno

sicacid

(CA)and

carnosol)

(i)Upregulationof

VLD

LRgene

asthe

principalcon

tributor

totheobserved

cholesterol

accumulationin

SC-RE-treated

cells

(ii)Dow

nregulationof

severalgenes

involved

inG1-S

Activationof

Nrf2transcriptionfactor

andcommon

regulators,suchas

XBP1

(Xbp

1)gene

relatedto

theun

folded

proteinrespon

se(U

PR)

[64]

8 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

NM

HT-29

10,20,30,40,50,

60,70μg/mL

NM

Carno

sicacid,carno

sol,rosm

arinicacid,

rosm

anol

NM

NM

[65]

Leaf

HGUE-C

-1,

HT-29,and

SW480

20–40mg/mL

CO2-supercritical

fluidextract

Carno

sicacid,carno

sol,andbetulin

icacid

NM

(i)Prooxidativecapabilityby

increasing

theintracellulargeneration

ofROS

(ii)Activationof

Nrf2

[66]

Glehn

ialittoralis

Leaf

HT-29

50mg/mL

Methanolic

Bergapten,isoim

pinellin,

xantho

toxin,

imperatorin,

panaxydiol,falcarind

iol,

falcarinol

Indu

cedapop

tosisby

the

decreasedexpression

oftheantiapop

toticBcl-2

mRNA

(i)Reduced

expression

ofBcl-2

(ii)Reduced

expression

levelsof

iNOS

andCOX-2

[67]

Verbena

officina

lisLeaf

HCT116

20mg/mL

Aqu

eous

Phenylethanoidglycosides,d

iacetyl-O-

isoverbascoside,diacetyl-O

-beton

yoside

A,and

diacetyl-O

-beton

yoside

A

(i)Substantialtum

orcellgrow

thinhibitory

activity

(ii)Tim

e-depend

ent

cytotoxicity

against

both

celllin

es

(i)Increasedlip

ophilicityof

molecules

seem

edto

berespon

siblefor

enhanced

cytotoxicity

(ii)Antiproliferativeactivity

isdeterm

ined

bythenu

mberof

acetyl

grou

psandalso

bytheirpo

sition

inthealiphaticrings

[68]

Menthaspicata

Leaf

RCM-1

12.5μg/mL

N-H

exan

eAceticacid

3-methylth

ioprop

ylester

(AMTP),methylthioprop

ionicacid

ethylester

(MTPE)

Exhibited

antimutagenic

activity

Auraptene

(7-geranyloxycou

marin)

having

amon

oterpene

moietyand

β-cryptoxanthin

(one

ofthe

tetraterpenes)increasedantibody

prod

uction

[69]

Euphoria

longan

aLa

m.

Seed

SW480

0–100μg/mL

Ethanolic

Corilagin,

gallicacid,ellagicacid

(i)Antiangiogenetic

prop

erties

(ii)Allfraction

sshow

edtheanti-V

EGF

secretionactivity

Release

andexpression

ofVEGF

indicatedthat

allfractions

show

edthe

anti-V

EGFsecretionactivity

[70]

Sutherland

iafrutescens

Flow

erCaco-2

1/50

dilution

oftheethano

licextract

Ethanolic

Aminoacids,includ

ingL-arginine

and

L-canavanine,p

initol,fl

avon

oids,and

triterpeno

idsapo

nins

aswellas

hexadecano

icacid

andγ-sitosterol

Disruptionof

thekey

molecules

inthePI3K

pathway

thereby

indu

cing

apop

tosis

Decreasein

cellviability

andincrem

ent

inpykn

osisas

wellasloss

incellu

lar

mem

braneintegrity

[71]

Melissa

officina

lisLeaf

HT-29,T84

346,120μg/mL

Ethanolic

Pheno

licacids(rosmarinicacid,

coum

aricacid,caffeicacid,

protocatechu

icacid,ferulicacid,

chlorogenicacid),flavon

oids,

sesquiterpenes,m

onoterpenes,

triterpenes

(i)Inhibited

proliferation

ofcolon

carcinom

acells

(ii)Indu

cedapop

tosis

throughform

ationof

ROS

(i)G2/M

cellcyclearrest

(ii)Cleavageof

caspases

3and7

(iii)

Indu

cedph

osph

atidylserine

externalizationin

colon

carcinom

acells

(iv)

Indu

cedform

ationof

ROSin

coloncarcinom

acells

[72]

9Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Sargassum

cristaefolium

Leaf

HT-29

500mg/mL

Ethanolic

Fucoidans

(i)Reduction

offree

radicals

(ii)DPPH

radical

scavenging

Accum

ulationof

cells

inG0/G1ph

ase

[73]

Hedyotisdiffusa

NM

HT-29

400mg/mL

Ethanolic

andthen

DMSO

Octadecyl(E)-p-coum

arate,P-E-

metho

xy-cinnamicacid,ferulicacid,

scop

oletin,succinicacid,aurantiam

ide

acetate,rubiadin

Supp

ress

tumor

cell

grow

thandindu

cethe

apop

tosisof

human

CRC

cells

(i)Block

G1/Sprogression

(ii)Indu

cetheactivation

ofcaspases

9and3

(iii)

InhibitIL-6-m

ediatedST

AT3

activation

(iv)

Dow

nregulatethemRNAand

proteinexpression

levelsof

cyclin

D1,CDK4,Bcl-1,and

Bax

[74]

Zingiberoffi

cina

leRoscoe

Peel

LoVo

100mg/mL

Ethanolic

Lino

leicacid

methylester,

α-zingiberene,and

zingiberon

e

Interesting

antiproliferative

activity

againstcolorectal

carcinom

a

NM

[75]

Scutellariabarbata

Leaf

LoVo

413.3mg/L

Methanolic

Scutellarein,scutellarin,

carthamidin,

isocartham

idin,w

ogon

in

Indu

cecelldeathin

the

human

coloncancer

cell

line

Increase

inthesub-G1ph

aseand

inhibition

ofcellgrow

th[76]

Pistacia

atlantica,

Pistacia

lentiscus

Resin

HCT116

100μg/mL

Hexan

eextract

Caryoph

yllene

Indu

cetheanoikisform

ofapop

tosisin

human

coloncancer

HCT116

cells

(i)Indu

ceG1ph

asearrest

(ii)Lo

ssof

adhesion

tothesubstrate

[56]

Citrusreticulata

Peel

SNU-C

4100μg/mL

Methanolic

Limon

ene,geranial,n

eral,geranyl

acetate,geraniol,β

-caryoph

yllene,n

erol,

nerylacetate

Indu

cetheapop

tosison

SNU-C

4,hu

man

colon

cancer

cells

Expressionof

proapo

ptoticgene,B

ax,

andmajor

apop

toticgene,caspase

3[77]

Echina

ceapallida,

Echina

cea

angustifo

lia,

Echina

cea

purpurea

Root

COLO

320

150mg/mL

Hexan

icCaffeicacid

derivatives,alkylamides,

polyacetylenes,p

olysaccharides

Indu

ceapop

tosisand

prom

otenu

clearDNA

fragmentation

(i)Indu

ceapop

tosisby

increasing

caspase3/7activity

(ii)Promotenu

clearDNA

fragmentation

[78]

Nasturtium

officina

leLeaf

HT-29

50μL/mL

Methanolic

Phenethylisothiocyanate,

7-methylsulfinylheptyl,8-methylsulfinyl

(i)Inhibition

ofinitiation

,proliferation

,and

metastasis

(i)InhibitedDNAdamage

(ii)Accum

ulationof

cells

inSph

aseof

thecellcycle

[79]

10 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Polysiphonia

NM

SW480,

HCT15,

HCT116,

DLD

-1

20and40

μg/mL

Methanolic

2,5-Dibromo-3,4-dihydroxybenzyl

n-prop

ylether

Potentiallycouldbe

used

asachem

opreventive

agentagainstcolon

cancer

(i)InhibitedWnt/β-catenin

pathway

(ii)Repressed

CRTin

coloncancer

cells

(iii)

Dow

nregulated

cyclin

D1

(iv)

Activated

theNFκBpathway

[80]

Aristolochiadebilis

Sieb.etZucc.

Stem

HT-29

200μg/mL

Methanolic

Aristolochicacid,n

itroph

enanthrene

carboxylicacids

Inhibition

ofproliferation

and

indu

ctionof

apop

tosisin

HT-29cells

(i)Indu

ctionof

sub-G1cellcycle

(ii)Generationof

ROSanddecrease

oftheMMP

(iii)

Bax

overexpression

andincrease

ofBax/Bcl-2

ratio

[81]

Myrtaceae

Leaf

HCT116

100μg/mL

(invitro),200

and

100μg/disc

(invivo)

Methanolic

Pheno

ls,fl

avon

oid,

betulin

icacid

Strong

inhibition

ofmicrovesselou

tgrowth

(i)Inhibition

oftube

form

ationon

Matrigelm

atrix

(ii)Inhibition

ofHUVECSmigration

(invitro)

(iii)

Decreased

nutrient

andoxygen

supp

ly

[82]

Spicaprun

ellae

Leaf

HT-29

200mg/mL

(invitro),

600mg/mL

(invivo)

Ethanolic

Rosmarinicacid

InhibitsCRCcellgrow

th

(i)Supp

resses

STAT3ph

osph

orylation

(ii)Regulates

theexpression

ofBcl-2,

Bax,cyclin

D1,CDK4,VEGF-A,and

VEGFR

-2

[83]

Phytolacca

american

aRoot

HCT116

3200

μg/mL

Ethanolic

Jaligon

icacids,kaem

pferol,q

uercetin,

quercetin3-glucoside,isoq

uercitrin,

ferulic

acid

Con

trol

ofgrow

thand

spread

ofcancer

cells

Reduction

intheexpression

sof

MYC,

PLA

U,and

TEK

[84]

Morus

alba

Leaf

HCT15

13.8μg/mL

Methanolic

Epicatechin,m

yricetin,q

uercetin

hydrate,luteolin,kaempferol,ascorbic

acid,gallic

acid,p

elargonidine,

p-coum

aricacid

Cytotoxiceffecton

human

coloncancer

cells

(HCT15)

(i)Apo

ptosisindu

ctionalso

involved

inthedo

wnregulationof

iNOS

(ii)Fragmentation

ofDNA

(iii)

Upregulationof

caspase3activity

[85]

Rhodiolaim

bricata

Leaf

HT-29

200μg/mL

Acetone

and

methanolic

Pheno

ls,tannins,and

flavon

oids

(i)Antioxidant

activity

(ii)Inhibited

proliferation

ofHT-29cells

(i)Scavenge

free

radicals

(ii)DPPH

radicalscavengingactivity

(iii)

Increasedmetalchelatingactivity

[86]

Asiasarum

heterotropoidesF.

