Review Article Antitumor Activity of Monoterpenes Found in Essential...

Review ArticleAntitumor Activity of Monoterpenes Found in Essential Oils

Marianna Vieira Sobral,1,2 Aline Lira Xavier,2

Tamires Cardoso Lima,3 and Damião Pergentino de Sousa1,2,3

1 Departamento de Ciencias Farmaceuticas, Universidade Federal da Paraıba, 58051-970 Joao Pessoa, PB, Brazil2 Programa de Pos-Graduacao em Produtos Naturais e Sinteticos Bioativos, Universidade Federal da Paraıba,Caixa Postal 5009, 58015-970 Joao Pessoa, PB, Brazil

3 Departamento de Farmacia, Universidade Federal de Sergipe, 49100-000 Sao Cristovao, SE, Brazil

Correspondence should be addressed to Damiao Pergentino de Sousa; damiao [email protected]

Received 11 April 2014; Revised 16 June 2014; Accepted 17 June 2014; Published 14 October 2014

Academic Editor: Chantal Pichon

Copyright © 2014 Marianna Vieira Sobral et al.This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Cancer is a complex genetic disease that is a major public health problem worldwide, accounting for about 7 million deaths eachyear. Many anticancer drugs currently used clinically have been isolated from plant species or are based on such substances.Accumulating data has revealed anticancer activity in plant-derived monoterpenes. In this review the antitumor activity of 37monoterpenes found in essential oils is discussed. Chemical structures, experimental models, and mechanisms of action forbioactive substances are presented.

1. Introduction

Cancer is a complex genetic disease that comprises specifichallmarks. They include sustaining proliferative signaling,evading growth suppressors, resisting cell death, enablingreplicative immortality, inducing angiogenesis, and activat-ing invasion and metastasis, apart from reprogramming ofenergy metabolism and evading immune destruction [1].According to the World Health Organization (WHO), theoverall impact of cancer has increased by more than thedouble in the last 30 years. It is estimated that in 2008 therewere roughly 12 million new cancer cases and seven milliondeaths worldwide. Future projections indicate that cancermortality will continue to rise, reaching 11.4 million in 2030[2]. The study of natural products has been the single mostsuccessful strategy for the discovery of new medicines usedin anticancer therapy, and more than two thirds of the drugsused in cancer treatment come directly fromnatural productsor are developed using knowledge gained from the activity oftheir ingredients [3, 4].

In these recent years, a large number of studies havedocumented the efficacy of essential oils and their chemical

constituents as source of new bioactive natural products[5], including against cancer [6, 7]. For example, Piaru andcollaborators [8] investigated the cytotoxicity of the essentialoils from Myristica fragrans and Morinda citrifolia. Theresults showed that the M. fragrans essential oil exhibitedgreater cytotoxic activity than the M. citrifolia oil, possiblydue to the presence of some potential anticancer substancessuch as limonene, terpinen-4-ol, eugenol, and myristicin.In another study, Ferraz and collaborators [9] revealedthe cytotoxic effect of leaf essential oil of Lippia gracilisSchauer and its constituents (thymol, p-cymene, 𝛾-terpinene,and myrcene). Interestingly, Maggi and collaborators [10]investigated the antiproliferative activity of essential oil fromVepris macrophylla.This oil demonstrated a strong cytotoxiceffect, which may be attributed by the presence of specificcomponents such as the monoterpenes citral, citronellol,and myrcene. Furthermore, Nikolic and collaborators [11]investigated the antitumor activity of Thymus serpyllum, T.algeriensis, and T. vulgaris essential oils on growth of fourhuman tumor cells. The specie T. serpyllum was the mostpotent in all tested cell lines and contains thymol as its majorconstituent, a phenolic compound known in the literature

Hindawi Publishing Corporatione Scientific World JournalVolume 2014, Article ID 953451, 35 pageshttp://dx.doi.org/10.1155/2014/953451

2 The Scientific World Journal

for its antiproliterative activity [12]. Therefore, the essentialoils and chemical constituents are natural products with highpharmacological potential against various types of tumors.

Cancer is a major cause of death worldwide, rankedbehind only cardiovascular disease. Considering that monot-erpenes are common in many plant species and are usedin cosmetic and pharmaceutical preparations, as well as thefood industry, it is important to review the pharmacologicalpotential of monoterpenes with anticancer activity.

The present study was carried out based on the literaturereview of monoterpenes from essential oils with antitu-mor activity. Chemical structures and names of bioactivecompounds are provided. The monoterpenes presented inthis review were selected with reference to effects shownin specific experimental models for evaluation of antitumoractivity and/or by complementary studies aimed to elucidatemechanisms of action Table 1. The selection of essential oilsconstituents in the database was related to various terms,including essential oils andmonoterpenes as well as names ofrepresentative compounds of these chemical groups refiningwith antitumor activity, cytotoxic activity, and cytotoxicity.The searchwas performed in the scientific literature databasesand Chemical Abstracts in September 2013.

1.1. Linalyl Acetate, Alpha-Terpineol, and Camphor. Linalylacetate, alpha-terpineol, and camphor in association linalylacetate, alpha-terpineol, and camphor caused inhibition ofthe growth of the human colon cancer cell lines (HCT-116p53+/+ and p53−/−) and were inactive on FHs74Int normalhuman intestinal cell lines [13]. Alpha-terpineol showedsignificant cytotoxicity against Hep G2, a hepatocellularcarcinomic human cell line; HeLa, an epithelioid carcinomiccell line; MOLT-4, a human lymphoblastic leukemia T cellline; K-562, a human chronicmyelogenous leukemia cell line;andCTVR-1, an early B cell line from the bonemarrow cells ofa patient with acute myeloid leukemia [14]. Different officinalplants of Lebanon, among them Satureja montana, haveshown cytotoxic activity against human erythroleukemicK562 cells. Its major constituent was the alpha-terpineolwhich demonstrated important cytotoxicity on the samecell line. Yet, this essential oil and alpha-terpineol inducederythroid differentiation of K562 cells [15]. Hassan andcollaborators [16] suggested that alpha-terpineol inhibits thegrowth of tumor cells through a mechanism that involvesinhibition of the NF-𝜅B pathway.

1.2. Alloocimene. Okamura and collaborators [17] evaluatedthe cytotoxicity of 12 monoterpenes. The acyclic monoter-pene alloocimene showed significant cytotoxic activity; its50% inhibitory concentration (IC

50) was the highest of 12, for

mouse P388 leukemia cell among others.

1.3. Menthol. Menthol was cytotoxic for murine leukemiaWEHI-3 cells in a concentration-dependent manner. Thein vivo activity on WEHI-3 cells was also examined [18].In SNU-5 cells, menthol induced cytotoxicity by inhibit-ing the expression of topoisomerases I, II alpha, and IIbeta and promoting the expression of NF-𝜅B [19]. This

compound also enhances the antiproliferative activity of1𝛼,25-dihydroxyvitamin D3 in LNCaP cells [20]. Wang andcollaborators [21] showed that menthol inhibited the prolif-eration and motility of prostate cancer DU145 cells. Li andcollaborators [22] demonstrated that menthol induced celldeath via the TRPM8 channel in a human bladder cancer cellline. Okamoto and collaborators [23] also studied the role ofmenthol in the blockade of TRPM8 activity and found that itreduced the invasion potential of oral squamous carcinomacell lines.

1.4. Beta-Dolabrin. Beta-dolabrin presented in vitro cyto-toxic effects against Ehrlich’s ascites carcinoma andKATO-IIIhuman stomach cancer cell line [24].

1.5. Alpha- and Gamma-Thujaplicin. Alpha-thujaplicin in-hibited cell growth of Ehrlich’s ascites carcinoma andKATO-III human stomach cancer [25]. Gama-thujaplicinalso showed strong cytotoxic effects against KATO-III andEhrlich’s ascites carcinoma at 0.32𝜇m/mL, with 85% and 91%inhibition of cell growth, respectively [24].

1.6. Borneol. The cytotoxicity of borneol and its DNA-damaging effectswere studied inmalignantHepG2hepatomacells,malignantCaco-2 colon cells, andnonmalignant humanVH10 fibroblasts. Borneol showed cytotoxicity in all cell linesand did not cause DNA strand breaks at the concentrationsstudied. With respect to DNA-protective effects, borneolprotectedHepG2 andVH10 cells, but notCaco-2 cells, againstH2O2-induced DNA damage [26]. Su and collaborators

[27] demonstrated that borneol potentiates selenocystine-induced apoptosis in human hepatocellular carcinoma cellsby enhancement of cellular uptake and activation of ROS-mediated DNA damage.

1.7. Ascaridole. Ascaridole exerts cytotoxic activity againstdifferent tumor cell lines (CCRF-CEM, HL60, and MDA-MB-231) [28]. Bezerra and collaborators [29] investigatedthe cytotoxicity and antitumor activity of ascaridole and inHL-60 and HCT-8 cells lines found IC

50values of 6.3 and

18.4 𝜇g/mL, respectively. Results from in vivo studies usingsarcoma 180 as a tumor model demonstrated inhibition ratesof 33.9% at 10mg/kg and 33.3% at 20mg/kg.

1.8. Carvacrol. Carvacrol produced significant cytotoxicactivity against mouse leukemia P388 [30] and Hep-2 [31].Horvathova and collaborators [32, 33] found that carvacrolexerted cytotoxic effects in K562, HepG2, and colonic Caco-2 cells and significantly reduced the level of DNA damageinduced in these cells by the strong oxidant H

2O2. The

cytotoxic and DNA-protective effects of carvacrol were alsodemonstrated by Slamenova and collaborators [34]. Car-vacrol displays cytotoxicity against B16-F10 melanoma cellsand this cytotoxicity is reduced by the addition of vitamin Cand vitamin E. In the P815 mastocytoma cell line, carvacrolshowed a dose-dependent cytotoxic effect, but when testedon normal human peripheral blood mononuclear cells, itshowed a proliferative effect rather than a cytotoxic one [31].

The Scientific World Journal 3Ta

ble1:Essentialoils

mon

oterpenesw

ithantitum

oractiv

ity.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism

Animal/celllinetested

IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

OCO

Lina

lyl a

ceta

te

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

Hum

ancoloncancer

celllin

esHCT

-116

(p53+/+)

10–30%∗,a

[13]

Hum

ancoloncancer

celllin

esHCT

-116

(p53−/−)

10–30%∗,a

O

Cam

phor

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

Hum

ancoloncancer

celllin

esHCT

-116

(p53+/+)

10–30%∗,a

[13]

Hum

ancoloncancer

celllin

esHCT

-116

(p53−/−)

10–30%∗,a

OH

𝛼-T

erpi

neol

HepG2(hepatocellularc

arcino

michu

man

celllin

e)ND

HeLa(

epith

elioid

carcinom

iccelllin

e)ND

Activ

e(ND)

MOLT

-4(hum

anlymph

oblasticleuk

emiaT-celllin

e)ND

[14]

K-562(hum

anchronicm

yelogeno

usleuk

emiacelllin

e)ND

CTVR-1(early

B-celllin

efrom

theb

onem

arrowcells

ofap

atient

with

acutem

yeloid

leuk

emia)

ND

OH

𝛼-T

erpi

neol

Activ

e(ND)

K-562(hum

anchronicm

yelogeno

usleuk

emiacelllin

e)56.15𝜇g/mL

[15]

Activ

e(inhibitio

nof

theN

F-𝜅Bpathway)

Smallcelllun

gcarcinom

a0.26

mM

[16]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

Allo

ocim

ene

Activ

e(ND)

Mou

seP3

88leuk

emiacell

34–54𝜇

g/mL∗

[17]

Men

thol

OH

Activ

e(decrease

ofMac-3

andCD

11bmarkersof

macroph

ages

andgranulocytes

precursors)

MurineleukemiaWEH

I-3cells

(invitro

)MurineleukemiaWEH

I-3cells

(invivo)

