Anticancer Activities of Essential Oils

PHYTOTHERAPY RESEARCH
Phytother. Res. 28: 1423–1446 (2014)

Published online 16 May 2014 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/ptr.5165
REVIEW
Anticancer Activities of Essential Oils
Constituents and Synergy with Conventional
Therapies: A Review
Jean-François Lesgards,1* Nicolas Baldovini,2 Nicolas Vidal1 and Sylvia Pietri1

1
Aix Marseille Université, CNRS, ICR UMR 7273, 13397, Marseille, France
2
Faculté des Sciences, University of Nice-Sophia Antipolis, CNRS UMR 7272, Institut de Chimie de Nice, Avenue Valrose, 06108, Nice,
Cedex 2, France
Many studies have shown that a large number of terpenoids and aromatic compounds contained in essential oils
have significant anticancer activities, both on cell lines and on tumors in animals. The activity of these constituents
is related to the activation of cell death (apoptosis) induced by the caspases proteins in cancer cells, with minor
modifications of healthy cells. Many phenomena seem to occur, among which are as follows: overexpression
and regulation of liver detoxification enzymes, changes in the membrane potential of cancer cells and mitochon-
dria, production of free radicals in cancer cells, inhibition of angiogenesis, and modification of tumor-inducing
genes. These active essential oil constituents appear to act synergistically with conventional chemotherapy and
radiotherapy, and some clinical studies in humans are beginning to be realized. In this review, we discuss about
the antitumoral activity of 13 essential oil components selected among the most studied in the literature, with a
focus on their possible mode of action. We also report current data on the anticancer properties of several total
essential oils. Copyright © 2014 John Wiley & Sons, Ltd.
Keywords: essential oils; terpenoids; apoptosis; membrane potential; oxidative stress.
with an inhibition of free radical formation rather than