Dried

A.radix

HCT116

20mg/mL

Ethanolic

Asarininandxantho

xylol

Inhibition

ofthegrow

thof

HCT116cells

(i)Caspase-dependent

apop

tosis

(ii)Regulationof

p53expression

attranscriptionlevel

[87]

11Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Podocarpus

elatus

Fruit

HT-29

500mg/mL

Methanolic

Pheno

licandanthocyanin

Reduction

ofproliferation

ofcolon

cancer

cells

(i)Cellcycledelayin

Sph

ase

(ii)93%

downregulationof

telomerase

activity

anddecrease

intelomere

length

(iii)

Indu

cedmorph

ologicalalteration

sto

HT-29cells

[88]

Echina

cea

purpurea

Flow

erCaco-2,

HCT116

0–2,000mg/mL

Hydroethanolic

Cicho

ricacid

(i)Inhibition

ofproliferation

(ii)Decreased

telomeraseactivity

inHCT116cells

(i)Decreased

telomeraseactivity

(ii)Activationof

caspase9

(iii)

Cleavageof

PARP

(iv)

Dow

nregulationof

β-catenin

[89]

Root

COLO

320

150mg/mL

Hexan

icCaffeicacid

derivatives,alkylamides,

polyacetylenes,p

olysaccharides

Indu

ceapop

tosisby

increasing

significantly

caspase3/7activity

and

prom

otenu

clearDNA

fragmentation

(i)Increase

significantlycaspase3/7

activity

(ii)Promotenu

clearDNA

fragmentation

[78]

Hop

(Hum

ulus

lupu

lusL.),

Fran

seria

artemisioides

Leaf

NM

100mg/kg

b.w./d

ayAqu

eous

Cou

marin,lignans,q

uino

nes

30%

redu

ctionof

tumor-

indu

ced

neovascularization

NM

[90]

NM

Caco-2

NM

Ethanolic

Pheno

liccompo

unds,fl

avon

oid,

diterpenes

Digestive,

gastroprotective,

antiseptic,anti-

inflam

matory,and

antiproliferative

activity

NM

[91]

Fruit

NL-17

0,50,100,

150μg/mL

Methanolic

α-M

angostin

(xanthon

e)NM

(i)Indu

ctionof

caspase3andcaspase9

activation

(ii)Indu

cedcellcyclearrestat

G1/G0

phase

[92]

Stem

,bark

HT-29

50μg/mL

Chloroform-solub

leβ-M

angostin, garcino

neD,

cratoxyxanthon

e

Cytotoxicactivity

against

HT-29hu

man

colon

cancer

Inhibition

ofp50andp65activation

[93]

Ann

onasqua

mosa

Linn

Leaf

HCT116

8.98

μg/mL

Crude,A

qethyl

acetate

Acetogenins

(ann

oreticuin&

isoann

oreticuin)

andalkaloids

dopamine,salsolinol,and

coclaurine

Inhibition

ofgrow

thand

proliferation

oftumor

cells

(i)Reactiveoxygen

species(ROS)

form

ation,

lactatedehydrogenase

(LDH)release

(ii)Activationof

caspases

3/7,8,and9

[94]

Derrisscan

dens

Stem

HT-29

5-15

μg/mL

Ethanolic

Benzylsandisofl

avon

es(genistein,

coum

arins,scandino

ne)

Apo

ptosisandmitotic

catastroph

eof

human

coloncancer

HT-29cells

(i)Inhibition

ofα-glucosidase

activity

(ii)Scavenge

free

radicals

[95]

12 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Eupatorium

cann

abinum

Aerialp

arts

HT-29

25μg/mL

Ethanolic

Pyrrolizidinealkaloids(senecionine,

senk

irkine,m

onocrotalin

e,echimidine)

Indu

cedalteration

ofcolony

morph

ology

(i)Upregulationof

p21and

downregulationof

NCL,

FOS,and

AURKA

(ii)Mitoticdisrup

tion

andno

napo

ptotic

celldeathviaup

regulation

ofBcl-xL,

limited

TUNELlabelin

g,andnu

clear

size

increase

[96]

Sorghu

mbicolor

The

derm

allayerof

stalk

HCT116&

coloncancer

stem

cells

>16and

103μg/mL

Phenolic-rich

ethanolic,acetone

Apigeninidin&luteolinidin

Antiproliferative

Targetp53-depend

entandp53-

independ

entpathways

[97]

Dermaland

seed

head

CCSC

NM

Methanolic

Apigeninidin,

luteolinidin,m

alvidin3-

O-glucoside,apigenin,

luteolin,

naringenin,n

aringenin

7-O-glucoside,eriod

ictyol

5-glucoside,taxifolin

,catechins

NM

(i)Elevation

ofcaspase3/7activity

(ii)Decreasein

β-catenin,cyclin

D1,

c-Myc,and

survivin

proteinlevels

(iii)

Supp

ressionof

Wnt/β-catenin

signalingin

ap53-depend

ent

(dermallayer)andpartialp

53-

depend

ent(seedhead)manner

[98]

Hibiscus

cann

abinus

Seed

HCT116

KSE

(15.625μg/mLto

1,000μg/mL)

Ethanolic

Gallic

acid,p

-hydroxybenzoicacid,

caffeicacid,vanillicacid,syringicacid,

andp-coum

aricandferulic

acids

Cytotoxicactivity

against

human

coloncancer

HCT116cells

Apo

ptosisviablockade

ofmid

G1-late

G1-Stransition

therebycausingG1ph

ase

cellcyclearrest

[99]

Salix

aegyptiaca

L.Bark

HCT116&

HT-29

300μg/mL

Ethanolic

Catechin,

salicin,catecho

land

smaller

amou

ntsof

gallicacid,epigallocatechin

gallate(EGCG),qu

ercetin,

coum

aric

acid,rutin,syringicacid,and

vanillin

Anticarcino

geniceffects

incoloncancer

cells

Apo

ptosisviainhibition

ofph

osph

atidylinositol

3-kinase/protein

kinase

Bandmitogen-activated

protein

kinase

signalingpathways

[100]

Rub

uscorean

umFruit

HT-29

400μg/mL

Aqu

eous

Polypheno

ls,gallic

acid,sanguine

Indu

ctionof

apop

tosis

(i)Indu

cedactivity

ofcaspases

3,7,

and9

(ii)Cleavageof

poly(adeno

sine

diph

osph

ate-ribose)po

lymerase

[101]

Codonopsis

lanceolata

Root

HT-29

200μg/mL

N-Butan

olfraction

Tannins,sapon

ins,po

lyph

enolics,

alkaloids

Apo

ptosisin

human

colontumor

HT-29cells

(i)Indu

cedG0/G1arrest

(ii)Enh

ancementof

expression

ofcaspase3andp53andof

the

Bax/Bcl-2

ratio

[102]

13Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Gleditsia

sinensis

Tho

rnHCT116

800μg/mL

Aqu

eous

Flavon

oid,

lupine

acid,ellagicacid

glycosides

(i)Increase

inp53levels

(ii)Dow

nregulationof

thecheckp

oint

proteins,cyclin

B1,

Cdc2,andCdc25c

Inhibition

ofproliferation

ofcolon

cancer

cells

[90]

Tho

rnHCT116

600μg/mL

Ethanolic

NM

Inhibitory

effecton

proliferation

ofhu

man

coloncancer

HCT116

cells

(i)Causedcellcyclearrestat

G2/M

phasetogether

withadecrease

ofcyclin

B1andCdc2

(ii)Progression

from

G2/M

phase

[91]

Ligustrum

lucidu

mFruit

DLD

-150

μg/mL

Aqu

eous

Oleanolicacid,u

rsolicacid

Inhibitedproliferation

(i)Reduction

ofTbx3rescuedthe

dysregulated

P14ARF-P53

signaling

[94]

Zingiberoffi

cina

leRhizome

HCT116

5μM

Ethanolic

6-Paradol,6-and

10-dehydrogingerdion

e,6-

and

10-gingerdione,4-,6-,8-,and

10-gingerdiol,6-methylgingerdiol,

zingeron

e,6-hydroxysho

gaol,6-,8-,

10-dehydroshogaol,diarylheptanoids

Inhibitory

effectson

the

proliferation

ofhu

man

coloncancer

cells

(i)Arrestat

G0/G1ph

ase

(ii)Reduced

DNAsynthesis

[103]

Grifola

frondosa

Fruit

HT-29

10ng/m

LAqu

eous

Pheno

liccompo

unds

(pyrogallol,caffeic

acid,m

yricetin,p

rotocatechuicacid)

Inhibition

ofTNBS-

indu

cedratcolitis

Indu

cedcellcycleprogressionin

G0/G1

phase

[104]

Cucum

aria

frondosa

The

enzymatically

hydrolyzed

epitheliu

mof

theedible

HCT116

<150

μg/mL

Hydroalcoholic

Mon

osulph

ated

triterpeno

idglycoside

fron

doside

A,the

disulphatedglycoside

fron

doside

B,the

trisulph

ated

glycoside

fron

doside

C

Inhibition

ofhu

man

coloncancer

cellgrow

th

(i)Inhibition

atSandG2-M

phases

withadecrease

inCdc25cand

increase

inp21W

AF1/CIP

(ii)Apo

ptosisassociated

withH2A

Xph

osph

orylationandcaspase2

[105]

Rolan

drafruticosa

Leaf

&twigs

HT-29

10and

5mg/kg/day

Methanolic

Sesquiterpenelacton

e(13-acetoxyrolandrolide)

Antiproliferativeeffect

againsthu

man

colon

cancer

cells

Inhibition

oftheNFκBpathway,N

FκB

subu

nitp65(RelA),up

stream

mediators

IKKβandon

cogenicK-ras

[106]

14 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Cydonia

oblonga

Miller

Leaf&Fruit

Caco-2

250–500μg/mL

Methanolic

Pheno

liccompo

und(flavon

oland

flavon

eheterosides,5-O-caffeoylqu

inic

acid)

Antiproliferativeeffect

againsthu

man

kidn

eyandcoloncancer

cells

(i)Supp

ressionof

factor

activation

,nu

clearfactor-kB(N

FκB)activation

,protein-1(A

P-1)transcription

factor,m

itogen

proteinkinases

(MAPKs),p

rotein

kinases(PKs),

namely,PKC,growth-factor

receptor-(G

FR-)mediatedpathways

andangiogenesis

(ii)Cellcyclearrestandindu

ctionof

apop

tosis,antioxidant,andanti-

inflam

matoryeffects

[107]

Morchella

esculenta

Fruits

HT-29

820mg/mL

Methylene

chloride

Steroids

(mainlyergosterol

derivatives)

&po

lysaccharides&galactom

annan

Antioxidant

activity

inHT-29coloncancer

cells

Inhibition

ofNF-Bactivation

inthe

NF-Bassay

[108]

Sedu

mkamtschaticum

Aerialp

art

HT-29

0–0.5mg/mL

Methanolic

Bud

dlejasapon

inIV

Indu

cedapop

tosisin

HT-29hu

man

colon

cancer

cells

Indu

ctionof

apop

tosisviamitocho

ndrial

pathway

bydo

wnregulationof

Bcl-2

proteinlevels,caspase

3activation

,and

subsequent

PARPcleavage

[109]

Ginseng

and

Glycyrrhiza

glabra

Leaf

HT-29

500μL

Aqu

eous

Uracil,adenine,adenosine,

Li-glycyrrhetinicacid,q

uiritin

NM

Antiproliferativeeffectdeterm

inationof

theproteinlevelsof

p21,cyclin

D1,

PCNA,and

cdk-2,which

arethekey

regulators

forcellcycleprogression

[110]

Orostachys

japonicus

Leaf

&stem

HT-29

2mg/mL

Aqu

eous

Flavon

oids,triterpenoids,

4-hydroxybenzoicacid,3,4-

dihydroxybenzoicacid,p

olysaccharide

Antiproliferationin

HT-29coloncancer

cells

Inhibitedproliferation

atG2po

intof

the

cellcycleandapop

tosisviatumor

supp

ressor

proteinp53

[111]

Ginkgobiloba

Fruit&leaf

HT-29

20–320mg/L

Aqu

eous

Terpene

lacton

esandflavon

oid

glycosides

(i)Inhibitedprogression

ofhu

man

colon

cancer

cells

(ii)Indu

cedHT-29cell

apop

tosis

Increase

incaspase3activities

and

elevationin

p53MRNredu

ctionin

Bcl-2

mRNA

[112]

Oryza

sativa

Seed

HT-29,SW

480,HCEC

100μg/mL

Ethyla

cetate

Pheno

liccompo

und(tricin,

ferulic

acid,

caffeicacid,and

metho

xycinn

amicacid)

Inhibition

ofthehu

man

coloncancer

cellgrow

th

(i)Indu

cedapop

tosisby

enhanced

activation

ofcaspases

8and3

(ii)Decreaseof

thenu

mberof

viable

SW480andHCECcells

(iii)

Reduced

colony-formingability

ofthesecells

[113]

15Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Cnidium

officina

leMakino

Root

HT-29

305.024/mL

Ethanolic

Ostho

le,aurapteno

l,im

peratorin

Inhibitedproliferation

ofhu

man

coloncancer

cells

(HT-29)

Inhibition

ofthecellu

larproliferation

via

G0/G1ph

asearrestof

thecellcycleand

indu

cedapop

tosis

[114]