ND

1or10m

g/kg

[18]

Activ

e(inhibitio

ngene

expressio

nof

topo

isomerases

I,IIalph

a,andIIbetaandprom

otingtheg

enee

xpression

ofNF-𝜅B)

SNU-5

(hum

angastric

carcinom

acellline)

1.62m

g/mL

[19]

Men

thol

OH

Activ

e(combinedwith

1𝛼,25-dihydroxyvitamin

D3)

LNCa

P(hum

anprostatecarcinom

acellline)

ND

[20]

Activ

e(TR

PM8channelactivation;

cellcycle

arrest)

DU145(hum

anprostatecarcinom

acellline)

53.41–90.66%∗,a

[21]

Activ

e(mito

chon

drialm

embraned

epolarizationvia

theT

RPM8channel)

T24(H

uman

bladderc

ancerc

ellline)

ND

[22]

Activ

e(agon

istof

TRPM

8)Oralsqu

amou

scarcino

mac

elllines

(HSC

3andHSC

4)ND

[23]

O

OH

𝛽-D

olab

rin

Activ

e(ND)

KATO

-III(hum

ansto

machcancer

celllin

e)67%

b[24]

Ehrlich’sascitesc

arcino

ma

75%

b

The Scientific World Journal 5

Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

O

OH

𝛼-Th

ujap

licin

Activ

e(ND)

KATO

-III(hum

ansto

machcancer

celllin

e)86%

b

[25]

Ehrlich’sascitesc

arcino

ma

87%

b

OO

H

𝛾-Th

ujap

licin

Activ

e(ND)

KATO

-III(hum

ansto

machcancer

celllin

e)85%

b

[24]

Ehrlich’sascitesc

arcino

ma

91%

b

Born

eol

OH

Activ

e(ND)


arcino

michu

man

celllin

e)2750𝜇M

[26]

Caco-2

(colon

malignant

celllin

e)2250𝜇M

Activ

e(po

tentiatessele

nocystine-indu

cedapop

tosis

andactiv

ationof

ROS-mediatedDNAdamage)


arcino

michu

man

celllin

e)ND

[27]

OO

Asc

arid

ole

CCRF

-CEM

(hum

anTcelllymph

oblast-

likec

ellline)

ND

Activ

e(ND)

HL6

0(acuteprom

yelocytic

cancer

celllin

e)ND

[28]

MDA-

MB-231(Hum

anmetastatic

breastcancer

cell

line)

ND

Activ

e(ND)

HL-60

(acuteprom

yelocytic

cancer

celllin

e)6.3𝜇

g/mL

[29]

HCT

-8(ileocecalcolorectaladeno

carcinom

a)18.4𝜇g/mL

6 The Scientific World JournalTa

ble1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

OO

Asc

arid

ole

Activ

e(ND)

Sarcom

a180

(invivo)

10or

20mg/kg

[29]

Carv

acro

lOH

Activ

e(ND)

Mou

seleuk

emiaP3

88celllin

eND

[30]

P815

(mastocytomac

ellline)

<0.00

4%v/v

[31]

P815

(mastocytomac

ellline)

1.2%v/v⋅

10−2

[39]

K-562(hum

anchronicm

yelogeno

usleuk

emia)

1.2%v/v⋅

10−2

[39]

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

CEM

(acuteTlymph

oblasticleuk

emia)

1.2%v/v⋅

10−2

[39]

MCF

-7(hum

anbreastadenocarcino

ma)

2.5%

v/v⋅

10−2

[39]

MCF

-7gem

(hum


mar

esistant

togemcitabine)

0.85%v/v⋅

10−2

[39]

P815

(mastocytomac

ellline)

0.067𝜇

M[46]

K-562(hum

anchronicm

yelogeno

usleuk

emia)

0.067𝜇

M[46]

Carv

acro

lOH

CEM

(acuteTlymph

oblasticleuk

emia)

0.04

2𝜇M

[46]

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis

)MCF

-7(hum


ma)

0.125𝜇

M[46]

MCF

-7gem

(hum


mar

esistant

togemcitabine)

0.067𝜇

M[46]

Activ

e(indu

ctionof

apop

tosis

)Hep2(la

rynx

epidermoidcarcinom

a)0.22–0

.32mM∗

[35]

Activ

e(indu

ctionof

apop

tosis)


arcino

michu

man

celllin

e)0.4m

mol/L

[36]

Activ

e(indu

ctionof

apop

tosis)

MDA-

MB231(hu

man

metastatic

breastcancer

celllin

e)100𝜇

M[37]


arcino

michu

man

celllin

e)ND

[32]

Activ

e(antio

xidant

activ

ity)

Caco-2

(colon

malignant

celllin

e)ND

[32]

K562

(erythromyeloblastoid

leuk

emiacelllin

e)150–

200𝜇

M[33]

Activ

e(ND)


arcino

michu

man

celllin

e)350𝜇

M[34]

Caco-2

(colon

malignant

celllin

e)60

0𝜇M

Carv

acro

lOH

Activ

e(Inhibitio

nof

DNAsynthesis

)Lu

ngtumorsind

uced

by1 D

MBA

inrats

0.1m

g/kg

[43]

Myoblastcells

60𝜇g/mL

[40]

Activ

e(preventio

nof

hepatocellu

larc

arcino

genesis)

DEN

-indu

cedhepatocellu

larc

arcino

genesis

15mg/kg

[38]

Activ

e(ND)


arcino

michu

man

celllin

e)53.09𝜇

g/mL

[42]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

OH

OH

HO

p-M

enth

a-1

,3,5

-trie

ne-

2,3

,6-tr

iol

Activ

e(ND)

Mou

seleuk

emiaP3

88celllin

e1.1𝜇g/mL

[44]

𝛾-T

erpi

nene

Activ

e(ND)

Mou

seleuk

emiaP3

88celllin

eND

[30]


arcino

michu

man)

>25𝜇g/mL

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

K562


leuk

emiacelllin

e)ND

[9]

B16-F10(m

elanom

a)9.2

8𝜇g/mL

Thym

ol

OH

Activ

e(ND)

Hep-2

(larynx

epidermoidcarcinom

a)0.71–0

.78m

M∗

[35]

Activ

e(ND)


arcino

michu

man

celllin

e)40

0𝜇M

[34]

Caco-2

(colon

malignant

celllin

e)700𝜇

MAc

tive(ND)

Mou

seleuk

emiaP3

88celllin

eND

[30]

Activ

e(ND)

Mou

seleuk

emiaP3

88celllin

e0.80𝜇g/mL

[44]

P815

(mastocytomac

ellline)

0.015%

v/v

[31]

P815

(mastocytomac

ellline)

3.1%

v/v⋅

10−2

[39]

K-562(hum

anchronicm

yelogeno

usleuk

emia)

>22%v/v⋅

10−2

[39]

Activ

e(cellcycle

arrestandapop

tosis)

CEM

(acuteTlymph

oblasticleuk

emia)

6.9%

v/v⋅

10−2

[39]

MCF

-7(hum


ma)

>22%v/v⋅

10−2

[39]

MCF

-7gem

(hum


mar

esistant

togemcitabine)

>22%v/v⋅

10−2

[39]

P815

(mastocytomac

ellline)

0.15𝜇M

[46]

K-562(hum

anchronicm

yelogeno

usleuk

emia)

0.44𝜇M

[46]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

Thym

ol

OH

CEM

(acuteTlymph

oblasticleuk

emia)

0.31𝜇M

[46]

Activ

e(cellcycle

arrestandapop

tosis)

MCF

-7(hum


ma)

0.48𝜇M

[46]

MCF

-7gem

(hum


mar

esistant

togemcitabine)

ND

[46]


arcino

michu

man

celllin

e)ND

[32]

Activ

e(antio

xidant

activ

ity)

Caco-2

(colon

malignant

celllin

e)ND

[32]

K562


leuk

emiacelllin

e)40

0–500𝜇

M[33]

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

HL-60

(acuteprom

yelocytic

cancer

celllin

e)ND

[12]

Activ

e(ND)


arcino

michu

man

celllin

e)60.01𝜇

g/mL

[42]

Thym

ohyd

roqu

inon

e

OH

HO

SCCVII(squ

amou

scellcarcino

ma)

87%

c

Activ

e(ND)

Fibrosarcoma(

FsaR

)celllines

(invitro

)92%

c[47]

Fibrosarcoma(

FsaR

)celllines

(invivo)

20mg/kg

O

O Thym

oqui

none

A549(lu

ngcarcinom

acellline)

72.0–146𝜇M∗

Activ

e(indu

ctionof

apop

tosis)

HEp

-2(la

rynx

epidermoidcarcinom

acellline)

22.9–34.6𝜇

M∗

[49]

HT-29

(colon

adenocarcino

mac

ellline)

51.0–53.3𝜇

M∗

MIA

PaCa

-2(pancreasc

arcino

mac

ellline)

60.0–6

7.9𝜇M∗

SF-539

(centralnervou

ssystem

cancer

celllin

e)ND

PC-3

(prostatec

ancerc

ellline)

ND

Activ

e(ND)

M-14(m

elanom

a)ND

[48]

OVC

AR-5(ovaria

ncancer

celllin

e)ND

MCF

-7(breastadeno

carcinom

acellline)

ND

Activ

e(ND)

A-549(lu

ngcarcinom

acellline)

13.0𝜇M

[50]

DLD

-1(colorectaladeno

carcinom

acellline)

5.9𝜇

MSC

CVII(squ

amou

scellcarcino

ma)

86%

c

Activ

e(ND)

Fibrosarcoma(

FsaR

)celllines

(invitro

)92%

c[47]

Fibrosarcoma(

FsaR

)celllines

(invivo)

20mg/kg


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

O

O Thym

oqui

none

Activ

e(proteasomeinh

ibition

andindu

ctionof

apop

tosis)

U87

MG(m

alignant

gliomac

ells)

T98G

(malignant

gliomac

ells)

61.46–

77.73𝜇

M∗

35.83–47.08𝜇

M∗

[51]

Activ

e(indu

ctionof

apop

tosis)

NCI

-H46

0(non

smallcelllun

gcancer

celllin

e)NCI

-H146(smallcelllun

gcancer

celllin

e)ND ND

[52]

Activ

e(do

wnregulationof

NF-𝜅Bexpressio

n)Mou

sexeno

graft

mod

elusingNCI

-H46

0(hum

anlarge

celllung

cancer)

20mg/kg

[52]

Activ

e(supp

ressionof

theN

F-𝜅Bactiv

ationpathway

andindu

ctionof

apop

tosis)

KBM-5

(hum

anmyeloid

celllin

e)A293(hum

anem

bryonick

idneycelllin

e)ND

ND

[56]

Activ

e(supp

ressionof

STAT

3activ

ationandindu

ction

ofapop

tosis)

Multip

lemyeloma

ND

[58]

Activ

e(inactiv

ationof

thes

tressrespon

sepathway

sensor

CHEK

1and

indu

ctionof

apop

tosis)

Hum

ancoloncancer

celllin

esHCT

-116

(p53+/+andp53−

/−)

ND

[57]

Activ

e(ND)

Ehrlich

ascitesc

arcino

mab

earin

gmice

Ehrlich

ascitesc

arcino

mab

earin

gmice

50mg/L

5mg/kg

[53]

[54]

Activ

e(do

wnregulationof

NF-𝜅B)

Ortho

topicm

odelof

pancreaticcancer

(invitro

)Ortho

topicm

odelof

pancreaticcancer

(invivo)

ND

3mg/mou

se[55]

[86]

Activ

e(antio

xidant

activ

ity)

Fibrosarcomaind

uced

by20-m

ethylch

olanthrene

(MC)

inmaleS

wiss

albino

mice(in

vitro

)Sw

issalbino

mice(

invivo)

ND

0.01%in

drinking

water

[59]