INTRODUCTION
direct free radical scavenging. G. biloba terpenoids
also participated among other compounds to the re-
Essential oils (EO), obtained by steam distillation or duction of the post-ischemic contractile dysfunction
expression, are usually complex mixtures of molecules that follows a brief period of regional ischemia (myo-
that belong almost exclusively to two distinct biosynthetic cardial stunning) in the pig heart (Rioufol et al., 2003).
families: terpenoids and phenylpropanoids. Only the most Besides the well-described pharmacological and clini-
volatile terpenoids are found in EO, the monoterpenic cal researches investigating terpenoids’ cardiovascular
(10 carbons) and sesquiterpenic (15 carbons) components or neuronal effects, it could be of particular interest to
representing the majority of the members of this class, highlight the important amounts of significant studies
albeit diterpenic constituents can occasionally be observed. exhibiting the properties of terpenoids or more gener-
The well-known antitumoral Taxol® (Bristol-Myers ally EOs in the field of cancer research. Radiotherapy
Squibb, NY, USA), extracted from Taxus brevifolia (Nutt., treatments (Sakhi Amrit et al., 2009), like many chemo-
Taxaceae), is a diterpenoid derivative, but it is not volatile therapies, are mainly based on the induction of an
enough to be obtained by hydrodistillation. overproduction of reactive oxygen species (ROS) in
Numerous studies conducted during the past decades tumor cells, and this mechanism is responsible, at least
have shown interesting properties of terpenoids in in part, of their antitumor effect. Anticancer drugs that
several important diseases (DeFeudis, 1998). We have can induce the production of free radicals belong to
already reported on the beneficial effects of terpenoids different classes including the following: intercalating
in cardiac ischemia/reperfusion associated with oxida- agents such as anthracyclines (doxorubicin), antimetab-
tive stress inhibition. Indeed antiischemic effects and olites such as 5-fluorouracil, mitomycin C, and platinum
improved myocardial functional recovery has been ob- derivatives such as cisplatin (Gilliam Laura and St Clair
served after repeated (15-day) oral treatments with Daret, 2011; Lamberti et al., 2012; Matsunaga et al., 2010).
Ginkgo biloba (L., Ginkgoaceae) extract (EGb 761) To date, researchers are unfortunately not able to
(60 mg/kg/day) and its terpenoid constituents such as locate the specific characteristics of malignant cells that
ginkgolides A and B (4 mg/kg/day) (Liebgott et al., would help to selectively act against them. This implies
2000; Pietri et al., 1997). These effects were associated that other rapidly dividing cells, such as blood cells or
cells responsible for hair growth or regeneration of the
intestinal epithelium, are also affected by chemotherapy.
* Correspondence to: Jean-François Lesgards, CNRS, ICR UMR 7273, Consequently, side effects such as hair loss, infections
Aix Marseille Université, Equipe SMBSO, Centre Scientifique de Saint-
Jerome, Service 522, Av. Escadrille Normandie Niemen 13397 Marseille
(destruction of white blood cells), anemia (destruction
Cedex 20, France. of red blood cells), and bleeding (platelet destruction)
E-mail: [email protected] are commonly encountered during chemotherapies. The
Received 05 December 2013
Revised 09 March 2014
Copyright © 2014 John Wiley & Sons, Ltd. Accepted 11 April 2014
1424 J.-F. LESGARDS ET AL.
quest for alternative and complementary treatments of When humans and laboratory animals (rat, guinea
cancerous diseases still motivates the search for new pig, hamster, rabbit, and dog) were given oral doses of
14
antitumoral agents. Among natural extracts, EOs consti- D-[ C] limonene, it was almost completely absorbed in
tute a particularly interesting source of potential antican- the intestine. Indeed, 75–95% of the radioactivity was
cer compounds. They are usually easily accessible and recovered in the urine within 2 or 3 days after ingesting
contain an amazingly large variety of structures. With the compound. In this study, most of the radioactivity
the help of highly resolutive gas chromatographic tech- was recovered in the first 24 h, and less than 10% was
niques, their chemical composition can be analyzed more recovered in feces (Kodama et al., 1976). Only a small
thoroughly than most of the non-volatile natural extracts. part of limonene was recovered in its original form in
This point facilitates considerably the identification of urine. Blood level was maximal after 2 h and remained
single active constituents during bioguided fractionations. at a high level for 10 h and then decreases until be-
Moreover, as discussed later, despite the apparent sim- coming negligible after 48 h. In this study, no significant
plicity of their structures, the combination of their small accumulation in organs was observed.
molecular weight with a globally apolar character often Essential oils constituents are also well absorbed by
imparts a good biodisponibility to many of these EO the skin and more effectively when brought into contact
constituents. Because many of the most abundant EO in a pure or oily solution (Cardozo Monica et al., 2011).
components are also often widespread as natural food Both enantiomers of carvone are well absorbed when
ingredients and in flavor and fragrance formulations, their applied to the skin (300 mg) and can be detected in the
toxicological profile is well known and often supports blood (20–80 g/L) (Jager et al., 2001). Moreover, this
their lack of acute toxicity. For all these reasons, EOs interesting study showed that the two enantiomers are
represent an interesting source of new antitumoral com- not metabolized in the same way, the (R)-isomer being
pounds. The studies in this field have been initiated rather better metabolized, whereas the unchanged form of
lately, but the recent literature demonstrates the growing its (S)-isomer was found three to four times higher
interest of the medical community for these potential than (R).
alternatives to the current chemotherapies.
Indeed, several terpenic EO constituents such as
β-caryophyllene (Park et al., 2011) can specifically induce
the production of ROS in the mitochondria of cancer cells SYNERGISTIC ACTIONS OF ESSENTIAL OILS
without increasing oxidative stress in normal cells. More
COMPONENTS WITH CONVENTIONAL
generally, many studies show that several terpenoids and
aromatics commonly encountered in EO have various TREATMENTS
effects on cancer cells, which can reactivate the natural
process of cell death program (apoptosis) and reduce Some particular EO constituents have been extensively
tumor vasculature. These components may act synergisti- studied in vitro and in animals (Fig. 1) and have shown
cally with current therapies, and new protocols for the significant anticancer capabilities in combination with
treatment of cancer have to be investigated in this area. chemotherapy agents. The combination of geraniol
(150 mg/kg) with 5-fluorouracil (20 mg/kg) significantly
reduces (53%) colon tumor volume in mice. 5-Fluoro-
uracil alone had no effect, and geraniol alone decreased
BIODISPONIBILITY OF ESSENTIAL OILS
CONSTITUENTS
Terpenoids are generally well absorbed by the body