Cnidium

officina

leMakino

Root

HT-29

0.1-5mg/mL

Aqu

eous

N-(3-

(Aminom

ethyl)benzyl)acetamidine

Inhibitedthe

invasiveness

ofcytokine-

treatedHT-29cells

throughtheMatrigel-

coated

mem

branein

aconcentration-

depend

entmanner

(i)Reduction

ofHT-29cellinvasion

throughtheMatrigel

(ii)Inhibitedcytokine-m

ediatedNO

prod

uction

,iNOSexpression

,and

invasiveness

ofHT-29cells

(iii)

InhibitedMMP-2

activity

[115]

Long

pepper

(PLX

)Fruit

HT-29and

HCT116

0.10

mg/mL

Ethanolic

Piperidinealkaloids,piperamides,

piperlon

gumine

(i)Indu

ctionof

apop

tosis,following

DNAfragmentation

inHT-29colon

cancercells

inatime-

depend

entmanner

(ii)Indu

cedcaspase-

independ

ent

apop

tosis

Indu

cedwho

lecellROSprod

uction

[116]

Achyran

thesaspera

Root

COLO

205

50-100

and150-

200μg/mL

Ethan

olic(EAA)an

daqueous(AAA)root

extracts

Aqu

eous

Pheno

liccompo

unds

(i)Enh

ancedgrow

thinhibitory

effectsof

AAAtowards

COLO

205cells

incontrast

toEAA

(ii)Stim

ulatoryroleof

AAAin

the

activation

ofcell

cycleinhibitors

(i)Triggered

mitocho

ndrialapop

tosis

pathway

andSph

asecellcyclearrest

(ii)Increasedlevelsof

caspase9,caspase

3,andcaspase3/7activity

[117]

Thymus

vulgaris

Leaf

HCT116

0.2,0.4,0.6,

0.8mg/mL

Carvacrol

andthym

olInhibitedproliferation

,adhesion

,migration

,and

invasion

ofcancer

cells

[118]

Dictyopteris

undu

lata

NM

SW480

40μg/mL

Ethanolic

Cyclozonarone

benzoq

uino

neNM

Indu

cedapop

tosisby

redu

cing

Bcl-2

levels,u

pregulatingBax,and

disrup

ting

themitocho

ndrialmem

branepo

tential,

leadingto

theactivation

ofcaspases

3and9

[119]

16 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Dendrobium

microspermae

NM

HCT116

0.25,0.5,

1.0mg/mL

Methanolic

NM

NM

Upregulationof

Bax

andcaspases

9and

3anddo

wnregulationof

Bcl-2

expression

ofgenes

[120]

Can

nabissativa

Dry

flow

er&

leaf

DLD

-1and

HCT116

0.3–5μM

Methanolic

Cannabidiol,p

hytocann

abinoids

Reduced

cell

proliferation

inaCB1-

sensitive

(i)Reduced

AOM-ind

uced

preneoplasticlesion

sandpo

lyps

(ii)Inhibitedcolorectalcancer

cell

proliferation

viaCB1andCB2

receptor

activation

[121]

Phoenix

dactylifera

L.Fruit

Caco-2

0.2mg/mL

Aqu

eous

Pheno

licacids(gallic,p

rotocatechuic,

hydroxybenzoic,vanillic,isovanillic,

syringic,caffeic,ferulic,sinapic,p

-coum

aric,isoferulic),flavon

oid

glycosides

(quercetin,luteolin

,apigenin,

andkaem

pferol),andanthocyanidins

Increasing

beneficial

bacterialgrowth

and

inhibition

ofproliferation

ofcolon

cancer

cells

NM

[122]

Melia

toosendan

Fruit

SW480,CT26

0,10,20,30,40,

50μg/mL

Ethanolic

Triterpenoids,fl

avon

oids,

polysaccharide,lim

onoids

NM

(i)Inhibitedcellproliferation

ofSW

480

andCT26

byprom

otingapop

tosisas

indicatedby

nuclearchromatin

cond

ensation

andDNA

fragmentation

(ii)Indu

cedcaspase9activity

which

furtheractivatedcaspase3and

poly(A

DP-ribose)

polymerase

cleavage,leading

thetumor

cells

toapop

tosis

[123]

CrocussativusL.

Flow

erHCT116

0.25,0.5,1,2,

4μg/mL

Ethanolic

Carotenoid,

pigm

ent,crocin,crocetin

Indu

cedDNAdamage

andapop

tosis

(i)Ind

uction

ofap53pattern-depend

ent

caspase3activation

withafullG2/M

stop

(ii)Indu

cedremarkabledelayin

S/G2

phasetransitwithentryinto

mitosis

[124]

Tepalsand

leaf

Caco-2

0.42

mg/mL

NM

Polypheno

ls, glycosidesof

kaem

pferol,

luteolin,and

quercetin

Proliferationof

Caco-2

cells

was

greatly

inhibited

NM

[125]

Luffaechina

taFruit

HT-29

50,100,and

200μg/mL

Methanolic

Amariin

,echinatin,sapon

ins,

hentriacon

tane,gypsogenin,

cucurbitacin

B,d

atiscacin,

2-O-β-D

-glucop

yranosylcucurbitacin

B,and

2-O-

β-D

-glucopyrano

sylcucurbitacinS

Increase

inthe

popu

lation

ofapop

totic

cells

(i)Inhibitedthecellu

larproliferation

ofHT-29cells

viaG2/M

phasearrestof

thecellcycle

(ii)Indu

cedapop

toticcelldeathviaROS

generation

(iii)

Accum

ulationof

caspase3

transcriptsof

HT-29cells

[126]

17Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Vitisaestivalis

hybrid

Fruits(w

ine)

CCD-18C

o25,50,100μg/mL

NM

Polypheno

lics

NM

(i)Decreased

mRNAexpression

oflip

opolysaccharide-

(LPS-)indu

ced

inflam

matorymediators

NFκ

B,

ICAM-1,V

CAM-1,and

PECAM-1

(ii)Enh

ancedexpression

ofmiR-126

(iii)

Decreased

gene

expression

and

redu

cedactivation

oftheNFκB

transcriptionfactor,N

FκB-

depend

ent

(iv)

Decreasein

ROS113M

AH

[127]

Xylopia

aethiopica

Dried

fruit

HCT116

0,5,10,15,20,25,

30μg/mL

Ethanolic

Ent-15-oxokaur-16-en-19-oicacid

(EOKA)

NM

(i)Indu

cedDNAdamage,cellcycle

arrestin

G1ph

ase,andapop

toticcell

death

[128]

Sorghu

m

Grain

ER-β;

nonm

alignant

youn

gadult

mou

secolono

cytes

1,5,10,

100μg/mL

Aqu

eous

Flavon

es(luteolin

andapigenin),

3-deoxyantho

cyaninsnaringenin

(eriod

ictyol

andnaringenin)

Reduced

cellgrow

thvia

apop

tosis

Increasedcaspase3activity

[129]

NM

HT-29,

HCT116

0.9-2.0mg/mL

Hydroethanolic

Procyanidin

B1,delphinidin-3-O-

glucoside,tann

in,cyanidin-3-O

glucoside

(i)Significantly

arrested

HT-29cells

inG1

(ii)Highestgrow

thinhibition

(iii)

Increasedpercentage

ofapop

toticcells

(i)Dow

nregulationof

apop

totic

proteins,suchas

cIAP-2,livin,

survivin,and

XIA

P,w

asseen

inHCT116cells

(ii)Inhibition

oftyrosine

kinase

[130]

Pana

xnotoginseng

(Burk.)F.H.C

hen

Root

LoVoand

Caco-2

0,100,250,and

500μg/mL

Alcoholic

Sapo

nin,

ginsenoside

NM

Delay

inprogressionof

theG0/G1,S,or

G2/M

cellcycleph

ases

[131]

Brassicaoleracea

L.var.italica

Broccoli

florets

HCT116

0,1,2.5,5,

10μg/mL

Ethanolic

Glucoiberin,3

hydroxy,4(α-L-

rham

nopyrano

syloxy),benzyl

glucosinolate4-vinyl-3-pyrazolid

inon

e4-(m

ethylsulph

inyl),bu

tylthiou

rea,β-

thioglucosideN-hydroxysulphates

NM

NM

[132]

18 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Cistanche

deserticola

Dried

stem

SW480

Invivo:

0.4g/kg/day

Invitro:

100μg/mL

Aqu

eous

Polysaccharides,p

henylethanoid

glycosides

(i)Decreased

numberof

mucosalhyperplasia

andintestinal

helicobacter

infection

(ii)Increasednu

mberof

splenicmacroph

age,

NKcells,and

splenic

macroph

ages

Decreased

frequencyof

hyperplasiaand

Helicobacterhepaticusinfectionof

the

intestine

[133]

Chaenom

eles

japonica

Fruit

Caco-2and

HT-29

10,25,50,75,100,

125,150μM

CE

NM

Procyanidins

NM

NM

[134]

Prun

usmum

eFruit

SW480,

COLO

,and

WiDr

150,300,and

600μg/mL

Hydrophobic

Triterpenoidsapo

nins

NM

(i)Inhibitedgrow

thandlysedSW

480,

COLO

,and

WiDr

(ii)Indu

ctionof

massive

cytoplasmic

vacuoles

[135]

Solanu

mlyratum

NM

COLO

205

50,100,200,300,

400μg/mL

EtOH

β-Lycotetraosyl

Indu

cedSph

asearrest

andapop

tosis

(i)Indu

cedDNAfragments

(ii)Increasedthelevelsof

p27,p53,

cyclin

B1,active-caspase

3,andBax

(iii)

Decreased

thelevelsof

Cdk

1,pro-

caspase9,Bcl-2

andNF-ÎB,p65,and

p50

[136]

Onopordum

cyna

rocephalum

Aerialp

arts

HCT116,HT-

29

0,0.04,0.12,0.2,

0.4,1.2mg/mL

0,0.2,0.4,1.2,2.0,

3.0mg/mL

Aqu

eous

Flavon

oids,lignans,and

sesquiterpene

lacton

esNM

(i)Increase

intheexpression

ofproapo

ptoticproteins

such

asp53,

p21,andBax

(ii)Inhibition

oftheantiapop

totic

proteinBcl-2

(iii)

Decreasein

cyclin

D1protein

[137]

Eleutherine

palm

ifolia

Bulbs

SW480

2.5,5,10

μg/mL

MeO

HEleutherin,

isoeleutherin

NM

(i)Inhibitedthetranscriptionof

TCF/β-

catenin

(ii)Decreasein

thelevelo

fnu

clear

β-catenin

protein

[138]

Asparagus

officina

lisSpears

HCT116

76μg/mL

Acetone

Steroidalsapon

ins(H

TSA

-1,H

TSA

P-2,

HTSA

P-12,HTSA

P-6,H

TSA

P-8)

NM

(i)Inhibition

ofAkt,p

70S6K,and

ERK

phosph

orylation

(ii)Indu

ctionof

caspase3activity,

PARP-1

cleavage,D

NA

fragmentation

,G0/G1cellcycle

arrestby

redu

cing

theexpression

ofcyclinsD,A

,and

E

[139]

19Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Phyllanthu

sem

blicaL.