[60]

Activ

e(antio

xidant

activ

ity)

Oste

oblasts

cells

(MG63)intissuec

ulture

32–6

4%∗,b

[61]

O

O Thym

oqui

none

Activ

e(indu

ctionof

p53-independ

entapo

ptosis)

Hum

anosteosarcomac

ells(p53-nullM

G63

cells)

(p53-m

utantM

NNG/H

OScells)

17𝜇M

38𝜇M

[62]

Activ

e(inhibitio

nof

NF-𝜅Bandantia

ngiogenesis

effect)

Oste

osarcoma(

invitro

)Oste

osarcoma(

invivo)

ND

6mg/kg

[63]

Activ

e(indu

ctionof

apop

tosis

viap

53-dependent

pathway)

HeLa(

epith

elioid

carcinom

iccelllin

e)2.80–5.93m

g/mL∗

[64]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

O

O Thym

oqui

none

Activ

e(involvem

ento

freactiveo

xygenspeciesa

ndactiv

ationof

ERKandJN

Ksig

nalin

g)

Caco-2

(hum

ancoloncancer

cell)

12.5–15.0𝜇

M∗

[65]

HCT

-116

(hum

ancoloncancer

cell)

14–30𝜇

M∗

LoVo

(hum

ancoloncancer

cell)

28–38𝜇

M∗

DLD

-1(hum

ancoloncancer

cell)

23–4

2𝜇M∗

HT-29

(hum

ancoloncancer

cell)

110𝜇

M

Activ

e(bind

ingto

bovine

serum

albu

min)

DLD

-1(hum

ancoloncancer

cell)

ND

[88]

HCT

-116

(hum

ancoloncancer

cell)

ND

Activ

e(ND)

A549(hum

anno

nsmallcelllun

gcancer

(NSC

LC)cell

line)

ND

[67]

Activ

e(antio

xidant

activ

ity)

ES-2

(ovaria

ncancer

celllin

e)ND

[66]

Activ

e(proo

xidant

cytotoxicm

echanism

)Prostatecancer

celllin

esND

[68]

Activ

e(ND)

66cl-

4-GFP

(resistantm

ouse

mam

maryglandcelllin

e)in

vivo

10mg/kg

[69]

Activ

e(disrup

tionin

cell-cycle

checkp

oints)

LNCa

P(prostatec

ancerc

ellline)

LNCa

P(prostatec

ancerc

ellline)

ND

ND

[70]

[71]

Activ

e(indu

ctionof

apop

tosis)

p53-nu

llmyeloblastic

leuk

emiaHL60

cells

23𝜇M

[72]

O

O Thym

oqui

none

Activ

e(increase

ofRO

Sgeneratio

nanddecreasedGSH

levels)

And

rogenreceptor

(AR)

independ

ent(C4

-2B)

100𝜇

mol/L

[73]

ARnaive(PC

-3)p

rostatec

ancerc

ells

86𝜇mol/L

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis

)CO

S31(canine

osteosarcoma)

ND

[74]

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)


arcino

michu

man

celllin

e)350𝜇

M[75]

Activ

e(cellcycle

arrest,

increase

inthee

xpressionof

thep

rotein

p53anddecrease

incyclinB1

protein)

Prim

arymou

sekeratin

ocytes,SP-1(papillo

ma)

I7spindlec

arcino

mac

ells

30𝜇M

60𝜇M

[76]

Activ

e(inhibitio

nof

telomerase)

Hum

anglioblastomac

ells

ND

[77]

Activ

e(inhibitio

nof

PDE1Aexpressio

n)Jurkatcell(acutelymph

oblasticleuk

emiacelllin

e)ND

[79]

Activ

e(do

wnregulated

MUC4

expressio

nand

indu

ctionof

apop

tosis)

TheM

UC4

-expressingpancreaticcancer

cells

FG/C

OLO

357

CD18/H

PAF

73𝜇mol/L

73𝜇mol/L

[80]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

O

O Thym

oqui

none

Activ

e(up

regulationof

PTEN

expressio

nand

indu

ctionof

apop

tosis)

Doxorub

icin-resistanth

uman

breastcancer

MCF

-7/D

OXcell

35–70%

a[82]

Activ

e(ND)

Parentalandmultid

rugresis

tant

(MDR)

human

tumor

celllin

es78𝜇M

[81]

Activ

e(thym

oquino

ne-lo

aded

nano

particlesa

ctivity

)MDA-

MB-231(hu

man

metastatic

breastcancer

cell

line)

ND

[84]

Activ

e(comparis

onof

thym

oquino

neversus

thym

oquino

ne-lo

aded

nano

particlesa

ctivities)

HCT

-116

(colon

cancer

celllin

e)15%versus

85%

b

[83]

MCF

-7(breastcancerc

ellline)

30%versus

88%

b

PC-3

(prostatec

ancerc

ellline)

30%versus

85%

b

U-266

(multip

lemyelomac

ellline)

55%versus

70%

b

HCT

116(colon

cancer

celllin

e)24%

c

Activ

ityof

deriv

atives

ofthym

oquino

neHCT

116p

53−/−

coloncancer

72%

c[85]


arcino

michu

man

celllin

e)75%

c

HL-60

(acuteprom

yelocytic

leuk

emiacells)

0.13–>

100𝜇

M∗

Activ

ityof

analogso

fthymoq

uino

ne518A

2(m

elanom

acellline)

3.9–>100𝜇

M∗

[87]

multid

rug-resis

tant

KB-V1/V

blcervix

7.0–79.9𝜇M∗

MCF

-7/Top

o(breastcarcino

ma)

2.8–>100𝜇

M∗

O

O Thym

oqui

none

Activ

e(ND)

Mou

seEh

rlich

ascitesc

arcino

matum

orND

[89]

Activ

e(inhibitio

nof

Akt

phosph

orylation;

indu

ctionof

apop

tosis;inh

ibition

ofHDAC

2proteins)

LNM35

(hum

anlung

cancer

cell)

50–78𝜇

M∗

HepG2(hum

anhepatomac

ell)

34𝜇M

HT2

9(hum

ancolorectalcancer

cell)

50–78𝜇

M∗

[96]

MDA-

MB-435(hum

anmam

maryadenocarcino

ma

cell)

50–78𝜇

M∗

MDA-

MB-231(hu

man

mam

marya

deno

carcinom

acell)

50–78𝜇

M∗

MCF

-7(hum

anmam

maryadenocarcino

mac

ell)

50–78𝜇

M∗

Activ

e(ND)

Invivo

activ

ityof

quinon

ereductase

andglutathion

etransfe

rase

inmiceliver

1,2or

4mg/kg

[90]

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis

viaA

ktmod

ulation)

MDA-

MB-46

8(hum

anmam

maryadenocarcino

ma)

12.30𝜇

M[92]

T-47D(hum

anmam

marydu

ctalcarcinom

a)18.06𝜇

M

Activ

e(indu

ctionof

apop

tosis)

HL-60

(hum

anprom

yelocytic

leuk

emiacell)

27.8𝜇M

[93]

518A

2(m

elanom

acellline)

28.3𝜇M


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

O

O Thym

oqui

none

HT-29

(colon

carcinom

acell)

46.8𝜇M

Activ

e(indu

ctionof

apop

tosis)

KB-V1(cervixcarcinom

acell)

25.8𝜇M

[93]

MCF

-7(hum

anmam

maryadenocarcino

mac

ell)

20.1𝜇M

Multid

rug-resis

tant

varia

nts

18.7–

57.2𝜇M∗

MCF

-7(breastcancerc

ellline)

32–4

8𝜇M∗

Activ

e(mod

ulationof

theP

PAR-𝛾activ

ationpathway)

MDA-

MB-231(breastcancer

celllin

e)11–

24𝜇M∗

[193]

BT-474

(breastcancerc

ellline)

18–38𝜇

M∗

Activ

e(cond

ition

Tcells

invitro

fora

doptiveT

cell

therapyagainstcancera

ndinfectious

disease)

OT-1(transgenicCD

8+)T

cells

ND

[95]

Activ

e(indu

ctionof

apop

tosis)

Mou

semod

elof

familialadenom

atou

spolyposis

375m

g/kg

[97]

Activ

e(comparis

onof

thym

oquino

neand

thym

oquino

nein

liposom

eseffects)

MCF

-7(breastcancerc

ellline)

T47D

(breastcancerc

ellline)

40𝜇M

versus

200𝜇

M15𝜇M

versus

75𝜇M

[99]

A431(hu

man

epidermoidcarcinom

a)10𝜇M

Activ

e(cellcycle

arrestandindu

ctionof

apop

tosis)

Hep-2

(larynx

epidermoidcarcinom

a)10𝜇M

[100]

Sarcom

a180

invivo

10mg/kg

O

O Thym

oqui

none

Activ

e(antim

icrotubu

ledrug)

U87

(hum

anastro

cytomac

ellline-solid

tumor

mod

el)ND

[101]

Jurkatcells

(acutelymph

oblasticleuk

emiacelllin

e)ND

Myr

cene

Activ

eMou

seP3

88leuk

emiacell

ND

[17]

HeLa(

human

cervicalcarcinom

a)>200𝜇

g/mL

Activ

e(ND)

A-549(hum

anlung

carcinom

a)>200𝜇

g/mL

[103]

HT-29

(hum

ancolonadenocarcino

ma)

celllin

es>200𝜇

g/mL

Crow

ngalltumors

50%

b

Activ

e(ND)

MCF

-7(breastcarcino

ma)

<10–2mug/m

L[102]

HT-29

(colon

adenocarcino

ma)

<10–2mug/m

LA-

549(lu

ngcarcinom

a)<10–2mug/m

L

Activ

e(cellcycle

arrestandindu

ctionof

apop

tosis)


arcino

michu

man

celllin

e)9.2

3𝜇g/mL

[9]

B16F

10(m

urinem

elanom

a)12.27𝜇

g/mL

The Scientific World Journal 13Ta

ble1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

Myr

cene

Activ

e(cellcycle

arrestandindu

ctionof

apop

tosis)

B16F

10(m

urinem

elanom

a)K5

62(erythromyeloblastoid

leuk

emiacelllin

e)12.27𝜇

g/mL

ND

[9]

Sobr

erol

OH

OH

Activ

e(indu

ctionof

theh

epaticdetoxificationenzymes

glutathion

eS-tr

ansfe

rase

GST

anduridine

diph

osph

ate-glucuron

osyltransfe

rase

UDPG

T)DMBA

-indu

cedratm

ammarycarcinogenesis

ND

[104]

Lim

onen

e

Activ

e(antitum

origeniceffectsindu

ctionof

apop

tosis)

Pancreatic,m

ammary,andprostatic

tumors

ND

[105]

Activ

e(inhibitio

nof

theisoprenylationof

smallG

proteins)

DMBA

-and

5 NMU-in

ducedratm

ammarycarcinom

as10%in

diet

[114]

Activ

e(combinedlim

onenea

nd4-hydroxyand

rostrenedion

e)NMU-in

ducedratm

ammarycarcinom

as5%

limon

enea

nd4-hydroxyand

rostrenedion

e(12.5m

g/kg)

[115]

Activ

e(ND)

DMBA

-indu

cedratm


ND

[116]

Activ

e(indu

ctionof

apop

tosis

andantia

ngiogenic

effect)

SW480(hum

ancolorectaladenocarcino

ma)

ND

[117]

Lim

onen

e

Activ

e(indu

ctionof

apop

tosis

andantia

ngiogenic

effect)

HT-29

(colon

adenocarcino

ma)

ND

[117]

Activ

e(im

mun

omod

ulatoryeffect)

BW5147

(murineT

celllymph

oma)

35𝜇g/mL

[118]

Activ

e(ND)

B16F

-10(m

elanom

acellsin

mice)

100𝜇

M/kg

[119]

Activ

e(indu

ctionof

theh

epaticdetoxificationenzymes

glutathion

eS-tr

ansfe

rase

GST

anduridine

diph

osph

ate-glucuron

osyltransfe

rase

UDPG

T)DMBA

-indu

cedratm


ND

[104]

Activ

ityof

deriv

atives

limon

ene(inhibitio

nof

protein

prenylation)

Invitro

assays

with

mam

malianandyeast

farnesyltransfe

rase

(PFT

)and

geranylgeranyltransfe

rase

(PGGT)

proteins

ND

[107]

Activ

e(inhibitio

nof

NNKmetabolicactiv

ation)

NNK-

indu

cedlung

tumorigenesisin

mice

183𝜇

mol

[120]

Activ

e(ND)

AflatoxinB

1-ind

uced

hepatocarcinogenesis

5%in

diet

[121]

Activ

e(indu

ctionof

apop

tosis)

K562


leuk

emiacelllin

e)HL-60

(acuteprom

yelocytic

leuk

emiacells)

ND

ND

[110]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

Lim

onen

e

Activ

e(ND)

Colon

iccarcinogenesisin

rats

5%[111]

Activ

e(high

affinitywith

HMG-C

oAredu

ctase)

insilico

approaches

ND

[112]

Activ

e(increase

ofGST

activ

ity)

Severaltissueso

ffem

aleA

/Jmice

20mg/0.3m

Lof

theo

il[122]

MCF

-7(hum


ma)

14𝜇g/mL

Activ

e(ND)

K562


leuk

emiacelllin

e)16𝜇g/mL

[106]

PC12

(ratadrenalpheochrom

ocytom

acellline)

>100𝜇

g/mL

A-549(lu

ngcarcinom

a)<10

–2mug/m

LAc

tive(ND)

MCF

-7(breastcarcino

ma)

<10

–2mug/m

L[102]

HT-29

(colon

adenocarcino

ma)

<10

–2mug/m

LA-

549(lu

ngcarcinom

a)ND

Activ

e(effecto

ngapjunctio

nintercellular

commun

ication)

W1-3

8(hum

anfib

roblastlun

gno

rmalcells)

ND

[113]

CACO

2(hum


ma)

ND

Lim

onen

e

Activ

e(effecto

ngapjunctio

nintercellular

commun

ication)

PaCa

(hum

anpancreaticcarcinom

acells)

ND

[113]

Activ

e(ND)

A-549(lu

ngcarcinom

a)0.098𝜇

L/mL

[108]


arcino

michu

man

celllin

e)0.150𝜇

L/mL

Activ

e(ND)

Molecular

docking

ND

[109]

Activ

e(involvem

ento

fc-m

ycon

coprotein)

NDEA

indu

cedhepatocarcinogenesis

5%in

diet

[123]

O Peril

lic ac

id

OH

HTB

-43(hum

anhead

andneck

squamou

scell

carcinom

acellline)

10%

c

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

SCC-

25(hum

anhead

andneck

squamou

scell

carcinom

acellline)

19%

c[126]

BroT

o(hum

anhead

andneck

squamou

scellcarcino

ma

celllin

e)9%

c

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

A549(hum

anlung

adenocarcino

ma)

H520(squ

amou

slun

gcellcarcinom

a)3.6m

MND

[125]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

OH

Peril

lyl a

lcoh

ol

Activ

e(indu

ctionof

apop

tosis)

9,10-Dim

ethylbenz(a)anthracene

(DMBA

)-initiated

and12-O

-tetradecanoylpho

rbol-13-acetate

(TPA

)-prom

oted

skin

tumorigenesis

6or

12mg/kg

[146]

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

Advanced

ratm

ammarycarcinom

as0.1g/kg

[147]

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis

)Bc

r/Ab

l-transform

edleuk

emiacells

ND

[148]

Activ

e(cellcycle

arrestandindu

ctionof

apop

tosis)

Bcr/Ab

l-transform

edmyeloid

celllin

es300–

400𝜇

m[139]

Activ

e(ND)

Ham

sterp

ancreatic

tumors

1.2–2.4g/kg

[127]

Activ

e(ND)

MIA

PaCa

2(hum

anpancreatictumor

cells)

60–9

0%2

[128]

PC-1(ham

sterp

ancreatic

adenocarcino

ma)

40g/kg

Activ

e(indu

ctionof

Bak-indu

cedapop

tosis)

B12/13

(pancreatic

adenocarcino

mac

ellline)

150𝜇

M[130]

Activ

e(inhibitio

nof

thep

renylatio

nof

grow

th-regulatoryproteins)

Pancreaticadenocarcino

mac

ells

ND

[129]

OH

Peril

lyl a

lcoh

ol

AsPC

-1(pancreatic

adenocarcino

mac

ellline)

300𝜇

mol/L

Activ

e(indu

ctionof

apop

tosis)

MIA

PaCa

-2(pancreatic

adenocarcino

mac

ellline)

350𝜇

mol/L

[131,149]

PANC-

1(pancreaticadenocarcino

mac

ellline)

350𝜇

mol/L

BxPC

-3(pancreatic

adenocarcino

mac

ellline)

550𝜇

mol/L

Activ

e(indu

ctionof

apop

tosis)

K562


leuk

emiacelllin

e)81.0𝜇mol/L

[133]

Activ

e(antia

ngiogenica

ctivity

)BL

MVEC

s(bo

vine

lung

microvascular

endo

thelial

cells)

ND

[135,136]

Activ

e(c-Myc-dependent

apop

tosis

)Bc

r/Ab

l-transform

edleuk

emiacells

ND

[134]

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

A549(hum

anlung

adenocarcino

mae

pithelialcellline)

H520(squ

amou

scell

carcinom

a)1.4

mM

1.7mM

[125]

Activ

e(inhibitio

nof

Na+/K

+ -AT

Pase

activ

ity)

Guineap

igbrainandkidn

eywereu

sedin

the

preparationof

homogenates

and

Na/K-AT

Pase-enrichedfractio

ns

1.0mM

forthe

brainenzyme

and1.5

mM

forthe

kidn

eyenzyme

[137]

OH

Peril

lyl a

lcoh

ol

Activ

e(inhibitio

nof

proteiniso

prenylationandcell

proliferatio

n)HT-29

(colon

adenocarcino

mac

ell)

ND

[138]

Activ

e(mod

ulationof

thee

xpressionof

AP-1target

genes)

Breastcancer

cells

ND

[140]

Activ

e(antitum

oreffectp

otentia

tedby

hypertherm

ia)

SCKmam

marycarcinom

acellsof

A/Jmice

20–58%

a[14

1]Ac

tive(inhibitio

nof

ubiquino

nesynthesis

andblockof

thec

onversionof

lathosteroltocholesterol)

NIH

3T3(m

ouse

fibroblastcellline)

ND

[142]

Activ

e(activ

ityof

metaboliteso

fperillylalcoho

l)Inhibitio

nof

proteinprenyltransfe

rasesinvitro

1mM

[107]

Activ

e(inhibitio

nof

theinvivo

prenylationof

specific

proteins)

NIH

3T3(m

ouse

fibroblastcellline)

0.5or

1.0mM

[143]

Activ

e(ND)

AflatoxinB

1-ind

uced

hepatocarcinogenesis

2%in

diet

[121]

Activ

e(antim

etastatic

activ

ity)

C6(glialcellline)

ND

[144]

Activ

e(ph

ases

I/IIstudy)

Hum

anmalignant

gliomas

0.3%

v/v

[145]

Activ

e(pretreated

before

expo

sure

toradiation)

HTB

-43(headandneck

squamou

scellcarcino

mac

ell

line)

71%

b[126]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

OH

Peril

lyl a

lcoh

ol

Activ

e(pretreated

before

expo

sure

toradiation)

SCC-

25(headandneck

squamou

scellcarcino

mac

ell

line)

68%

b

[126]

BroT

o(headandneck

squamou

scell

carcinom

acell

line)

53%

b

Activ

e(radio-/C

hemosensitizer)

Glio

mac

ells

ND

[152]

Activ

e(cellcycle

arrest;

indu

ctionof

apop

tosis)

PC12

(ratadrenalpheochrom

ocytom

acellline)

ND

[150]

Activ

e(ph

armacokineticsstudies)

Pharmacokineticsstudies

indo

gsND

[151]

Activ

e(ph

aseI)

Hum

anadvanced

malignancies

800–

2400

mg/m

2 /dose

[153]

Activ

e(telomerasea

ctivity

)Prostatecancer

cells

ND

[132]

O

1,8

-Cin

eole

/euc

alyp

tol

Activ

e(ND)


arcino

michu

man

celllin

e);

HeLa(

human

cervicalcarcinom

a);

MOLT

-4(hum

anlymph

oblasticleukemiaTcelllin

e);

K-562(

human

chronicm

yelogeno

usleuk

emiacelllin

e);

CTVR-1(an

early

Bcelllin

efrom

theb

onem

arrowcells

ofap

atient

with

acutem

yeloid

leuk

emia)

ND

[14]

O

1,8

-Cin

eole

/euc

alyp

tol

Activ

e(ND)

Melanom

aH157cells

Carcinom

aHT14cells

3.4–

95.3%

2

5.7–96.2%

2[159]

Activ

e(indu

ctionof

apop

tosis)

KB(hum

anpapillo

mac

ellline)

ND

[160]

SK-O

V-3(hum

anovarianadenocarcino

ma)

1.10‰

(v/v)

Activ

e(ND)

HO-8910(hum

anepith

elialovaria

ncancer)

2.90‰

(v/v)

[158]

Bel-7

402(hum

anhepatocellu

larc

arcino

ma)

3.47‰

(v/v)

Activ

e(bind

stotheC

aspase

3)Molecular

dockingstu

dies

ND

[109]

OH

Peril

la al

dehy

de

MCF

-7(breastcarcino

ma)

ND

Activ

e(ND)

K-562(hum

anchronicm

yelogeno

usleuk

emiacelllin

e)ND

[106]

PC-12(ratadrenalgland

pheochromocytom

a)ND


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

OH

Terp

inen

-4-o

l


arcino

michu

man

celllin

e)ND

HeLa(

epith

elioid

carcinom

iccelllin

e)ND

Activ

e(ND)

MOLT

-4(hum

anlymph

oblasticleuk

emiaT-celllin

e)ND

[14]

K-562(hum

anchronicm

yelogeno

usleuk

emiacelllin

e)ND

CTVR-1(early

Bcelllin

efrom

theb

onem

arrowcells

ofap

atient

with

acutem

yeloid

leuk

emia)

ND

Activ

e(indu

ctionof

apop

tosis)

Hum

anmela

nomaM

14WTcells

andtheirresistant

varia

nts

ND

[161]

Activ

e(ND)

Drug-sensitive

anddrug-resistantm

elanom

acells

ND

[162]

Activ

e(cellcycle

arrestandindu

ctionof

necrosis)

AE17(m

esothelio

mam

urinec

ancerc

ells)

B16(m

elanom

acells)

0.01–0

.02

0.04–0

.05

[163]

Activ

e(ND)

A-549(lu

ngcarcinom

a);D

LD-1

(hum


ma)

>100𝜇

M>100𝜇

M[50]

O

Citr

al

Activ

e(ND)

P388

mou

seleuk

emiacells

ND

[164

]Ac

tive(ND)

MCF

-7(breastcarcino

ma)

92.3%

c[165]

Activ

e(indu

ctionof

apop

tosis-activatingp53)

Endo

metria

lcancerc

elllines

Ishikawaa

ndEC

C-1

(end

ometria

lcarcino

mac

ellline)

2.3𝜇

g/mL

[166]

Activ

e(indu

ctionof

apop

tosis)

NB4

(acuteprom

yelocytic

leuk

emiacelllin

e)3.995𝜇g/mL

[167]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

O

Carv

one

Activ

e(indu

ctionof

apop

tosis)