Seed,p

ulp

HCCSC

s,HCT116

200μg/mL

Methanolic

Trigonelline,n

aringin,

kaem

pferol,

embinin,

catechin,isorham

netin,

quercetin

(i)Supp

ressed

proliferation

(ii)Indu

cedapop

tosis

independ

entfrom

p53stem

ness

prop

erty

(in

HCCSC

s)(iii)

Antiproliferative

prop

erties

(i)Supp

ressed

cellproliferation

and

expression

ofc-Myc

andcyclin

D1

(ii)Indu

cedintrinsicmitocho

ndrial

apop

toticsignalingpathway

[140]

Red

grape

NM

HT-29,

HCT116

0.9-2.0mg/mL

Hydroethanolic

Delph

inidin

glycosides,q

uercetin

derivatives,delphinidin-3-O-glucoside

(high),cyanidin-3-O-glucoside

(i)Highestgrow

thinhibition

(ii)Increasedthe

percentage

ofapop

toticcells

(i)Dow

nregulationof

apop

totic

proteins,suchas

cIAP-2,livin,

survivin,and

XIA

P(ii)Inhibition

oftyrosine

kinase

[130]

Black

lentil

NM

HT-29,

HCT116

0.9-2.0mg/mL

Hydroethanolic

Delph

inidin

glycosides,p

rocyanidin

B1,

delphinidin-3-O-glucoside

(high),

cyanidin-3-O

-glucoside

(i)Significantly

arrested

HT-29cells

inG1

(ii)Highestgrow

thinhibition

(iii)

Increasedpercentage

ofapop

toticcells

(i)Dow

nregulationof

apop

totic

proteins,suchas

cIAP-2,livin,

survivin,and

XIA

P(ii)Inhibition

oftyrosine

kinase

[130]

Graptopetalum

paraguayense

Leaf

Caco-2,BV-2

0.2,0.4,0.6,0.8,

1.0mg/mL

Hydroethanolic

Oxalic

acid,h

ydroxybu

tanedioicacid,

gallicacid,q

uercetin,chlorogenicacid

glucanswithfucose,xylose,ribose

(GW100)

arabino-rham

nogalactan

s(G

W100E

)

(i)Great

potentialin

antiproliferation

(ii)Significant

immun

omod

ulatory

activities

onBV-2

cells

andinterleukin-

6(IL-6)

(GW100)

(i)Scavenging

α,α

-diphenyl-β-

picrylhydrazylradicals(D

PPH)

(GW100E

excelledin

scavenging

DPPH),2,2-azino-bis[3-

ethylbenzothiazolin

e-6-sulfo

nicacid]

radicals(A

BTS),sup

eroxideanions

(O2)

(GW100)

(ii)Significant

inhibition

oftumor

necrosisfactor-a(TNF-a),scavenging

ABTSandO2

[141]

Butea

monosperm

aFlow

erSW

480

200,370μg/mL

Floral

n-Butanol

Significant

antiproliferative

effect

(i)Significantlydo

wnregulated

the

expression

ofWnt

signalingproteins

such

asβ-catenin,A

PC,G

SK-3β,

cyclin

D1,andc-Myc

(ii)Increasedintracellularlevelo

fROS

[142]

20 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Rehman

nia

glutinosa

NM

CT26

5,20,80μM

NM

Catalpo

lInhibitedproliferation

andgrow

thinvasion

ofcoloncancer

cells

(i)Dow

nregulated

MMP-2

andMMP-9

proteinexpression

s(ii)Reduction

intheangiogenicmarkers

secretions

[143]

Telectadium

dongna

iense

Bark

HCT116

1.5,2.0μg/mL

MeO

Hextract

4-Dicaffeoylqu

inicacid,q

uercetin

3-rutino

side,p

eriplocin

NM

(i)Inhibition

ofβ-catenin/TCF

transcriptionalactivityandeffectson

Wnt/β-catenin

(ii)Dow

nregulationof

theexpression

ofWnt

targetgenes

[144]

Gloriosasuperba

Root

SW620

30ng/m

LProteinhydrolysate

extract

Protein

hydrolysate

NM

(i)Upregulationof

p53

(ii)Dow

nregulationof

NFκB

[145]

Boswellia

serrata

Resin

HT-29

100,150μg

Methanolic

Boswellic

acid

Decreased

cellviability

(i)Reduction

inmPGES-1,VEGF,

CXCR4,MMP-2,M

MP-9,H

IF-1,

PGE2expression

(ii)Increm

entin

thecaspase3activity

(iii)

Inhibition

ofcellmigration

and

vascular

sprout

form

ation

[146]

Typhonium

flagelliforme

Leaf

WiDr

70μg/mL

Ethyla

cetate

Glycoside

flavon

oid,

isovitexin,alkaloids

NM

Inhibition

ofCOX-2

expression

[28]

Diospyros

kaki

Fruit

HT-29

2,000μg/mL

Hydroacetoneextract

Polypheno

lIm

paired

cell

proliferation

and

invasion

NM

[147]

Carpobrotus

edulis

Leaf

HCT116

1,000mg/mL

Hydroethanolic

Gallic

acid,q

uercetin,sinapicacid,

ferulic

acid,luteolin

7-o-glucoside,

hyperoside,isoqu

ercitrin,ellagicacid,

isorhamnetin3-O-rutinoside

Inhibitedproliferation

(i)Possessionof

high

DPPH

scavenging

activityandeffective

capacityforiron

bind

ing

(ii)Inhibition

ofNOradical,lin

oleicacid

peroxidation

,protein

glycation,

and

oxidativedamage

[148]

Pipermethysticum

Root

HT-29

10,20,30,40,

50μg/mL

Aqu

eous

11-H

ydroxy-12-metho

xydihydrokavain,

11-hydroxy-12-metho

xydihydrokavain,

prenylcaffeate,pinostrobin

chalcone,11-

metho

xytetrahydroyangon

in,awaine,

methysticin,d

ihydromethysticin,

5,6,7,8-tetrahydroyangon

in,k

avain,

7,8-dihydrokavain,

yangon

in,

desm

etho

xyyangon

in,fl

avokaw

ainB

Inhibitedthegrow

thNM

[26]

21Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Salvia

ballotiflora

Groun

daerial

parts

CT26

6.76

μg/mL

Hexan

e-washed

chloroform

extract

19-D

eoxyicetexon

e,7,20-dihydroanastomosine,icetexon

e,19-deoxyisoicetexone

Cytotoxicactivity

NM

[149]

Tinospora

cordifo

liaStem

HCT116

1,10,30,50

μM

Hydroalcoholic

Clerodane

furano

diterpeneglycoside,

cordifo

liosidesAandΒ,sitosterol,

ecdysteron

e,2β

,3β:15,16-diepo

xy-4α,

6β-dihydroxy-13(16),14-clerodadiene-

17,12:18,1-diolid

e

Indu

cedchromatin

cond

ensation

and

fragmentation

ofnu

clei

offewcells

(i)Con

siderableloss

ofMMP

(ii)Decreased

inmitocho

ndriafunction

(iii)

Increasedcytochromecin

the

cytosol

(iv)

Indu

cedROS/oxidativestress

(v)Increasedautoph

agy

[150]

Euterpeoleracea

Fruit

NM

35μg/mL

Hydroethanolic

Vanillicacid,orientin,

isoorientin

NM

(i)Scavenging

capacity

towards

ROO

andHOCl

(ii)Inhibition

ofnitrosocompo

und

form

ation

[151]

Salvia

miltiorrhiza

NM

HCT116

7:4±1:0

,4:4±0:5

μg/mL

Ethanolic

Diterpene

quinon

eNM

Decreased

levelsof

pro-caspases

3and9

[152]

Coffea

Bean

HCT116

1mg/mL

Aqu

eous

Chlorogenicacid

complex

(CGA7)

NM

(i)DNAfragmentation

,PARP-1

cleavage,caspase

9activation

,do

wnregulationof

Bcl-2

and

upregulation

ofBax

[153]

Illicium

verum

Fruit

HCT116

10mg/mL

Ethanolic

Gallic

acid

quercetin

Indu

ctionof

apop

tosis

andinhibition

ofkey

stepsof

metastasis

NM

[154]

Garcinia

propinqu

aCraib

Leaf

HCT116

NM

CH2C

l2extract

Benzoph

enon

es,xanthon

es,and

caged

xantho

nes

Potentinhibitory

cytotoxicities

NM

[155]

Stem

,bark

HCT116

14.23,23.95μM

MeO

H,C

H2Cl 2,and

EtOAcextract

Xerop

heno

neA,d

oitunggarcinon

esA

andB,sam

pson

ione,7β-H

-11-benzoyl-

5α-ydroxy-6,10-tetramethyl-1-

(3-m

ethyl-2-bu

tenyl)-

tetracyclotetradecane-2,12,14-trione,

hypersam

pson

eM,assiguxanthon

eA

(cud

raxantho

neQ),40

10-O

-methylm

acluraxantho

ne(16),41-

and

5-O-m

ethylxanthon

eV1

NM

NM

[156]

22 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Malus

pumila

Miller

cv.A

nnurca

Fruit

Caco-2

400mg/L

Methanolic

Chlorogenicacid,(+)catechin,

(–)epicatechin,isoqu

ercetin,

rutin,

phloridzin,p

rocyanidin

B2,ph

loretin,

quercetin

WNTinhibitors

and

redu

cedWNTactivity

elicited

byWNT5A

NM

[157]

Malus

domestica

cv.L

imoncella

Fruit

Caco-2

400mg/L

Methanolic

Chlorogenicacid,(+)catechin,

(–)epicatechin,isoqu

ercetin,

rutin,

phloridzin,p

rocyanidin

B2,ph

loretin,

quercetin

WNTinhibitors

and

redu

cedWNTactivity

elicited

byWNT5A

NM

[157]

Coixlacrym

a-jobi

var.ma-yuen

Leaf

HCT116

0.5,1mg/mL

Aqu

eous

Coixspirolactam

A,coixspirolactam

B,

coixspirolactam

C,coixlactam,m

ethyl

dioxindo

le-3-acetate

NM

Inhibitedmigration

,invasion,

and

adhesion

viarepression

oftheERK1/2

andAkt

pathwaysun

derhypo

xic

cond

itions

[158]

Mesua

ferrea

Stem

,bark

HCT116,HT-

293.3,6.6,and

11.8μg/mL

NM

Fraction

s(α-amyrin,SF-3,n-Hex)

Dow

nregulationof

multipletumor

prom

oter

Upregulationof

p53,Myc/M

ax,and

TGF-βsignalingpathways

[159]

Taraxacum

Root

SGC7901,

BGC823

3mg/mL

Aqu

eous

NM

NM

Proliferationandmigration

through

targetinglncR

NA-C

CAT1

[160]

Portulacaoleracea

Leaf

HT-29CSC

s2.25

μg/mL

Alcoholic

Oxalic,m

alicacid

NM

Inhibitedexpression

oftheNotch1and

β-catenin

genes,regulatory

andtarget

genesthat

mediatetheNotch

signal

transduction

pathway

[161]

Hordeum

vulgareL.

NM

HT-29

NM

Aqu

eous

&juice

Protein,d

ietary

fiber,theBvitamins,

niacin,vitam

inB6,manganese,

phosph

orus,carbohydrates

(i)Inhibited

proliferation

ofcancer

cells

(ii)Cytotoxicactivity

Free

radicalscavengingactivity

[162]

Paraconiothyrium

sp.

NM

COLO

205

andKM12

12.5μM

Methylethylketone

extract

n-Hexane,CH

2Cl 2,E

tOAc,andMeO

Hfraction

s(A

−D)

(i)Growth

inhibitory

activity

(ii)Antiproliferative

effect

NM

[163]

Mentha×

piperita

Leaf

HCT116

5,10,20,30,40,

50μg/mL

Aqu

eous

Polypheno

lsNM

Inhibitedreplicationof

DNAand

transcriptionof

RNAwhich

indu

cethe

ROS

[164]

23Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Mam

mea

longifo

liaPlan

ch.and

Trian

aFruit

SW480

25,50,100μg/mL

Methanolic

NM

NM

Mitocho

ndria-relatedapop

tosisand

activation

ofp53

[165]

Rollin

iamucosa

(Jacq.)Baill.

NM

HCT116,

SW-480

<4,<

20μg/mL

EtOH

Rollitacin,jim

enezin,m

embranacin,

desacetyluvaricin,

laherradurin

Cytotoxicactivity

NM

[54]

Ann

ona

diversifo

liaSaff.

NM

SW-480

0.5μg/mL

NM

Cherimolin-2

Cytotoxicactivity

NM

[54]

A.purpu

reaMoc.