Hep-2

(larynx

epidermoidcarcinom

a)0.47–0

.62m

M∗

[35]

Activ

e(ND)

HeLa(

human

cervicalcarcinom

a)74.5𝜇g/mL

[168]

Activ

e(indu

ctionof

oxidatives

tress)

Cultu

redprim

aryratn

euronandN2a

neurob

lasto

ma

(NB)

cells

ND

[169]

Activ

e(ND)

MCF

-7(breastcarcino

ma)

0.63𝜇M

[46]

K-562(hum

anchronicm

yelogeno

usleuk

emiacelllin

e)0.17𝜇M

P-815(m

ouse

lymph

oblastlik

emastocytomac

ellline)

0.16𝜇M

CEM

(hum

anacutelym

phob

lasticleukemia)

0.11𝜇M

𝛼-P

inen

e

Activ

e(oxidatives

tressandrepo

rter

gene

activ

ities

ofantio

xidant

respon

seele

ment(ARE

),activ

ator

protein1

(AP-1),and

nucle

arfactor

NF-𝜅B)

A549(lu

ngcarcinom

a)HepG2(hepatocellularc

arcino

michu

man

celllin

e)250p

pm203p

pm[174]

Activ

e(im

mun

omod

ulatoryeffect)

BW5147

(murineT

celllymph

oma)

Normalmurinelym

phocytes

1100𝜇

g/mL

72𝜇g/mL

[118]


arcino

michu

man

cell)

1393.3𝜇g/mL

K562

(hum

anchronicm

yelogeno

usleuk

emiacelllin

e)679.1𝜇g/mL

Activ

e(ND)

H-460

(lung

largec

ellcarcino

ma)

501.8𝜇g/mL

[170]

N-87(gastriccarcinom

a)840.6𝜇

g/mL

SW-620

(colon

adenocarcino

ma)

786.2𝜇

g/mL

Activ

e(ND)

Dualreverse

virtualscreening

protocol

ND

[109]

Activ

e(ND)

SK-O

V-3(hum

anovarianadenocarcino

ma)

HO-8910(hum

anepith

elialovariancancer)

0.052‰

(v/v)

0.11‰

(v/v)

[158]

𝛼-P

inen

e

Activ

e(ND)

Bel-7

402(hum

anhepatocellu

larc

arcino

ma)

0.32‰

(v/v)

[158]

Activ

e(ND)

MCF

-7(m

ammaryadenocarcino

ma)

MDA-

MB-231(mam

maryadenocarcino

ma)

MDA-

MB-46

8(m

ammaryadenocarcino

ma)

UACC

-257

(malignant

melanom

a)

64.3𝜇g/mL5

>100𝜇

g/mL5

27.7𝜇g/mL5

13.5𝜇g/mL5

[171]

Activ

e(indu

ctionof

apop

tosis)

U937(histiocytic

lymph

omac

ells)

ND

[172]

HeLa(

human

cervicalcarcinom

a)172.7𝜇

g/mL

Activ

e(ND)

A-549(hum

anlung

carcinom

a)183.2𝜇

g/mL

[103]

HT-29

(hum

ancolonadenocarcino

ma)

>200𝜇

g/mL

MCF

-7(hum

anbreastcarcinom

acellline)

20.6𝜇g/mL

Activ

e(ND)

MDA-

MB-46

8(hum

anbreastcarcinom

acellline)

39.2𝜇g/mL

[173]

UACC

-257

(hum

anbreastcarcinom

acellline)

16.3𝜇g/mL


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

𝛽-P

inen

e

Activ

e(ND)

A-549(lu

ngcarcinom

a)DLD

-1(hum


ma)

85.0𝜇M

>100𝜇

M[50]

MCF

-7(breastcarcino

ma)

Activ

e(ND)

A375(hum

anmelanom

a)ND

[170]


arcino

michu

man

celllin

e)Ac

tive(im

mun

omod

ulatoryeffect)

BW5147

(murineT

celllymph

oma)

114.81𝜇

g/mL

[118]

MCF

-7(breastcarcino

ma)

176.5–242.6m

M∗

Activ

e(ND)

A375(hum

anmelanom

a)198.5–264.7𝜇

M∗

[91]


arcino

michu

man

cell)

147.1–198.5𝜇M∗

Activ

e(ND)

MCF

-7(hum

anbreastcarcinom

acells)

MDA-

MB-231(hu

man

breastcarcinom

acells)

MDA-

MB-46

8(hum

anbreastcarcinom

acells)

UACC

-257

(hum

anbreastcarcinom

acells)

ND

ND

ND

ND

[171]

Activ

e(ND)

Dualreverse

virtualscreening

protocol

ND

[109]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

Ger

anio

l

OH

Activ

e(cellcycle

arrest)

(Caco-2)

human

coloncancer

celllin

e70%

a[179]

Activ

e(blockade

ofthem

orph

ologicalandfunctio

nal

differentiatio

nof

thec

ells)

Hum

ancolonicc

ancerc

ells

30%

c[175]

Caco-2

(hum

anepith

elialcolorectaladeno

carcinom

acells)

250𝜇

M

Activ

e(thym

idylates

ynthasea

ndthym

idinek

inase

expressio

n)SW

620(hum

ancolonadenocarcino

ma)

330𝜇

M[176]

TC-118

(colorectaltum

or)

150m

g/kg

Activ

e(ND)

Hum

anMIA

PaCa

2pancreatictumor

cells

andhamste

r(tr

ansplanted

PC-1pancreaticadenocarcino

mas)

60–9

0%a

40g/kg

diet

[128]

Activ

e(effectson

mevalon

atea

ndlip

idmetabolism

)HepG2(hepatocellularc

arcino

michu

man

celllin

e)≥90%

a[177]

Activ

e(high

affinitywith

HMG-C

oAredu

ctase)


arcino

michu

man

celllin

e)ND

[178]

Activ

e(high

affinitywith

HMG-C

oAredu

ctase)

Insilico

approaches

ND

[112]

Activ

e(activ

ityof

thed

etoxify

ingenzymeg

lutathione

S-transfe

rase)

Mucosao

fthe

smallintestin

eand

largeintestin

eND

[122]

Ger

anio

l

OH

Activ

e(indu

ctionof

apop

tosis)

Hepatocarcino

genesis

inrats

25mg/100g

[180]

Activ

e(indu

ctionof

apop

tosis;inh

ibition

ofRh

oAactiv

ation)

Hepatocarcino

genesis

inrats

25mg/100g

[181]

Activ

e(ND)

MIA

PaCa

2(hum

anpancreatictumor

cells)

PC-1(ham

sterp

ancreatic

adenocarcino

ma)

60–9

0%a

40g/kg

diet

[128]

Activ

e(nu

clear

factor

erythroid2-relatedfactor-2

(Nrf2

)activation)

4NQO-in

ducedoralcarcinogenesisin

mou

se200m

g/kg

[182]

Activ

e(ND)

Dualreverse

virtualscreening

protocol

ND

[109]


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

Lina

loolO

HAc

tive(inhibitio

nof

mito

chon

drialcom

plexes

Iand

II,

increase

ofRO

Sanddecrease

ofAT

PandGSH

levels)


arcino

michu

man

celllin

e)0.4–

2𝜇M

[187]

Activ

e(ND)

C32(amelanoticmelanom

acellline)

23.2𝜇g/mL

[94]

Activ

e(ND)

HeLa(

human

cervicalcarcinom

acells)

AGS(stomachcarcinom

acells)

BCC-

1/KMC(skincarcinom

acells)

H520(lu

ngcarcinom

acells)

0.37𝜇g/mL

14.1𝜇g/mL

14.9𝜇g/mL

21.5𝜇g/mL

[184]

Lina

loolO

H

Activ

e(ND)

U2O

S(bon

ecarcino

mac

ells)

21.7𝜇g/mL

[184]

Activ

e(ND)

U937(histiocytic

lymph

omac

ellline)

P3HR1

(Burkittlymph

omac

ellline)

3.51𝜇

g/mL

4.21𝜇g/mL

[185]

Activ

e(indu

ctionof

apop

tosis

byactiv

ationof

p53and

CDKIs)

Kasumi-1

(acutemyeloid

leuk

emia)

49.53

–127.14𝜇M

HL-60

(acutemyeloid

leuk

emia)

49.53

–127.14𝜇M

THP-1(acutem

yeloid

leuk

emia)

>144.04𝜇M

U937(acutemyeloid

leuk

emia)

>144.04𝜇M

KG-1(acutemyeloid

leuk

emia)

>144.04𝜇M

NB4

(acutemyeloid

leuk

emia)

>144.04𝜇M

[188]

K562

(blastcrisiso

fchron

icmyeloid

leuk

emia)

>144.04𝜇M

Molt-4

(acuteT-lymph

oblasticleukemia)

49.53

–127.14𝜇M

H-9

(acuteT-lymph

oblasticleuk

emia)

ND

Jurkat(acuteT-lymph

oblasticleukemia)

>144.04𝜇M

Raji(hum

anBu

rkitt’slymph

oma)

49.53

–127.14𝜇M

L428

(Hod

gkin’slymph

oma)

>144.04𝜇M

Lina

loolO

HAc

tive(po

tentiatedo

xorubicin-indu

cedcytotoxicity;

indu

ctionof

apop

tosis)

MCF

7WT(hum


ma)

0.62–0

.79𝜇

M[189]

multid

rugresistant

MCF

7Ad

rR1.2

4–3.0𝜇

M

Activ

e(ND)

C32(amelanoticmelanom

acellline)

23.2𝜇g/mL

[186]

Renaladeno

carcinom

acells

23.8𝜇g/mL

Activ

e(indu

ctionof

apop

tosis;promotioncell

differentiatio

n)HL-60

(acuteprom

yelocytic

leuk

emiacells)

ND

[190]

Activ

e(combinatio

nof

doxorubicin-lin

aloo

lincreased

doxorubicininflu

xin

tumor

cells)

Mou

seP3

88leuk

emiacells

(invitro

)ND

[191]

Mou

seP3

88leuk

emiacells

(invivo)

1.0mg/kg/day


Table1:Con

tinued.

Com

poun

dAntitu

mor

activ

ityand/or

mechanism


IC50,

%survival,%

mortalityor

%grow

thinhibitio

n,or

dose

Reference

Cym

ene

Activ

e(ND)

A-549(lu

ngcarcinom

a)DLD

-1(colorectala

deno

carcinom

a)43.0𝜇g/mL

46.0𝜇g/mL

[50]

Terp

inol

ene

Activ

e(ND)

MCF

-7(hum

anbreastcancer

cells)

1.3mg/L

[192]

ND:not

determ

ined.

∗Va

riablev

aluesrefer

todifferences

onthec

oncentratio

nsused,tim

eoftreatment,celllin

e,and/or

assayused.

a %survivaland/or

proliferatio

n.b %

grow

thinhibitio

n.c %

mortality.


In the work of Stammati and collaborators [35], the authorscompared the cytotoxic effects and molecular mechanismsof 5 monoterpenes: carvacrol, thymol, carveol, carvone,and isopulegol. Yin and collaborators [36] have proved theinvolvement of apoptosis in the cytotoxic effects of carvacrolon HepG2 cells. Arunasree [37] investigated the mechanismof carvacrol-induced cell death in MDA-MB 231 humanmetastatic breast cancer cells and demonstrated that thiscompound induced apoptosis in a dose-dependent manner[37]; the mechanism of action of carvacrol may in fact berelated to its antioxidant activity and not associated witha DNA-damaging effect. Jayakumar and collaborators [38]demonstrated that carvacrol protects the antioxidant systemin DEN-induced hepatocellular carcinogenesis. Carvacrolinduced cell cycle arrest at S phase and induced apoptosis inP815 tumor cell line [39]. Zeytinoglu and collaborators [40]found that carvacrol inhibited growth of myoblast cells evenafter activation of a mutated N-ras oncogene. The essentialoil of Origanum onites and carvacrol, its major constituent,showed strongly inhibition of the mutagenicity inducedby 4-nitro-o-phenylenediamine and 2-aminofluorene usingSalmonella typhimurium strains TA98 and TA100. Theseresults indicate that the essential oil and carvacrol havepharmacological importance for the prevention of cancerbecause of its significant antimutagenicity effect [41]. Thecarcinogenesis-reducing potential of carvacrol was demon-strated by Ozkan and Erdogan [42]. Carvacrol was also testedagainst lung tumors induced by dimethylbenz[𝛼]anthracene(DMBA) in rats in vivo and it was found to have strong anti-tumor activity at 0.1mg/kg i.p. Although the mechanism ofaction of antitumor activity of carvacrol was not investigatedin this study, evidence for an inhibitory effect on angiogenesiswas observed [43].

1.9. p-Mentha-1,3,5-triene-2,3,6-triol. From the methanolextract of Majorana syriaca, Hirobe and collaborators [44]isolated the p-mentha-1,3,5-triene-2,3,6-triol. The screeningfor cytotoxicity on P388 cells showed significant activity forits monoterpene.

1.10. Terpinene. Terpinene showed significant evidence forantioxidant activity and cytotoxic activity against mouseleukemia P388 cells [31]. Ferraz and collaborators [9] eval-uated the cytotoxicity of the essential oil of Lippia gracilis andits constituents against HepG2, K562, and B16-F10 tumor celllines. Terpinene showed cytotoxic activity selectively for B16-F10 cells.

1.11. Thymol. Thymol presented cytotoxic effect against Hep-2 cells [35], P815 mastocytoma cells [31], HepG2 humanhepatoma cells, Caco-2 human colonic cells, andV79hamsterlung cells [34]. Thymol showed antioxidant activity andcytotoxic activity against the mouse leukemia P388 cell line[30, 44]. Jayakumar and collaborators [38, 42] demonstratedthat thymol is cytotoxic against HepG2 human hepatomacells, colonic Caco-2 cells, and K562 cells, via a mechanismthat may be related to antioxidant activity and not associatedwith aDNA-damaging effect.The effects of thymol onmurine

B16-F10 melanoma cells were tested by Paramasivam andcollaborators [45], and thymol exhibited cytotoxicity with anIC50

value of 88.5 𝜇g/mL. Thymol cytotoxicity was reducedby addition of vitamin C and vitamin E. Radical scavengers(butylated hydroxytoluene and butylated hydroxyanisole)were able to significantly recover cell viability. Yin andcollaborators [36] demonstrated that thymol induced cellcycle arrest at G0/G1 phase. Deb and collaborators [12]demonstrated that thymol induced apoptosis in HL-60 cellsvia caspase-dependent and caspase-independent pathways.Oskan and collaborators [42] demonstrated the antioxidantactivity and carcinogenesis-reducing potential of thymol.In the work of Jaafari and collaborators [46], the authorscompared the cytotoxic effects and molecular mechanismsof 5 monoterpenes: carvacrol, thymol, carveol, carvone, andisopulegol.

1.12. Thymohydroquinone. Studies have shown significantcytotoxic activity for thymohydroquinone in squamous cellcarcinoma (SCCVII) and fibrosarcoma (FsaR) cell lines.Thisactivity was dose dependent andmore effective against tumorcells than L929 fibroblasts.Thymohydroquinone also showeda tumor inhibition rate of 52% in vivo [47]. On the other hand,Johnson and collaborators [48] showed that the reduction ofthymoquinone to thymohydroquinone resulted in a 1.7-folddecrease in its cytotoxic potency against PC-3 tumor cells[48].

1.13. Thymoquinone. Thymoquinone possesses antiprolifera-tive and proapoptotic activities in several cell lines [48–50].Ivankovic and collaborators [47] showed cytotoxicity and alsoantitumor activity of thymoquinone. Cecarini and collabo-rators [51] demonstrated that thymoquinone induced time-dependent selective proteasome inhibition in glioblastomacells and isolated enzymes and suggested that thismechanismcould be implicated in the induction of apoptosis in cancercells.The activity of thymoquinone against nonsmall cell lungcancer (NSCLC) and small cell lung cancer (SCLC) cell lines,alone and in combination with cisplatin (CDDP), was eval-uated by Jafri and collaborators [52]. The authors observedthat thymoquinone inhibited cell proliferation, reduced cellviability, and induced apoptosis. Thymoquinone inhibitedcell proliferation by nearly 90%and showed synergistic effectswith cisplatin. Thymoquinone was able to induce apoptosisin NCI-H460 and NCI-H146 cell lines. In a mouse xenograftmodel, the combination of thymoquinone and CDDP waswell tolerated and significantly reduced tumor volume andtumor weight. Badary and collaborators [53] investigatedthe effects of thymoquinone on cisplatin-induced nephro-toxicity in mice and rats, and results revealed that thymo-quinone induced amelioration of cisplatin nephrotoxicity andpotentiated its antitumor activity. This natural product isalso capable of improving the therapeutic efficacy of ifos-famide by decreasing ifosfamide-induced nephrotoxicity andimproving its antitumor activity [54]. The chemosensitizingeffect of thymoquinone on conventional chemotherapeuticagents was also demonstrated by Banerjee and collaborators.


In vitro studies demonstrated that preexposure of cells to thy-moquinone followed by gemcitabine or oxaliplatin resultedin greater growth inhibition compared with gemcitabine oroxaliplatin used alone. The mechanism involves downregu-lation of nuclear factor-𝜅B (NF-𝜅B), Bcl-2 family genes, andNF-𝜅B-dependent antiapoptotic genes [55]. Thymoquinonedownregulated NF-𝜅B expression, which may explain itsvarious cellular activities [52]. Sethi and collaborators [56]evaluated the involvement of suppression of the NF-𝜅Bactivation pathway in apoptosis induced by thymoquinone.Gali-Muhtasib and collaborators [57] demonstrated thatthymoquinone triggered inactivation of the stress responsepathway sensor CHEK1 and contributed to apoptosis incolorectal cancer cells. In human, multiple myeloma cellsthymoquinone inhibited proliferation, induced apoptosis,and induced chemosensitization, through suppression of thesignal transducer and activator of transcription 3 (STAT3)activation pathway [58]. Badary and collaborators [59, 60]demonstrated a powerful chemopreventive activity for thy-moquinone against MC-induced fibrosarcoma tumors, sug-gesting that its mechanisms of action include antioxidantactivity and interference with DNA synthesis, coupled withenhancement of detoxification processes [59, 60]. Barron andcollaborators [61] examined the effects of thymoquinone andselenium (an endogenous antioxidant) on the proliferation ofMG 63 osteoblasts cells in tissue culture and found that thecombined use of these substances may be an effective treat-ment option against human osteosarcoma cells. The utiliza-tion of thymoquinone in the treatment of human osteosar-coma is also suggested by Roepke and collaborators [62], whoshowed that it induced p53-independent apoptosis, which isimportant because loss of p53 function is frequently observedin osteosarcoma patients. In contrast, Peng and collaborators[63] demonstrated antitumor and antiangiogenesis effects ofthymoquinone on osteosarcoma through theNF-𝜅Bpathway.Yazan and collaborators [64] reported that thymoquinonewas cytotoxic to HeLa cells in a dose- and time-dependentmanner and induced apoptosis via a p53-dependent pathway.Reactive oxygen species were also involved in mediatingthymoquinone-induced apoptosis in a panel of human coloncancer cells (Caco-2, HCT-116, LoVo, DLD-1, and HT-29)through activation of ERK and JNK signaling [65]. Wilson-Simpson and collaborators [66] evaluated the participationof thymoquinone in the treatment of ES-2 ovarian tumorcells, and Farah and collaborators [67] evaluated the effects ofantioxidants and thymoquinone on the cellular metabolismof A549 cells. Zubair and collaborators [68] demonstratedthat redox cycling of endogenous copper by thymoquinoneled to ROS-mediated DNA breakage and cell death. Taliband Abu Khader [69] studied the combinatorial effects ofthymoquinone on the anticancer activity and hepatotoxicityof the prodrugCB 1954. Furthermore, findings fromRichardsand collaborators [70, 71] revealed that sustained delivery ofantioxidants with thymoquinone may be a means of treatingprostate cancer safely and effectively. In HEp-2 human laryn-geal carcinoma cells, GSH depletion and caspase 3 activationmediated thymoquinone-induced apoptosis [49]. Caspase 3activation (as well as caspase 8 and caspase 9) is related tothymoquinone-induced apoptosis in p53-null HL-60 cancer

cells [72]. In prostate cancer cells, thymoquinone inducedGSH depletion and increased ROS generation [73]. Shoieband collaborators [74] demonstrated that the mechanism ofaction of thymoquinone on cancer cells involves apoptosisand cell cycle arrest. Apoptosis and cell cycle arrest werealso evidenced in the studies of Hassan and collaborators[75] in the HepG2 hepatocellular carcinoma cell line andin the studies of Gali-Muhtasib and collaborators [76] inprimary mouse keratinocytes, papilloma (SP-1), and spindle(I7) carcinoma cells. Gurung and collaborators [77] suggestedthat in glioblastoma cells thymoquinone induced DNA dam-age, telomere attrition through telomerase inhibition, andcell death. More recently, Paramasivam and collaborators[78] showed that thymoquinone produced cytotoxic effectson Neuro-2a mouse neuroblastoma cells through caspase3 activation, with downregulation of XIAP. Abusnina andcollaborators [79] demonstrated that thymoquinone inducesacute lymphoblastic leukemia cell apoptosis. Thymoquinonealso has potential as a novel therapeutic agent against pan-creatic cancer. Torres and collaborators [80] demonstratedthat thymoquinone downregulated MUC4 expression inpancreatic cancer cells and induced apoptosis by two differentpathways. The activity of thymoquinone against multidrugresistant (MDR) human tumor cell lines was also evaluatedby Worthen and collaborators [81]. el-SA and collaborators[82] show that thymoquinone upregulated PTEN expressionand induced apoptosis in doxorubicin-resistant humanbreastcancer cells. This study suggested that thymoquinone maynot be an MDR substrate and that radical generation maynot be critical to its cytotoxic activity [81]. Ravindram andcollaborators [83] demonstrated that encapsulation of thy-moquinone into nanoparticles enhanced its antiproliferativeand chemosensitizing effects. The same type of study wasconducted by Ganea and collaborators [84]. Wirries andcollaborators [85] reported that structural modifications maycontribute to the further clinical studies with thymoquinone.Banerjee and collaborators [86] and Effenberger and col-laborators [87] also analyzed thymoquinone analogs withpotential cytotoxicity against cancer cells. El-Najjar and col-laborators [88] showed that bovine serum albumin played aprotective role against thymoquinone-induced cell death. Al-Shabanah and collaborators [89] demonstrated that thymo-quinone protected against doxorubicin-induced cardiotoxi-city without compromising its antitumor activity. Nagi andAlmakki [90] investigated a potential role for thymoquinonein protection against chemical carcinogenesis and toxicity byinducing quinone reductase and glutathione transferase inmice liver. Thymoquinone inhibited proliferation, inducedapoptosis, and chemosensitized human multiple myelomacells through suppression of the signal transducer and activa-tor of transcription 3 (STAT3) activation pathway [91]. Rajputand collaborators [92] showed thatmolecular targeting of Aktby thymoquinone promoted G1 arrest through translationinhibition of Cyclin D1 and induced apoptosis in breastcancer cells. Effenberger-Neidnicht and collaborators [93]showed that thymoquinone boosted the anticancer effects ofdoxorubicin in certain cancer cell. Tundis and collaborators[94] demonstrated the possible involvement of the PPAR-𝛾 pathway in the anticancer activity of thymoquinone in


breast cancer cells. Thymoquinone enhances survival andactivity of antigen-specific CD8-positive T cells in vitro, aresult that can be useful in the cancer therapy [95]. Exposureof cancer cells derived from lung, liver, colon, melanoma, andbreast to increasing thymoquinone concentrations presenteda significant inhibition of viability with an inhibition of Aktphosphorylation, DNA damage, and activation of mitochon-drial proapoptotic pathways. Thymoquinone inhibited theinvasive potential of various cancer cells. Moreover, thymo-quinone synergizes with cisplatin to inhibit cellular viability.Tumor growth inhibition was associated with a significantincrease in activated caspase 3. In silico target identifica-tion suggested several potential targets of thymoquinone,in particular HDAC2 proteins and 15-hydroxyprostaglandindehydrogenase [96]. Lang and collaborators [97] showed thatthymoquinone interfered with polyp progression in ApcMinmice through induction of tumor-cell specific apoptosis andmodulation of Wnt signaling through activation of GSK-3𝛽. Thymoquinone also induced apoptosis in oral cancercells through P38𝛽 inhibition [98]. Odeh and collaborators[99] described the encapsulation of thymoquinone into aliposome, which maintained stability and improved bioavail-ability, while it maintained anticancer activity. Das and col-laborators [100] showed that thymoquinone and diosgenin,alone and in combination, inhibited cell proliferation andinduced apoptosis in squamous cell carcinoma. Alhosinand collaborators [101] demonstrated that thymoquinoneinduced degradation of 𝛼- and 𝛽-tubulin proteins in humancancer cells without affecting their levels in normal humanfibroblasts.