&Sesséex

Dun

alNM

HT-29

1.47

μg/mL

CHCl 3-M

eOH

Purpu

rediolin,p

urpu

renin,

anno

glaucin,

anno

nacinA

Cytotoxicactivity

NM

[54]

Viguieradecurrens

(A.Gray)

A.G

ray

NM

NM

3.6μg/mL

Hex;E

tOAc;MeO

H

β-Sitosterol-3-O-β-D

-glucopyrano

side;

β-D

-glucopyrano

sylo

leanolate;

β-sitosterol-3-O-β-D

-glucopyrano

side,

andoleano

licacid-3-O

-methyl-β-D

-glucuron

opyranosiderono

ate

Cytotoxicactivity

NM

[54]

Helianthella

quinqu

enervis

(Hook.)A.G

ray

NM

HT-29

2-10

μg/mL

NM

Dem

ethylencecalin

Cytotoxicactivity

NM

[54]

Smallanthu

smaculatus

(Cav.)

H.R

ob.

NM

HCT15

<20μg/mL

Acetone

Fraction

F-4,fraction

F-5,ursolic

acid

Cytotoxicactivity

NM

[54]

Bursera

fagaroides

(Kun

th)En

gl.

NM

HF6

1.8×

10-4to

2.80

μg/mL

Hydroalcoholic

Pod

ophyllotoxin,

β-peltatin-Amethyl

ether,5′-desmetho

xy-β-peltatin-A

methylether,d

esmetho

xy-yatein,

deoxypod

ophyllotoxin,

burseranin,

acetylpo

doph

yllotoxin

NM

(i)Inhibitorof

microtubu

les

(ii)Abilityto

arrestcellcyclein

metaphase

[54]

Viburnu

mjucund

umC.V.

Morton

NM

HCT15

<20μg/mL

Acetone

Ursolicacid

Cytotoxicactivity

NM

[54]

Hem

iangium

excelsum

(Kun

th)

A.C.Sm.

NM

HCT15

<10(μg/mL)

MeO

HPE

,EtOAc,MeO

HCytotoxicactivity

NM

[54]

24 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Hyptispectinata

(L.)Po

it.

NM

Col2

<4,<

20μg/mL

NM

Pectino

lideA,p

ectino

lideB,p

ectino

lide

C,α

-pyron

e,borono

lide,deacetylepiol-

guine

Cytotoxicactivity

NM

[54]

H.verticillata

Jacq.

NM

Col2

<4,<20

μg/mL

NM

Dehydro-β-peltatin,

methylether

dibenzylbu

tyrolacton

e,(-)-yatein,

4′-dem

ethyl-deoxypod

ophy

llotoxin

Non

specificcytotoxic

activity

NM

[54]

H.sua

veolens(L.)

NM

HF6

2.8-12

μg/mL

Chloroform

and

butanol

β-A

popicrop

odop

hyllin

Non

specificcytotoxic

activity

NM

[54]

Salvia

leucan

tha

Cav.

Leaf,root,

stem

HF6,H

T-29,

HCT15

14.9,12.7,

9.9μg/mL

CHCl 3

NM

Cytotoxicactivity

NM

[54]

Vitex

trifo

liaL.

NM

HCT15

3.5to

<1(μg/mL)

Hexan

ean

ddichloromethane

Salvileucalin

B,H

ex:leaf,Hex:stem,

DCM:leaf,DCM:stem

Cytotoxicactivity

NM

[54]

Persea

american

aMill.

NM

HT-29

<4μg/mLand

<20μg/mL

Ethanolic

1,2,4-trihydroxyno

nadecan,

1,2,4-trihydroxyheptadec-16-ene,

1,2,4-trihydroxyheptadec-16-yne

Cytotoxicactivity

NM

[54]

Linu

mscabrellu

mRoots,aerial

parts

HF6

0.2,0.5,2.3μg/mL

Chloroform

and

butanol

DCM:M

eOH,6MPTOXPTOX

NM

(i)Indu

ctionof

cellcyclearrestin

G2/M

(ii)Inhibition

oftubu

linpo

lymerization

[54]

Phoradendron

reichenb

achian

um(Seem.)Oliv.

NM

HCT15

3.6,3.9,and

4.3μg/mL

NM

Moron

icacid

Cytotoxicactivity

NM

[54]

Cup

hea

aequ

ipetalaCav.

NM

HCT15

18.70μg/mL

Acetone

NM

Cytotoxicinactivity

NM

[54]

Galphim

iaglau

caCav.

NM

HCT15

0.63,0.50,

1.99

μg/mL

EtOH,M

eOH,

aqueous

NM

Cytotoxicactivity

NM

[54]

Mim

ulus

glabratus

Kun

thNM

HF6

12.64μg/mL

MeO

HNM

Cytotoxicactivity

NM

[54]

Picram

nia

antidesm

aSw

.NM

HCT15

0.6to

4.5μM

NM

10-Epi-uveoside,uveoside,

picram

niosideE,p

icramniosideD

Cytotoxicactivity

NM

[54]

25Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Penstemon

barbatus

(Cav.)

Roth

NM

HF6

15.19μg/mL

MeO

HNM

Cytotoxicactivity

NM

[54]

P.campanu

latus

(Cav.)Willd.

NM

HF6

6.74

μg/mL

MeO

HNM

Cytotoxicactivity

NM

[54]

Veronica

american

aSchw

ein.

exBenth.

NM

HF6

0.169and

1.46

μg/mL

MeO

HNM

Cytotoxicactivity

NM

[54]

Zea

maysL.

NM

HCT116,SW

-480,SW

-620

NM

NM

13-H

ydroxy-10-oxo-trans-11-

octadeceno

icacid

Cytotoxicactivity

NM

[54]

Colub

rina

macrocarpa(Cav.)

G.D

onNM

HCT15

10,2.1,9.1μg/mL

PE,E

tOAc,MeO

HNM

Cytotoxicactivity

NM

[54]

Coixlacrym

a-jobi

Seed,

endo

sperm,

andhu

llHT-29

0.1–1,000μg/mL

Methanolic,h

exan

e

Phytosterols(cam

pesterol,stigm

asterol,

andβ-sitosterol),gam

ma-lin

olenicacid

(GLA

),arachido

nicacid

(AA),

eicosapentaeno

icacid

(EPA)and

docosahexaenoicacid

(DHA),lin

oleic

acid

NM

(i)Influenceof

signaltransduction

pathwaysthat

involvethemem

brane

phosph

olipids

(ii)Enh

ancementof

ROSgeneration

and

decrease

ofcellantioxidantcapacity

[166]

Abu

tilonindicum

Leaf

HT-29

210μg/mL

Aqu

eous

Flavon

oids

(4H-pyran-4-one,2,3-

dihydro-3,5-dihydroxy-6-methyl,

2-etho

xy-4-vinylph

enol,N

,N′

-dim

ethylglycine,lup

-20(29)-en-3-one,

linolenin,1-m

ono-,9-hexadecanoicacid

methylester,linolenicacid

methylester),

phenolic(aminoacids,terpenoids,fatty

acids,methylp

almitoleate)

NM

(i)Increase

inthelevelsof

reactive

oxygen

speciesandsimultaneou

sredu

ctionin

cellu

larantioxidant,

mitocho

ndrialmem

braneloss,D

NA

damage,andG1/Sph

asecellcycle

arrest

[167]

Gallarhois

NM

HCT116,HT-

2912.5,25,50,100,

200μg/mL

Aqu

eous

with

steamingprocess

Gallotann

ins

Increasedcontentsof

gallicacid

andellagic

acid

(i)Indu

cedapop

tosisthroughthe

activation

ofcaspases

3,8,9

(ii)Mod

ulated

activation

ofmitogen

andproteinkinases,p38,andc-Jun

NH2-term

inalkinase

[168]

26 Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Artem

isia

annu

aLinn

éPow

der

HCT116

20,30,40,60,80,

100μg/mL

Ethanolic

Pheno

liccompo

unds

Inhibitedcellviability

andincreasedLD

Hrelease

(i)PTEN/p53/PDK1/Akt

signal

pathwaysthroughPTEN/p53

indu

ceapop

tosis

(ii)Increasedapop

toticbodies,caspase3

and7activation

(iii)

Regulated

cytochromec

translocationto

thecytoplasm

and

Bax

translocationto

the

mitocho

ndrialmem

brane

[169]

Nelum

bonu

cifera

stam

enPow

der

HCT116

100,200,

400μg/mL

Ethanolic

crud

eNM

NM

(i)Increasedthesub-G1po

pulation

,mRNAlevelsof

caspases

3and8,

levelsof

IκBαandcaspase9

(ii)Mod

ulated

theBcl-2

family

mRNA

expression

(iii)

Reduced

themRNAlevelsof

NFκB

[170]

Cornsilk

NM

LoVo,

HCT116

1.25,2.5,5,10,

20μg/mL

Aqu

eous

Proteins,po

lysaccharides,flavon

oid,

vitamins,tann

ins,alkaloids,mineral

salts,steroids

NM

(i)Increase

intheBax,cytochrom

ec,

caspases

3and9levels

[171]

Lycium

barbarum

L.Pow

der

HT-29

1,2,3,4,5μg/mL

NM

Neoxanthin,

all-trans-β-cryptoxanthin,

polysaccharides,caroteno

ids,flavon

oids

NM

(i)Upregulationof

p53andp21

expression

(ii)Dow

nregulationof

theCDK2,

CDK1,cyclin

A,and

cyclin

Bexpression

(iii)

ArrestintheG2/M

phaseofcellcycle

[172]

Chrysobalan

usicacoL.

Freeze-dried

fruit

HT-29

1,2.5,5,10,

20μg/mL

Crude

ethylacetate

Delph

inidin,cyanidin,

petunidin,

and

peon

idin

NM

(i)IncreasedintracellularROS

prod

uction

(ii)Decreased

TNF-α, IL-1β

,IL-6,and

NFκB1expression

s

[173]

Zan

thoxylum

piperitum

De

Cando

lleFruit

Caco-2,

DLD

-1200μg/mL

Aqu

eous

NM

NM

(i)Increasedtheph

osph

orylationof

c-JunN-terminalkinase

(JNK)

[174]

Celtisaetnensis

(Torna

b.)Strobl

(Ulm

aceae)

Twigs

Caco-2

5,50,100,250,or

500μg/mL

Methanolic

Flavon

oidandtriterpeniccompo

unds

NM

(i)Increase

inthelevelsof

ROS

(ii)Decreasein

RSH

levelsand

expression

ofHO-1

[175]

27Oxidative Medicine and Cellular Longevity

Table1:Con

tinu

ed.

Scientificname

Partsused

Cellline

Con

c.Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Rosacanina

Peeland

pulp

Caco-2

62.5,125,250,

500μg/mL

Total

extract

(fraction1),vitam

inC(fraction2),

neutralpolyphenols

(fraction3),and

acidicpolyphenols

(fraction4)

Polypheno

lsDecreased

prod

uction

ofreactive

oxygen

species

(ROS)

NM

[176]

Rhazyastricta

Leaf

HCT116

47,63,79,and

95μg/cm

2Crude

alkaloid

Alkaloids

NM

(i)Dow

nregulated

DNA-binding

and

transcriptionalactivitiesof

NFκ

BandAP-1

proteins

(ii)Increase

inBax,caspases3/7and9,

p53,p21andNrf-2

levels

(iii)

Decreasein

expression

ofERK

MAPK,B

cl-2,cyclin

D1,CDK-4,

survivin,and

VEGF

[177]

Green

coffee

NM

Caco-2

10-1,000

μg/mL

NM

5-Caffeoylqu

inicacid

(5-C

QA),

3,5-dicaffeoylqu

inicacid

(3,5-D

CQA),

ferulic

acid

(FA),caffeicacid

(CA),

dihydrocaffeicacid

(DHCA),

dihydroferulicacid

(DHFA

)

Reduced

viability

ofcancer

cells

NM

[178]

Flourensia

microphylla

Leaf

HT-29

NM

Ethanolic

and

acetone

Pheno

liccompo

unds

NM

(i)Inhibition

ofIL-8

(ii)Activationof

apop

tosisby

the

increm

ento

fthe

Bax/Bcl-2

ratioand

expression

ofTNFfamily

[179]

∗NM:n

otmention

ed.