1.14. Myrcene. Myrcene showed significant cytotoxic effectsin crown gall tumors, MCF-7 breast carcinoma, HT-29 colonadenocarcinoma [102], and other cell lines [9]. Silva andcollaborators [103] investigated the cytotoxicity of myrceneagainst HeLa (human cervical carcinoma), A-549 (humanlung carcinoma), HT-29 (human colon adenocarcinoma),and Vero (monkey kidney) cell lines as well as mousemacrophages. Okamura and collaborators [17] performeda screening of 12 monoterpenes. Among them, the acyclicmonoterpene, myrcene, exhibited significant cytotoxicityagainst P388 leukemia cell.

1.15. Sobrerol. Sobrerol showed anticarcinogenic activity dur-ing the initiation phase of DMBA-induced carcinogene-sis, which was mediated through induction of the hepaticdetoxification enzymes glutathione-S-transferase and uridinediphosphoglucuronosyl transferase [104].

1.16. Limonene. Studies have demonstrated the antitumori-genic effects of limonene against pancreatic cancer and breastcancer [105]. Limonene showed antioxidant and radical scav-enging activities in several model systems and cytotoxicityagainst MCF-7, K562, PC 12 [106], A-549, HT-29 cell lines[107], and HepG2 hepatocarcinoma cell lines [108]. Bhat-tacharjee and Chatterjee [109] promoted the identificationof proapoptotic, anti-inflammatory, antiproliferative, anti-invasive, and potential antiangiogenic activities of limonene

by employing a dual reverse virtual screening protocol. Aprobabilistic set of antitumor targets was generated, whichcan be further confirmed by in vivo and in vitro experi-ments. Ji and collaborators [110] demonstrated that inductionof apoptosis by d-limonene was mediated by a caspase-dependent mitochondrial death pathway in human leukemiacells. Furthermore, d-limonene induced apoptosis in HL-60cells through activation of caspase-8 [111]. Pattanayak and col-laborators [112] verified that limonene inhibited the activity ofHMG-CoA reductase due to greater binding affinity with thereceptor and thus reduced the possibility of cancer growth.Chen and collaborators [113] suggested that the anticanceractivity of limonene might be related to inhibition of themembrane association of P21ras protein and increased gapjunction intercellular communication. Haag and collabora-tors [114] demonstrated that limonene induced regressionof mammary carcinomas, and when given in combinationwith 4-hydroxyandrostrenedione it resulted in greater ratmammary tumor regression (83.3%) than either agent givenalone [115]. Elson and collaborators [116] demonstrated thatlimonene reduced the average number of rat mammary car-cinomas that developed in 7,12-dimethylbenz[𝛼]anthracene-treated rats when the terpene was fed during the initiationor promotion/progression stages of carcinogenesis. Chi-dambara and collaborators [117] tested citrus volatile oil richin d-limonene and verified that the oil induced apoptosis andacted as an antiangiogenic with a preventative effect on coloncancer. Limonene also showed a selective antiproliferativeaction on tumor lymphocytes [118], and it inhibited themetastatic progression of B16F-10 melanoma cells in mice[119]. Limonene had anticarcinogenic activity when fed dur-ing the initiation stage of DMBA-induced rat mammary car-cinogenesis, and this mechanism was mediated through theinduction of the hepatic detoxification enzymes glutathione-S-transferase and uridine diphosphoglucuronosyl transferase[104]. Gelb and collaborators [107] tested the ability oflimonene to inhibit protein prenylation enzymes in vitroand found that it was a weak inhibitor of both mammalianand yeast protein farnesyltransferase (PFT) as well as pro-tein geranylgeranyl transferase (PGGT). D-Limonene is aneffective inhibitor of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolic activation [120]. Elegbede and Gould[121] investigated the effects of limonene at the initiation stageof aflatoxin B1-induced hepatocarcinogenesis and found thatlimonene significantly inhibited aflatoxin-DNA adduct for-mation in hepatocytes, which suggested that limonene mayhave potential as a chemopreventive agent against aflatoxin-induced liver cancer. D-Limonene inhibited the developmentof colonic aberrant crypt foci induced by azoxymethane inF344 rats, which suggested that this monoterpenoid mightbe a chemopreventive agent for colonic carcinogenesis in rats[111]. D-Limonene induced GST activity 2.4–3.0-fold higherthan controls in the mouse liver and mucosa of the smallintestine and large intestine, which suggested chemopreven-tive activity [122]. Parija and Ranjan [123] demonstrated theinvolvement of YY1 in NDEA-induced hepatocarcinogenesisand chemoprevention mediated by d-limonene.


1.17. p-Mentha-2,8-dien-1-ol and p-Mentha-8(9)-en-1,2-diol.Zheng and collaborators [124] demonstrated the abilityof p-mentha-2,8-dien-1-ol and p-mentha-8(9)-en-1,2-diol toinhibit benzo[𝛼]pyrene-induced carcinogenesis in themouseforestomach. The number of tumors per mouse was alsosignificantly decreased by these compounds. No tumor inhi-bition was observed with p-mentha-2,8-dien-1-ol.

1.18. Perillic Acid. Yeruva and collaborators [125] demon-strated that perillic acid demonstrated dose-dependent cyto-toxicity in A549 andH520 cell lines, inducing cell cycle arrestand apoptosis. Combination studies revealed that previousexposure of cells to perillic acid sensitized the cells to cisplatinand radiation in a dose-dependent manner. Samaila andcollaborators [126] showed that perillic acid has potential foruse as a radiosensitizer in chemoradiation therapy of headand neck cancers.

1.19. Perillyl Alcohol. Stark and collaborators [127] and Burkeand collaborators [128] demonstrated that perillyl alcohol hasantitumor activity against pancreatic carcinomas at nontoxicdoses and may be an effective chemotherapeutic agent forhuman pancreatic cancer. The antitumor activity of perillylalcohol against pancreatic cancers may stem from its abilityto inhibit the prenylation of growth-regulatory proteins otherthan K-Ras, including H-Ras [129]. Furthermore, the anti-tumor activity of perillyl alcohol in pancreatic cancers maybe due to preferential stimulation of Bak-induced apoptosisin malignant cells compared to normal cells [130]. Furtherstudies to evaluate the cytotoxicity mechanisms of perillylalcohol against pancreatic cancer cells were conducted byLebedeva and collaborators [131]. Sundin and collabora-tors [132] demonstrated that the perillyl alcohol inhibitedtelomerase activity in prostate cancer cells. Perillyl alcoholin combination with STI571 enhances the ability of STI571to inhibit proliferation and induce apoptosis in K562 cells[133]. In bcr/abl-transformed leukemia cells perillyl alcoholinduced c-myc-dependent apoptosis [134]. InA549 andH520cell lines, Yeruva and collaborators [125] demonstrated thatperillyl alcohol presented dose-dependent cytotoxicity withcell cycle arrest and apoptosis. Elevated expression of bax,p21, and increased caspase 3 activity were evidenced. Otherstudies revealed that perillyl alcohol sensitized cancer cellsto cisplatin and radiation in a dose-dependent manner.Perillyl alcohol attenuated in vitro angiogenesis, modulatedangiogenic factor production, and inhibited cell proliferationand survival in endothelial and tumor cells [135]. Loutrati andcollaborators [136] also demonstrated that perillyl alcohol, inadditional to its anticancer activity, may be an effective agentin the treatment of angiogenesis-dependent diseases. Garciaand collaborators [137] demonstrated that perillyl alcohol isan Na/K-ATPase inhibitor and suggested that its antitumoraction could be linked to itsNa/K-ATPase binding properties.Perillyl alcohol reduced 21–26 kDa proteins isoprenylation to50% of the control level at a concentration of 1mMbut had noeffect on the isoprenylation of 67, 47, or 17 kDa proteins [138].Sahin and collaborators [139] demonstrated that perillylalcohol selectively induced G0/G1 arrest and apoptosis in

Bcr/Abl-transformed myeloid cell lines. In the same yearSatomi and collaborators [140] demonstrated induction ofAP-1 activity by perillyl alcohol in breast cancer cells. Ahn andcollaborators [141] verified that cytotoxicity of perillyl alcoholagainst cancer cells is potentiated by hyperthermia. Ren andGould [142] demonstrated an inhibition of ubiquinone andcholesterol synthesis by perillyl alcohol, and the authorssuggested that these effects may contribute to the antitu-mor activity of the molecule. Manassero and collaborators[108] tested the ability of perillyl alcohol to inhibit proteinprenylation enzymes in vitro and verified that it is a weakinhibitor of both mammalian and yeast forms of proteinfarnesyltransferase and protein geranylgeranyl transferase.In NIH3T3 cells, Ren and collaborators [143] verified thatperillyl alcohol inhibited the in vivo prenylation of specificproteins by type I and type II geranylgeranyl-protein trans-ferases but not by farnesyl-protein transferase. Elegbede andGould [121] investigated the effects of perillyl alcohol at theinitiation stage of aflatoxin B1-induced hepatocarcinogenesis.In this study, analysis of liver samples showed that perillylalcohol significantly inhibited aflatoxin-DNA adduct forma-tion in hepatocytes, and therefore this monoterpene mayhave potential for use as a chemopreventive agent againstaflatoxin-induced liver cancer. Balassiano and collaborators[144] observed the effects of perillyl alcohol in the glial C6cell line in vitro and antimetastatic activity in a chorioal-lantoic membrane model and suggested a possible use forperillyl alcohol as an in vivo antimetastatic drug. Da Fonsecaand collaborators [145] discussed perillyl alcohol intranasaldelivery as a potential antitumor agent.The chemopreventiveeffect of topical application of perillyl alcohol on DMBA-initiated and 12-O-tetradecanoylphorbol-13-acetate- (TPA-)promoted skin tumorigenesis and its mechanisms of actionwere investigated in Swiss albinomice [146].Themechanismsof action of perillyl alcohol were investigated in advanced ratmammary carcinomas by Ariazi and collaborators [147], andit was found that it activated the TGF-beta signaling pathwayand induced cytostasis and apoptosis in mammary carcino-mas. These authors also identified differentially expressedgenes in mammary carcinomas treated with perillyl alco-hol. Perillyl alcohol-mediated cell cycle arrest was foundto precede apoptosis, which raised the possibility that theprimary effect of perillyl alcohol is to induce G0/G1 arrest,with apoptosis as a consequence of this growth arrest [139,148]. Using a novel and innovative approach, Lebedeva andcollaborators [149] demonstrated that chemoprevention byperillyl alcohol, coupled with viral gene therapy, reducedpancreatic cancer pathogenesis. Perilla aldehyde is a majorintermediary metabolite of perillyl alcohol in the rat invivo and may contribute to the anticancer effect of perillylalcohol [150]. Phillips and collaborators [151] investigatedthe pharmacokinetics of active drug metabolites after oraladministration of perillyl alcohol in dogs. Samaila and col-laborators [126] verified that perillyl alcohol has potential asa radiosensitizer in chemoradiation therapy of head and neckcancers. Rajesh and collaborators [152] also studied the roleof perillyl alcohol as a radiosensitizer and chemosensitizer inmalignant glioma. Ripple and collaborators [153] conducteda phase I dose-escalation trial of perillyl alcohol given p.o.


on a continuous basis 4 times per day to characterize itsmaximum tolerated dose, toxicities, pharmacokinetic profile,and antitumor activity.This studywas conducted after a phaseI clinical trial of perillyl alcohol in which no objective tumorresponses were noted when it was administered daily [154]. Aphase I trial of perillyl alcohol in patients with advanced solidtumors was conducted by Azzoli and collaborators [155]. Aphase I pharmacokinetic trial of perillyl alcohol in patientswith refractory solid malignancies was performed by Hudesand collaborators [156], in which the authors verified thatperillyl alcohol at 1600–2100mg/m2 p.o. 3 times dailywaswelltolerated on a 14-day on/14-day off dosing schedule. A phaseII trial of perillyl alcohol in patients withmetastatic colorectalcancer was conducted by Meadows and collaborators [157],in which the authors found that oral perillyl alcohol did nothave clinical antitumor activity when used for patients withadvanced colorectal carcinoma, despite preclinical evidenceof anticancer activity.

1.20. 1,8-Cineole/Eucalyptol. The cytotoxicity of 1,8-cineolewas investigated against SK-OV-3, HO-8910, and Bel-7402cell lines [158]. Monoterpene 1,8-cineole demonstrated mod-erate cytotoxicity in Hep G2, HeLa, MOLT-4, K-562, andCTVR-1 cell lines [14]. Asanova and collaborators [159]demonstrated that 1,8-cineole had moderate antioxidant andcytotoxic properties and pronounced analgesic and antitu-mor activity. Cha and collaborators [160] found that 1,8-cineole induced apoptosis in KB cells via mitochondrialstress and caspase activation. Bhattacharjee and Chatterjee[109] promoted the identification of proapoptotic, anti-inflammatory, antiproliferative, anti-invasive, and potentialantiangiogenic activities of eucalyptol by employing a dualreverse virtual screening protocol. A probabilistic set of anti-tumor targets was generated, which can be further confirmedby in vivo and in vitro experiments.

1.21. Perilla Aldehyde. Perilla aldehyde showed markedantioxidant and radical scavenging activity using differentmodel systems, including 1,1-diphenyl-2-picrylhydrazyl radi-cal (DPPH) and beta-carotene-linoleic acid blenching assays,and also inhibited MCF-7, K562, and PC-12 cell growth ina dose- and time-dependent manner, with IC

50values that

ranged from 0.25–5.0mmol/L [106].

1.22. Terpinen-4-ol. Terpinen-4-ol showed cytotoxicityagainst Hep G2, HeLa, MOLT-4, K-562, CTVR-1 [14], andhuman M14 melanoma cells [161]. Bozzuto and collaborators[162] demonstrated that this monoterpene interfered withthe migration and invasion processes of drug-sensitive anddrug-resistant melanoma cells. Terpinen-4-ol also inducednecrosis and cell cycle arrest in murine cancer cell lines [163].

1.23. Citral. Citral is cytotoxic against P388 mouse leukemia[164], HeLa [165], Ishikawa, and ECC-1 cancer cells [166]. Xiaand collaborators [167] reported that citral had a therapeuticeffect on leukemia.

1.24. Carvone. Carvone inhibited viability and proliferationof Hep-2 cells in a dose-dependent manner, with morpho-logical analysis suggesting an involvement of apoptosis. Inthe SOS chromotest, carvone did not cause DNA damageat nontoxic doses. In the DNA repair test, a marked dose-dependent differential toxicity was observed [35]. Carvonealso presented a dose-dependent cytotoxic effect againstHeLa cells [168]. In contrast, more recently, Aydin and col-laborators [169] reported that carvone could be a promisinganticancer agent to improve brain tumor therapy. In thework of Jaafari and collaborators [46], the authors com-pared the cytotoxic effects and molecular mechanisms offive monoterpenes: carvacrol, thymol, carveol, carvone, andisopulegol. The results showed that the carvacrol is the mostactive monoterpene. However, the data of IC

50(0.17 𝜇M on

K562 cells) showed that carvone has significant cytotoxicity.Although carvacrol induce cell cycle arrest in S phase, noeffect on cell cycle was observed for carvone.

1.25. Alpha- and Beta-Pinene. Alpha- and beta-pineneshowed cytotoxicity on tumor lymphocytes [106] and inothers different tumor and nontumor cell lines [157, 170]. Inthe same cases, this cytotoxicity was comparable to doxorubi-cin [171]. Alpha- and beta-pinene did not show antitumoractivity in vivo using the Ehrlich ascites tumor model [157].The cytotoxic potential of alpha-pinene was investigatedin SK-OV-3, HO-8910, Bel-7402 [158], and U937 cell lines[172]. The cytotoxicity of alpha-pinene was comparable todoxorubicin [173]. Bhattacharjee and Chatterjee [109]promoted the identification of proapoptotic, anti-inflammatory, antiproliferative, anti-invasive, and potentialantiangiogenic activities of alpha-pinene by employing adual reverse virtual screening protocol. Jin and collaborators[174] demonstrated that alpha-pinene triggered oxidativestress and related signaling pathways in A549 and HepG2cells. The cytotoxic potential of beta-pinene was investigatedin MCF-7, A375, and HepG2 cancer cells [94] and in otherdifferent tumor and nontumor cell lines [50].

1.26. Geraniol. Carnesecchi and collaborators [175] demon-strated that this monoterpene sensitized human coloniccancer cells to 5-Fluorouracil treatment in vitro. In a laterwork, Carnesecchi and collaborators [176] demonstratedthat geraniol modulated DNA synthesis and potentiated 5-fluorouracil effects on human colon tumor xenografts. Bhat-tacharjee and Chatterjee [109] promoted the identificationof proapoptotic, anti-inflammatory, antiproliferative, anti-invasive, and potential antiangiogenic activities of geraniol byemploying a dual reverse virtual screening protocol. A prob-abilistic set of antitumor targets was generated, which can befurther confirmed by in vivo and in vitro experiments. Geran-iol suppressed pancreatic tumor growth without significantlyaffecting blood cholesterol levels [128]. Polo and de Bravo[177] demonstratedmultiple effects of geraniol onmevalonateand lipid metabolism in Hep G2 cells that affected cellproliferation. More recently, Crespo and collaborators [178]reported transcriptional and posttranscriptional inhibition ofHMGCR and PC biosynthesis by geraniol in 2 Hep-G2 cell


proliferation-linked pathways. Geraniol inhibited the activityof HMG-CoA reductase, which reduced the possibility ofcancer growth [112]. Geraniol also inhibited growth andpolyamine biosynthesis in human colon cancer cells [179].Zheng and collaborators [122] suggested that geraniol showedpromise as a chemopreventive agent because it showed strongGST-inducing activity in the mucosa of the small intestineand the large intestine. Ong and collaborators [180] and Car-dozo and collaborators [181] suggested that geraniol showedpromising chemopreventive effects against hepatocarcino-genesis. More recently, Madankumar and collaborators [182]evidenced that geraniol presents chemopreventive potentialagainst oral carcinogenesis.

1.27. Citronellol. Citronellol exhibited weak cytotoxic effectsagainst HL60 tumor cells [183].

1.28. Camphene. Wright and collaborators [165] verified thatthe cytotoxic activity of humulene on MCF-7 cells wasantagonized by camphene.

1.29. Linalool. Linalool showed cytotoxic effects on C32cells [94], BCC-1/KMC, AGS, RTCC-1/KMC, U

2OS, HeLa,

H520, H661, OSCC-1/KMC, J82 [184], human leukemia,and lymphoma cell lines [185], amelanotic melanoma C32cells, and renal cell adenocarcinoma cells [186]. Usta andcollaborators [187] verified that linalool decreased HepG2viability by inhibiting mitochondrial complexes I and II,increasing reactive oxygen species, and decreasing ATPand GSH levels. Gu and collaborators [188] showed thatlinalool preferentially induced robust apoptosis of a variety ofleukemia cells by upregulation of p53 and cyclin-dependentkinase inhibitors. A study conducted by Ravizza and collabo-rators [189] demonstrated that linalool reversed doxorubicinresistance in human breast adenocarcinoma cells. Maedaand collaborators [190] demonstrated that linalool signifi-cantly suppressed HL60 cell proliferation, induced apoptosis,and promoted cell differentiation. The effect of linalool ondoxorubicin-induced antitumor activity was evaluated byMiyashita and Sadzuca [191].

1.30. Cymene. The anticancer activity of p-cymene was stud-ied by Bourgou and collaborators [50]. Ferraz and collab-orators [9] investigated the cytotoxic effect of p-cymenein three cell lines: HepG2, K562, and B16-F10. The resultsdemonstrated that p-cymene was cytotoxic only to B16-F10cell lines, showing IC

50= 20.06𝜇g/mL.

1.31. Terpinen-4-ol and 𝛼-Terpinolene. Badary [54] investi-gated the cytotoxicity of terpinen-4-ol against two differ-ent cell lines, A-549 and DLD-1. For both cell lines, thismonoterpene induced weak cytotoxicity. In another study,the cytotoxicity of the Helichrysum gymnocephalum essentialoil was evaluated [192]. In addition, this work aimed toestablish correlations between the identified compounds andtheir biological activities (antiplasmodial and cytotoxic).They reviewed researches for essential oils having an activityagainst P. falciparum and/or on MCF-7 cell line in order to

identify, by correlation, the main active compounds. The 𝛼-terpinolene, present in the oil, showed a higher relationshipwith the cytotoxic activity against MCF-7 cell [192].

2. Conclusions

Several studies have shown in vitro and in vivo antitumoractivity of many essential oils obtained from plants. Theantitumor activity of essential oils of many species has beenrelated to the presence of monoterpenes in their composition[8–12].This review shows that many monoterpenes are beingexamined for in vitro and in vivo antitumor activity, present-ing important results that provide insights for the use of suchcompounds for the treatment of cancer. In addition, somestudies show that monoterpenes are already in clinical phasetrials for drug development, as in the case of Perillyl alcohol[145]. However, despite many studies showing the evaluationof possible mechanisms of action of these compounds, themajority of studies still present only preliminary screeningdata and therefore do not describe any mechanism of action.For these studies, the monoterpenes are classified only as“active.” Thus, additional research is needed to be developedto elucidate how various monoterpenes act to inhibit theproliferation and to induce tumor cell death.

Abbreviations

DMBA: 7,12-Dimethylbenz[𝛼]anthraceneDEN: DiethylnitrosamineROS: Reactive oxygen speciesGSH: Reduced glutathioneNMU: N-Nitroso-N-methylureaNNK: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-

butanoneHMG-CoA: 3-Hydroxy-3-methylglutaryl-CoAGST: Glutathione S-transferaseNDEA: N-Nitrodiethylamine.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

This researchwas supported byConselhoNacional deDesen-volvimento Cientıfico e Tecnologico (CNPq) and Coorde-nacao de Aperfeicoamento de Pessoal de Nıvel Superior(CAPES).

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