28 Oxidative Medicine and Cellular Longevity

Table2

(a)Efficacy

ofmedicinalplantson

coloncancer

inin

vivo

mod

els

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Vitisvinifera

Seed

Invivo

(murine)

Caco-2

Invivo:400–

1,000mg/kg

Invitro:

10–25μg/mL

Aqu

eous

Procyanidins

(i)Increasedcrypt

depthand

grow

th-

inhibitory

effects

(ii)Inhibitedcell

viability

(iii)

Significantly

decreasedthe

histological

damagescore

Reduced

MPO

(myeloperoxidase)activity

[180]

Seed

Invivo

HT-29,

SW480

5mg/kg

Aqu

eous

NM

NM

Decreased

VEGF,

TNF,

MMP-1,M

MP-3,M

MP-7,

MMP-8,M

MP-9,and

MMP-13protein

expression

[181]

Skin

Invivo

NM

7.5,30,

60μg/mL

Methanolic

4′-G

eranyloxyferulic

acid

NM

NM

[30]

Seed

Invivo

(murine)

NM

0.12%

w/w

NM

Catechin,

epicatechin

NM

(i)Supp

ressed

proliferation

,sph

ere

form

ation,

nuclear

translocationof

β-catenin

andWnt/β-

cateninsignaling

(ii)Elevatedp53,Bax/Bcl-2

ratio,andcleaved

PARPand

mitocho

ndrial-

mediatedapop

tosis

[31]

Cam

ellia

sinensis

Leaf

Invivo

(murine)

HT-29

Invitro:0,10,

30,50μM

Invivo:1.5mg

perday

Aqu

eous

Catech in,

epigallocatechin

gallate

1.9-fold

increase

intumor

endo

thelial

cellapop

tosis

InhibitedtheERK-1

and

ERK-2

activation

,VEGF

expression

,and

VEGF

prom

oter

[182]

Invivo

(murine)

HCT116

0.5%

NM

NM

Reduced

basement

mem

brane

Inhibition

ofMMP-9

and

VEGFsecretion

[183]

Invivo

(murine)

Caco-2,

HT-29

300μM

Aqu

eous

Theaflavins

(TF-2,TF-3,TF-1)

Indu

cedapop

tosis

ofhu

man

colon

cancer

cells

Inhibition

ofedem

aform

ationcorrelated

toattenu

ationof

COX-2

expression

andprom

oter

analysisrevealed

[36]

29Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

mod

ulationof

NFκB,A

P-

1,CREB,and

/orNF-Il-6

(C/EBP)

Invivo

(murine)

HT115

25μg/mL

Hydroethanolic

Pheno

liccompo

unds

(p-hydroxyph

enyl

ethano

l,pino

resino

l&dihydroxyphenyl

ethano

l)

NM

Inhibition

viaredu

ced

expression

ofarangeof

α5

&β1

[184]

Sasa

quelpaertensis

Leaf

Invivo

HT-29,

HCT116

0,100,200,

300mg/L

Ethanolic

p-Cou

maricacid,tricin

Inhibition

ofcolony

form

ation

(i)Non

adherent

sphere

form

ationsupp

ressed

CD133+

&CD44+

popu

lation

(ii)Dow

nregulated

expression

ofcancer

stem

cellmarkers

[41]

Anoectochilu

sNM

Invivo

CT26

Orald

oseof

50&10

mg/mou

seperday

Aqu

eous

Kinseno

side

Stim

ulated

proliferation

oflymph

oidtissues

Activationof

phagocytosis

ofperitonealmacroph

ages

[185]

Purple-fleshed

potatoes

Fruit

Invivo

Colon

cancer

stem

cells

5.0μg/mL

Ethanol,

methanol,ethyl

acetate

Antho

cyanin,β

-catenin,

cytochromec

Reduction

incolon

CSC

snu

mberand

tumor

incidence

(i)Increase

incytochrome

clevelsfrom

p53status

andmaybe

mitocho

ndria-

mediatedapop

tosis

(ii)Supp

ressed

levelsof

cytoplasmicand

nuclearβ-catenin

[58]

Phaseolus

vulgaris

Leaf

Invivo

HT-29

Nm

Ethanolic

Polysaccharides,

oligosaccharides

Indu

ctionof

apop

tosisand

inhibitproliferation

(i)Inactivation

ofthe

retino

blastoma

phosph

oprotein

(ii)Indu

cedG1arrest

(iii)

Supp

ressionof

NF-jb1

(iv)

Increase

inEGR1

expression

[59]

30 Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Rosmarinus

officina

lisL.

Leaf

Invivo

HT-29

SC-RE

30μg/mLand

CA12.5μg/mL

Ethanolic

Polypheno

ls(carno

sic

acid

(CA)andcarnosol)

(i)Activationof

Nrf2

transcriptionfactor

(ii)Activated

common

regulators,suchas

XBP1(Xbp

1)gene,

SREBF1/SREBF2

(Srebp

1/2),C

EBPA

andNR1I2(Pxr)genes

Leaf

Invivo

(rat)

NM

NM

Ethanolic

Rosmanol

andits

isom

ers,carnosol,

rosm

adial,carnosicacid,

and12-m

etho

xycarnosic

acid,carno

sicacid,

carnosol

Interactions

with

thegutmicrobiota

andby

adirecteffect

oncolono

cyteswith

respectto

theon

set

ofcancer

orits

progression

NM

Wasabia

japonica

Rhizomes

Invivo

COLO

205

5mg/mL

Methanolic

6-(M

ethylsulfinyl)hexyl

isothiocyanate

Anticolon

cancer

prop

erties

through

theindu

ctionof

apop

tosisand

autoph

agy

(i)Activationof

TNF-α,F

as-L,

caspases

(ii)Truncated

Bid

and

cytochromec

(iii)

Decreased

phosph

orylationof

Akt

andMtor

(iv)

Promoted

expression

ofmicrotubu

le-

associated

protein1

light

chain3-IIand

AVO

form

ation

[186]

Zingiberaceae

Rhizome

HT-29

HT-29

5g/kg

Dichlorom

ethanic

Turmeron

eSupp

ressed

the

proliferation

ofHT-

29coloncancercells

(i)LD

Hrelease

(ii)ROSgeneration

(iii)

Collapsein

mitocho

ndrial

mem

branepo

tential

(iv)

Cytochrom

ecleakage

(v)Activationof

caspase9

andcaspase3

[187]

31Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Pana

xqu

inqu

efolius

Root

Invivo

(murine)

NM

30mg/kg

Ethanolic

Ginseno

sides

(protopanaxadiol

orprotop

anaxatriol)

Attenuated

azoxym

ethane/D

SS-

indu

cedcolon

carcinogenesisby

redu

cing

thecolon

tumor

numberand

tumor

load

(i)Reduced

experimental

colitis

(ii)Attenuatedon

AOM/D

SS-ind

uced

coloncarcinogenesis

(iii)

Proinflam

matory

cytokinesactivation

(iv)

Supp

ressed

DSS

(v)Dow

nregulated

inflam

matorycytokine

gene

expression

[188]

Myrtaceae

Leaf

Invivo

(murine)

HCT116

100μg/mL

(invitro)

200

and100μg/disc

(invivo)

Methanolic

Pheno

lics,flavon

oids,

betulin

icacid

Inhibition

oftumor

angiogenesis

(i)Inhibition

ofangiogenesisof

tube

form

ationon

Matrigel

matrixandHUVECS

migration

(invitro)

(ii)Decreased

nutrient

andoxygen

supp

lyand

consequentlytumor

grow

thandtumor

size

(invivo)

(iii)

Increasedextent

oftumor

necrosis

[82]

Spicaprun

ellae

Leaf

Invivo

HT-29

200mg/mL

(invitro),

600mg/mL

(invivo)

Ethanolic

Rosmarinicacid

Indu

ctionof

apop

tosisand

inhibition

ofcell

proliferation

and

tumor

angiogenesis

(i)Indu

cedapop

tosis

(ii)Inhibitedcancer

cell

proliferation

and

angiogenesisST

AT3

phosph

orylation

(iii)

Regulated

expression

ofBcl-2,B

ax,cyclin

D1,CDK4,VEGF-A,

andVEGFR

-2(invivo)

[83]

Gym

naster

koraiensis

Aerialp

art

Invivo

(murine)

NM

500μmol/kg

Ethanolic

Gym

nasterkoreaynesB,

C,E

,2,9,16-

heptadecatrien-4,6-

dyne-8-ol

Anti-inflam

matory

andcancer

preventive

activities

(i)Significant

decrease

inexpression

ofCOX-2

(ii)Increase

inserum

IL-6

[189]

32 Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Allium

fistulosum

Edible

portions

Invivo

(murine)

CT26

50mg/kg

b.w.

Hot

water

p-Cou

maricacid,ferulic

acid,sinapicacid,

quercitrin,isoqu

ercitrin,

quercetol,kaem

pferol

Supp

ressionof

tumor

grow

thand

enhanced

survival

rateof

testmice

(i)Decreased

expression

ofinflam

matory

molecular

markers

(ii)Dow

nregulated

expression

ofMMP-9

andICAM

(iii)

Metaboliteprofi

ling

andcand

idateactive

phytochemical

compo

nents

[190]

Ann

ona

squa

mosaLinn

Leaf

Invivo

(animal)

HCT116

8.98

μg/mL

Crude

ethyl

acetate

Acetogenins

(ann

oreticuin&

isoann

oreticuin)

and

alkaloidsdo

pamine,

salsolinol,and

coclaurine

(i)Inhibitedgrow

thandproliferation

oftumor

cells

Reactiveoxygen

species

(ROS)

form

ation,

lactate

dehydrogenase(LDH)

release,andcaspases

3/7,8,

9activation

[191]

Eupatorium

cann

abinum

Aerialp

arts

Invivo

(murine)

HT-29

25μg/mL

Ethanolic

Pyrrolizidinealkaloids

(senecionine,senkirkine,

mon

ocrotalin

e,echimidine)

Cytotoxicityagainst

coloncancer

cells

(i)Upregulationof

p21

anddo

wnregulationof

NCL,

FOS,and

AURKA,ind

icating

redu

cedproliferation

capacity

(ii)Mitoticdisrup

tion

and

nonapo

ptoticcelldeath

viaup

regulation

ofBcl-xL

[96]

Flacourtia

indica

Aerialp

arts

Invivo

(murine)

HCT116

500μg/mL

Methanolic

Pheno

licglucoside

(flacou

rticin,4

′-benzoylpo

liothrysoside)

Antiproliferative

andproapo

ptotic

effectsin

HCT116

cells

Apo

ptosisviageneration

ofROSandactivation

ofcaspases

(PARP)

[192]

Sorghu

mbicolor

The

derm

allayerof

stalk

Invivo

(murine)

HCT116

&colon

cancer

stem

cells

>16and

103μg/mL

Phenolic,acetone

Apigeninidin&

luteolinidin

Antiproliferative

effect

(i)Targetp53-depend

ent

and

p53-independ

ent

pathways

[97]

33Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Gleditsia

sinensis

Tho

rnIn

vivo

(murine)

HCT116

800μg/mL

Aqu

eous

Flavon

oid,

lupine

acid,

ellagicacid

glycosides

Inhibited

proliferation

ofcoloncancer

(i)Increasedp53levels

(ii)Dow

nregulationof

the

checkp

oint

proteins,

cyclin

B1,Cdc2,and

Cdc25c

[90]

Tho

rnIn

vivo

(murine)

HCT116

600μg/mL

Ethanolic

NM

Inhibitory

effecton

theproliferation

ofhu

man

coloncancer

HCT116cells

(i)CausedG2/M

phasecell

cyclearrest

[91]

Zingiber

officina

leRhizome

Invitro/in

vivo

(murine)

HCT116

5μM

Ethanolic

6-Paradol,6-and

10-dehydrogingerdion

e,6-

and10-gingerdione,

4-,6-,8-,and

10-

gingerdiol,6-

methylgingerdiol,

zingeron

e,6-

hydroxysho

gaol,6-,

8-,10-dehydrosho

gaol,

diarylheptanoids

Inhibitory

effectson

theproliferation

ofhu

man

coloncancer

cells

(i)Arrestof

G0/G1ph

ase

(ii)Reduced

DNA

synthesis

(iii)

Indu

cedapop

tosis

[103]

Cucum

aria

frondosa

The

enzymatically

hydrolyzed

epitheliu

mof

theedible

Invivo

(murine)

HCT116

<150

μg/mL

Hydroalcoholic

Mon

osulph

ated

triterpeno

idglycoside

fron

doside

A,the

disulphatedglycoside

fron

doside

B,the

trisulph

ated

glycoside

fron

doside

C

(i)Inhibition

atS

andG2-M

phase

withadecrease

inCdc25c

(ii)Increase

inp21W

AF1/CIP

(i)Inhibition

thegrow

thof

human

colon

(ii)Apo

ptosisassociated

withH2A

Xph

osph

orylationand

caspase2

[105]

Rolan

dra

fruticosa

Leaf&twigs

Invivo

(murine)

HT-29

10and

5mg/kg/day

Methanolic

Sesquiterpenelacton

e(13-

acetoxyrolandrolide)

Antiproliferative

effectagainst

human

coloncancer

cells

(i)Inhibition

oftheNFκB

pathway,sub

unitp65

(RelA)andup

stream

mediatorsIKKβand

oncogenicK-ras

[106]

Cydonia

oblongaMiller

Leaf&fruit

Invivo

(murine)

Caco-2

250–500μg/mL

Methanolic

Pheno

liccompo

und

(flavon

olandflavon

eheterosides,5-O-

caffeoylqu

inicacid)

Antiproliferative

effectagainst

human

kidn

eyand

coloncancer

cells

(i)Supp

ressionof

NFκ

Bactivation

,activator

(AP-1),mitogen-

activatedprotein

kinases,namely,PKC,

(GFR

)-mediated

pathways

(ii)Cellcyclearrest

(iii)

Indu

ctionof

apop

tosis,

antioxidant,andanti-

inflam

matoryeffects

[107]

34 Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Sedu

mkamtschaticum

Aerialp

art

Invivo

(murine)

HT-29

0–0.5mg/mL

Methanolic

Bud

dlejasapon

inIV

Indu

cedapop

tosis

inHT-29hu

man

coloncancer

cells

(i)Indu

cedapop

tosisvia

mitocho

ndrial-

depend

entpathway

triggeredby

downregulationof

Bcl-2

proteinlevels,caspase

3activation

,and

subsequent

PARP

cleavage

[109]

Gan

oderma

lucidu

mCaps&stalks

Invivo

(murine)

HT-29

0-0.1mg/mL

Triterpeneextract

(hot

water)

extract

Polysaccharides

(mainly

glucans&

glycop

roteins),

triterpenes(ganod

eric

acids,gano

deric

alcoho

ls,and

their

derivatives)

Cytokineexpression

inhibiteddu

ring

earlyinflam

mation

incolorectal

carcinom

a

Indu

cedautoph

agy

throughinhibition

ofp38

mitogen-activated

kinase

andactivation

offarnesyl

proteintransferase(FPT)

[193]

Ginkgobiloba

Fruit&leaf

Invivo

(murine)

HT-29

20–320

mg/L

Aqu

eous

Terpene

lacton

esand

flavon

oidglycosides

Inhibited

progressionof

human

coloncancer

cells

indu

cedHT-29

cellapop

tosis

(i)Activationin

caspase3,

redu

ctionin

Bcl-2

expression

,and

elevationin

p53

expression

[112]

Rub

usoccidentalis

Fruit

Invivo

(murine)

JB6Cl41

25μg/mL

Methanolic

β-C

arotene,α-carotene,

ellagicacid,ferulicacid,

coum

aricacid

Inhibitedtumor

developm

ent

(i)Im

paired

signal

transduction

pathways

leadingto

activation

ofAP-1

andNFB

RU-M

Efraction

[194]

Oryza

sativa

Seed

Invivo

(murine)

HT-29,

SW480,

HCEC

100μg/mL

Ethylacetate

extract

Pheno

liccompo

und

(tricin,

ferulic

acid,

caffeicacid,and

metho

xycinn

amicacid)

Inhibitedgrow

thof

human

coloncancer

cells

(i)Indu

ctionof

apop

tosis

byenhanced

activation

ofcaspases

8and3

(ii)Decreased

thenu

mber

ofviableSW

480and

HCECcells

[113]

Cistanche

deserticola

Dried

stem

Invivo

(murine)

SW480

Invivo:

0.4g/kg/day

Invitro:

100mg/mL

Aqu

eous

Polysaccharides,

phenylethano

idglycosides

Decreased

mucosal

hyperplasiaand

helicobacter

infection

(i)Increasednu

mberof

splenicmacroph

ages

andNKcells

(ii)Decreased

frequencyof

hyperplasiaandH.

hepaticusinfectionof

theintestine

[133]

35Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Rehman

nia

glutinosa

NM

Invivo

(male

C57BL6

miceand

Sprague-

Daw

leyrats)

CT26

28mg/kg

NM

Catalpo

l

(i)Inhibited

proliferation

,grow

th,and

expression

ofangiogenic

markers

(i)VEGF,

VEGFR

2,HIF-

1α,bFG

Finhibitedthe

expression

sof

inflam

matoryfactors

such

asIL-1β,IL-6,and

IL-8

[143]

Oleaeuropaea

Olivemill

wastewater

Invivo

(murine)

NM

NM

Methanolic

Hydroxytyrosol

Interferes

with

tumor

cellgrow

thNM

[195]

Leaf

Invivo

(xenograft

mod

el)

(murine)

HCT116,

HCT8

0,5,10,20,30,

50,and

70μg/mL

Phenolic

Oleurop

einand

hydroxytyrosol

NM

(i)Activationof

caspases

3,7,and9

(ii)Decreaseof

mitocho

ndrial

mem

branepo

tential

andcytochromec

release

(iii)

Increase

inintracellularCa2+

concentration

[196]

Ginkgobiloba

L.Leaf

Invivo

(rat)

NM

0.675and

1.35

g/kg

Methanolic

Flavon

oidglycosides,

terpenelacton

es,and

gink

golic

acids

(i)Supp

ressed

tumor

cell

proliferation

,prom

oted

apop

tosis,and

mitigated

inflam

mation

NM

[197]

Rhu

strilobata

Nutt.

NM

Invivo

(ham

ster)

NM

400mg/kg,

100mg/kg

Aqu

eous

Tannicacid,gallic

acid

Cytotoxicactivity

NM

[54]

Ann

ona

diversifo

liaSaff.

NM

Invivo

(mice)

SW-480

1.5,

7.5mg/kg/day

NM

Laherradurin

Cytotoxicactivity

NM

[54]

A.m

uricataL.

NM

Invivo

(rat)

NM

250/500mg/kg

EtOAc

A,B

,and

C,and

cis-and

trans-anno

muricin-D

-on

esCytotoxicactivity

NM

[54]

Plum

eria

acutifo

liaPo

ir.

NM

Invivo

(ham

ster)

NM

400mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

Lasian

thaea

podocephala

(A.G

ray)

K.M

.Becker

NM

Invivo

(ham

ster)

NM

200mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

36 Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Flourensia

cernua

DC.

NM

Invivo

(ham

ster)

NM

350mg/kg/day

Aqu

eous

Flavon

oids,

sesquiterpenoids,

mon

oterpeno

ids,

acetylenes,p

-acetop

heno

nes,

benzop

yrans,

benzofurans

Cytotoxicactivity

NM

[54]

Ambrosia

ambrosioides

(Cav.)W.W

.Pa

yne

NM

Invivo

(ham

ster)

NM

400mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

Alnus

jorullensis

Kun

thNM

Invivo

(ham

ster)

NM

175mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

Dim

orphocarpa

wislizeni

(Engelm.)

Rollin

s

NM

Invivo

(ham

ster)

NM

100mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

Euphorbia

pulcherrim

aWilld.ex

Klotzsch

NM

Invivo

(ham

ster)

NM

200mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

Acalypha

monostachya

Cav.

NM

Invivo

(ham

ster)

NM

400mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

Crotalaria

longirostrata

Hook.&

Arn.

NM

Invivo

(ham

ster)

NM

400mg/kg/day,

350mg/kg/day

EtOH-CHCl 3

NM

Cytotoxicactivity

NM

[54]

Asterohyptis

stellulata

(Benth.)Ep

ling

NM

Invivo

(ham

ster)

NM

50mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

Acacia

constricta

A.

Gray

NM

Invivo

(ham

ster)

NM

400mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

Holodiscus

dumosus

A.

Heller

NM

Invivo

(ham

ster)

NM

350mg/kg/day

Aqu

eous

NM

Cytotoxicactivity

NM

[54]

Butea

monosperm

aFlow

erIn

vivo

(rat)

HT-29

150mg/kg

n-Butan

olextract

Isocoreopsin,butrin,and

isobutrin

Free

radical

scavenging

and

anticancer

activities

NM

[198]

37Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientificname

Partsused

Mod

elDose

Typeof

extract

Impo

rtantcompo

unds

Cellulareffect

Mechanism

sReferences

Taraxacum

spp.

Root

Invivo

(xenograft

murine

mod

el)

HT-29,

HCT116

40mg/kg/day

Aqu

eous

α-A

myrin,β

-amyrin,

lupeol,and

taraxasterol

Indu

ced

programmed

cell

death

NM

[199]

∗NM:n

otmention

ed.

(b)Other

effectsof

medicinalplantsin

invivo

mod

els

Scientific

name

Parts

used

Mod

elDose

Typeof

extract

Impo

rtant

compo

unds

Cellulareffect

Mechanism

sReferences

Allium

sativum

Root

Invivo

(murine)

NM

2.4mLof

daily

Ethanolic

Allicin,

S-allylm

ercaptocysteine

Significantlysupp

ressed

both

thesize

andnu

mber

ofcolonadenom

as

Enh

ancementof

detoxifying

enzymes:SACandGST

activity

[200]

Oleaeuropaea

Fruit

Invivo

Caco-2

50μM

Aqu

eous

Pheno

liccompo

unds,

authentichydroxyl

tyrosol(HT)

(i)Effectof

OPEandHT

onCB1associated

withredu

ced

proliferation

ofCaco-2

cells

(ii)Increase

inCB1

expression

inthe

colonof

ratsreceiving

dietaryEVOO

Increase

inCnr1gene

expression

,CB1proteinlevels

[201]

Invivo

(murine)

HT115

25μg/mL

Hydroethanolic

Pheno

liccompo

unds

(p-hydroxyph

enyl

ethano

l,pino

resino

l&dihydroxyphenyl

ethano

l)

NM

Inhibition

viaredu

cedexpression

ofa

rangeof

α5&β1

[184]

Origanu

mvulgareL.

Leaf

Invivo

(murine)

NM

20,40,

60mg·k

g−1

Aqu

eous

Rosmarinicacid,

caffeicacid,

flavon

oids

Antioxidant

status

(i)IncreasedLP

Oprod

uctsand

activityofSO

DandCATenzymes

andGST

andGPxactivity

(ii)Antioxidant

andanticarcinogenic

effect

[202]

Hazelnu

tSkin

Invivo

NM

The

flow

rate

0.21

mL/min

andinjection

volume9.4μL

Aqu

eous

Flavan-3-ols,in

mon

omericand

polymericform

s,and

phenolicacids

(i)Decreased

circulating

levelsoffree

fattyacids

andtriglycerides

(ii)Higherexcretionof

bileacid

Increase

ofthetotalantioxidant

capacity

ofplasma

[203]

Applesan

dapplejuice

Fruit

Invivo

NM

90mg/L

Aqu

eous

Pheno

licacids,

flavon

oids,tannins,

stilb

enes,

curcum

inoids

NM

NM

[204]

38 Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientific

name

Parts

used

Mod

elDose

Typeof

extract

Impo

rtant

compo

unds

Cellulareffect

Mechanism

sReferences

Grifola

frondosa

Fruit

Invivo

(murine)

HT-29

10ng/m

LAqu

eous

Pheno

liccompo

unds

(pyrogallol,caffeic

acid,m

yricetin,

protocatechu

icacid,

etc.)

Inhibition

ofTNBS-

indu

cedratcolitis

(i)Indu

cedcellcycleprogressionin

G0/G1ph

aseandapop

toticdeath

[104]

Ruta

chalepensis

Leaf

Invivo

(hum

an)

NM

250μg/mL

Ethanolic

Rutin,gallic

acid,

catechin

hydrate,

naringin

Oxidative

profi

lein

patientswithcoloncancer

NM

[205]

Can

nabis

sativa

Dry

flow

er&leaf

Invivo

(murine)

DLD

-1and

HCT116

0.3–5μM

Methanolic

Cannabidiol,

phytocannabino

ids

NM

(i)Reduced

cellproliferation

ina

CB1-sensitiveandAOM-ind

uced

preneoplasticlesion

sandpo

lyps

(ii)Inhibition

ofcolorectalcancer

cell

proliferation

viaCB1and

CB2

receptor

activation

[121]

Melia

toosendan

Fruit

Invivo

(murine)

SW480,

CT26

0,10,20,30,40,

50μg/mL

Ethanolic

Triterpenoids,

flavon

oids,

polysaccharide,

limon

oids

NM

(i)Inhibitedcellproliferation

ofSW

480andCT26

byprom

oting

apop

tosisas

indicatedby

nuclear

chromatin

cond

ensation

and

DNAfragmentation

(ii)Indu

cedcaspase9activity

which

furtheractivatedcaspase3and

poly(A

DP-ribose)

polymerase

cleavage,leading

thetumor

cells

toapop

tosis

[123]

Smallanthu

ssonchifoliu

sRoot

Invivo

(murine)

NM

73.90,150.74,

147.65,and

123.26

mg/kg

Aqu

eous

Fructans

NM

Reduction

incidenceof

colontumors

expressing

alteredβ-catenin

[206]

Punica

gran

atum

Peel

Invivo

(adu

ltmale

Wistar

rats)

NM

4.5g/kg

Methanolic

Gallic

acid,

protocatechu

icacid,

cateachin,

rutin,

ellagicacid,

punicalagin

NM

(i)Reduction

inTGF-β,B

cl-2,E

GF,

CEA,C

CSA

-4,M

MP-7

andin

COX-2,cyclin

D1,survivin

content

(ii)Dow

nregulated

expression

ofβ-catenin,K

-ras,c-M

ycgenes

[207]

Linu

musitatissimum

Seed

Invivo

(male

Sprague-

Daw

ley

rats)

NM

500mg/kg

Alkaline

Secoisolariciresinol

diglucoside,

carboh

ydrates,

proteins,and

tann

ins

Reduced

theserum

fasting

glucoselevels

Significantlyredu

cedtheHbA

1c,

insulin

levels,and

proinfl

ammatory

cytokines

[208]

Diospyros

kaki

Fruit

Invivo

(male

NM

15mg/kg

Hydroacetone

Polypheno

l(i)D

ecreased

attenu

ation

ofcolonlength

inDecreased

expression

ofCOX-2

and

iNOSin

thecolonictissue

[147]

39Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientific

name

Parts

used

Mod

elDose

Typeof

extract

Impo

rtant

compo

unds

Cellulareffect

Mechanism

sReferences

CD-1

mice)

diarrhea

severity

(ii)Reduced

mortality

rate

(iii)

Reduction

ofthe

extent

ofvisibleinjury

(ulcer

form

ation)

and

ofmucosal

hemorrhage

Mun

tingia

calabu

raLeaf

Invivo

(rat)

NM

50,250,

500mg/kg

Methanolic

Rutin,gallic

acid,

ferulic

acid,and

pino

cembrin

Reduction

ofthecolonic

oxidativestress,increasing

theantioxidantslevels

possiblyviathesynergistic

action

ofseveral

flavon

oids

NM

[209]

Portulaca

oleracea

NM

Invivo

(murine)

HT-29

CSC

s2.25

μg/mL

Alcoholic

NM

Regulatoryandtarget

genesthat

mediatethe

Notch

signaltransduction

pathway

Inhibition

ofexpression

ofthe

Notch1andβ-catenin

genes

[161]

Aloevera

Gel

Invivo

(murine)

NM

400mg/kg/day

Gel

Polysaccharides

NM

(i)Viainhibition

ofthecellcycle

progression

(ii)Indu

ctionof

cellu

larfactors,such

asextracellularsignal-regulated

kinases1/2,cyclin-dependent

kinase

4,andcyclin

D1;on

the

otherhand

,PAGincreasedthe

expression

ofcaud

al-related

homeoboxtranscriptionfactor

2

[210]

Artem

isia

annu

aLinn

éPow

der

Invivo

(xenograft

murine

mod

el)

HCT116

20,

40mg/kg/day

Ethanolic

Pheno

liccompo

unds

NM

(i)Indu

cedapop

tosisvia

PTEN/p53/PDK1/Akt

signal

pathwaysthroughPTEN/p53

(ii)Inhibitedcellviability

and

increasedLD

Hreleaseand

apop

toticbodies,caspase

3and7

activation

,and

redu

ced

mitocho

ndriamem

brane

potential

(iii)

Regulated

cytochromec

translocationto

thecytoplasm

andBax

translocationto

the

mitocho

ndrialmem

brane

(iv)

Regulationof

proteins

[169]

40 Oxidative Medicine and Cellular Longevity

Table2:Con

tinu

ed.

Scientific

name

Parts

used

Mod

elDose

Typeof

extract

Impo

rtant

compo

unds

Cellulareffect

Mechanism

sReferences

Hordeum

vulgare

Pow

der

Invivo

(xenograft

murine

mod

el)

HT-29

2g/kg

and

1g/kg

Aqu

eous

(fermented)

β-G

lucan,

protein,

aminoacids,ph

enolic

compo

unds

NM

(i)Promoted

tumor

apop

tosisby

upregulating

themRNA

expression

ofBax

andcaspase3

anddo

wnregulatingthemRNA

expression

ofBcl-2

andcyclin

D1

(ii)Decreased

mRNAexpression

ofBcl-2

andcyclin

D1

(iii)

Upregulated

expression

slevelsof

Bax

andcaspase3

[211]

Dendrophthoe

pentan

dra

Leaf

Invivo

(murine)

NM

125,250,

500mg/kg

Ethanolic

Quercetin-3-

rham

nose

NM

(i)Decreased

thelevelsof

IL-22,

MPO

levels,p

roliferationof

epithelialcells

(ii)InhibitedSph

aseof

thecellcycle

(iii)

Upregulated

p53wild

-typegene

expression

[212]

Aqu

ilaria

crassna

Stem

,bark

Invivo

(murine)

HCT116

2,000mg/kg/day

100,200mg/kg

NM

Resin

andessential

oils

NM

NM

[213]

Berberis

integerrim

aNM

Invivo

(murine)

NM

50and

100mg/kg

Hydroalcoholic

NM

NM

NM

[214]

Salix

aegyptiaca

Bark

Invivo

(murine)

NM

100and

400mg/kg

Ethanolic

Catechin,

catechol,

andsalicin

NM

Decreased

levelo

fEGFR

,nuclear

β-catenin,and

COX-2

[215]

41Oxidative Medicine and Cellular Longevity

alkaloids, glycosides, and phenols, such as quercetin andluteolin, and kaempferol and luteolin glycosides.

In a systematic review of the plants being studied,some mechanisms were mainly common, including theinduction of apoptosis by means of an increase of expressionand levels of caspase 2, caspase 3, caspase 7, caspase 8, andcaspase 9 in cancer cells, increasing the expression of theproapoptotic protein Bax and decreasing the expression ofthe antiapoptotic proteins.

Many herbal extracts block specific phase of the cell cycle.For instance, the extract prepared from the leaves of Annonamuricata inhibits the proliferation of colon cancer cells andinduces apoptosis by arresting cells in the G1 phase [53].

They can also prevent the progress of the G1/S phase in can-cer cells [74]. In general, the herbal extracts reported herehave been able to stop cancer cells at various stages, such asG2/M, G1/S, S phase, G0/G1, and G1 phase, and couldprevent their proliferation and growth.

Other important anticancer mechanisms are the increaseof both p53 protein levels and transcription of its gene. Eventhe increase of p21 expression is not without effect [137]. Inan in vitro study on the Garcinia mangostana roots, theresults were indicative of the inhibitory effect of the extractof this plant on p50 and P65 activation [93]. Moreover,reduction of cyclin D1 levels and increase of p21 levels areamong these mechanisms [137], as well as inhibition of NFκB

Cellular damage(cancer)

Enhancement

ASC

Increasing p53 protein in the cell nucleus

p53

Increased expression of CIP1 and WAF1genes

Increasing the expression of pre-apoptoticproteins and simultaneously reducing the

expression of anti-apoptotic proteins

Induction of mitochondrialpermeability

Increased protein levels of p21 andrelated RNAs

Inhibition of Cdc2 andCdk2

Cyt C

Release of cytochrome C

Activation of Apaf-1

Junction of pro-caspase 9 to Apaf-1

Activation of caspase 9

Activating caspase 3 and 7

Activation of endonuclease

Effective medicinal plants inthe treatment of colon cancer through the

effect of increasing p53 protein

Apoptosis

Inhibition of cell entryto S phase

S phase(DNA synthesis)

Cells thatcease

division

G1(gap 1)

G2(gap 2)

M(mitosis)

Figure 1: Cell damage and cancer trigger p53 activation. The p53 protein activates the apoptotic protein Bax. Bax inhibits the antiapoptoticprotein Bcl-2. During apoptosis, cytochrome c is released from mitochondria. To activate the Apaf-1 protein, the interaction between theseproteins and cytochrome C is necessary. Pro-caspase 9 attaches to Apaf-1 and activates caspase 9. Caspase 9 activates caspases 3 and 7 andapoptosis occurs.

42 Oxidative Medicine and Cellular Longevity

and reduction of the transcription of its genes, which contrib-ute to reduce the number of cancerous cells [127]. Otherimportant anticancer mechanisms are the inhibition ofCOX-2, as well as the reduction of the protein levels inthis pathway [34]. In addition to this, in some cases,the inhibition of MMP-9 can be mentioned as the signif-icant mechanism of some herbal extracts to kill cancercells [183].

4. Conclusion and Perspectives

The findings of this review indicate that medicinal plantscontaining various phytochemicals, such as flavonoids, poly-phenol compounds, such as caffeic acid, catechins, saponins,polysaccharides, triterpenoids, alkaloids, glycosides, andphenols, such as quercetin and luteolin, and kaempferoland luteolin glycosides, can inhibit tumor cell proliferationand also intduce apoptosis.

Plants and their main compounds affect transcriptionand cell cycle via different mechanisms. Among these path-ways, we can point to induction of superoxide dismutase toeliminate free radicals, reduction of DNA oxidation, induc-tion of apoptosis by inducing a cell cycle arrest in S phase,reduction of PI3K, P-Akt protein, and MMP expression,reduction of antiapoptotic Bcl-2, Bcl-xL proteins, anddecrease of proliferating cell nuclear antigen (PCNA), cyclinA, cyclin D1, cyclin B1, and cyclin E. Plant compounds alsoincrease the expression of both cell cycle inhibitors, such asp53, p21, and p27, and BAD, Bax, caspase 3, caspase 7,caspase 8, and caspase 9 proteins levels. In general, this studyshowed that medicinal plants are potentially able to inhibitgrowth and proliferation of colon cancer cells. But the clinicalusage of these results requires more studies on these com-pounds in in vivo models. Despite many studies’ in vivomodels, rarely clinical trials were observed among the stud-ies. In fact, purification of herbal compounds and demon-stration of their efficacy in appropriate in vivo models, aswell as clinical studies, may lead to alternative and effectiveways of controlling and treating colon cancer.

Conflicts of Interest

There is no conflict of interest regarding the publication ofthis paper.

Authors’ Contributions

Dr. Paola Aiello and Maedeh Sharghi contributed equallyto this work. Shabnam Malekpour Mansourkhani and AzamPourabbasi Ardekan contributed equally to this work.

Acknowledgments

The authors appreciate and thank Dr. MoahammadFirouzbakht for his cooperation in draft editing.

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