(through oral and transdermal pathways, or by inhalation)
and are easily metabolized by oxidation, hydroxylation,
and conversion in glucuronides or sulfates, although
some of these molecules remain unchanged (Chaves
et al., 2008; Satou et al., 2013). Elimination in the
urine (75–95%) and feces (<10%) is quickly observed
and is usually completed after 1–3 days (Kodama
et al., 1976). During this time, EO components trans-
ported by the blood may exert their action under
original form or through their metabolites.
After oral absorption in rats, glucuronide and sulfate
derivates of carvacrol and thymol (observed in high
amounts in thyme and oregano EO) are found rapidly
in urine, together with the corresponding oxidized
forms (Austgulen et al., 1987). A small amount is found
in the first 24 h and then increases during the slow elimi-
nation phase. In rabbits, terpenoids such as citronellal,
7-hydroxycitronellal, citral, perillaldehyde, myrtenal,
cuminaldehyde, thujone, and carvone are also rapidly
metabolized (Ishida et al., 1989). Farnesol is hydroxylated
by cytochrome P450 in the liver, kidney, and intestine in
mammals including humans (DeBarber et al., 2004; Figure 1. Chemical structures of active compounds from
Staines et al., 2004). essential oils.
Copyright © 2014 John Wiley & Sons, Ltd. Phytother. Res. 28: 1423–1446 (2014)
ANTICANCER ACTIVITIES OF ESSENTIAL OILS IN CANCER THERAPY 1425
tumor size by 26% (Carnesecchi et al., 2004). Other D-Limonene

mice treated with geraniol (20 mg/kg) and docetaxel or
Taxotere® (Sanofi-Aventis, Paris, France) (2 mg/kg) Limonene is one of the most widespread monoterpene
for 38 days exhibited a reduction of pancreas tumor and is present in the majority of the EOs, in amounts
volume (70% compared with control), which was much up to 90% in lemon and citrus EO.
more important when combining the two products than In vitro and in vivo results suggest that limonene is
when using each alone (at least three times more effec- effective against neuroblastoma and leukemia as well
tive than geraniol alone) (Kim et al., 2011). The combi- as other cancers from breast, liver, lungs, skin, stomach,
nation of simvastatin (5 μM) and geraniol (50 μM) and other organs. Results were obtained on skin cancer
significantly inhibits the proliferation of liver cancer in mice in the 1970s and showed inhibition of tumors
cells (Polo et al., 2011), whereas these products alone formation induced by carcinogens (Homburger et al.,
are not effective. 1970; Van Duuren and Goldschmidt, 1976). Since these
The sesquiterpene β-elemene shows a synergistic first studies, many reports have confirmed the retarding
action with cisplatin in lung cancer cell lines (Li et al., effect of limonene in the development of tumors in
2009), as well as with docetaxel (Zhao et al., 2007), or various cancers (stomach, lung, and breast). Limonene
in combination with radiation therapy in lung cancer has shown its effectiveness in blocking the initiation of
cells (Li et al., 2011). β-Elemene substantially increased mammary tumors in animal models (Asamoto et al.,
cisplatin cytotoxicity toward human bladder cancer 2002; Gould et al., 1994). A study has shown that the
5637 and T-24 cells, small-cell lung cancer, and carcino- administration of 0.2 mL of limonene twice a week for
mas of the brain, breast, cervix, ovary, and colorectal 8 weeks, 1 h before administration of nornitrosonicotine
tract in vitro, with dose-modifying factors ranging from decreased by more than 33% lung and stomach cancers
5 to 124 (Li et al., 2013). compared with the control group (Wattenberg and
Another interesting compound is the ubiquitous Coccia, 1991). Reduction of mammary tumors induced
β-caryophyllene. Results suggest that β-caryophyllene by 7,12-dimethylbenz[a]anthracene (DMBA) reached
facilitates the passage of paclitaxel through cancer cells 72% in a study in which rats were fed a diet containing
membrane and thus potentiates its anticancer activity 1–10 g/kg limonene throughout the duration of the study
(Legault and Pichette, 2008). Limonene, another wide- (27 weeks) (Elegbede et al., 1984). Limonene thus
spread terpene, increases oxidative stress in cancer cells blocks the initiation of cancer and also its progression.
in combination with docetaxel, which is accompanied by Indeed, when limonene is administered 1 week after
a decreased level of glutathione (GSH) and activation of the carcinogen, it is also effective, and 50% less tumors
caspases and apoptosis (Rabi and Bishayee, 2009). are observed in rats after 23 weeks (Maltzman and Gould,
Among aromatic EO constituents, eugenol is one of 1991). Limonene also induces regression of existing
the most active and then most studied. Eugenol induces tumors (7.5% limonene ad libitum after 3–5 weeks of
apoptosis of cervical cancer cells without toxicity to treatment) (Chander et al., 1994; Haag et al., 1992; Jirtle
healthy cells and potentiates the effect of chemothera- et al., 1993), and in some animals, the tumors completely
peutic agents: gemcitabine (Hussain et al., 2011) or disappeared. These studies show that the amount of
sulforaphane (Hussain et al., 2012). limonene administered (Haag et al., 1992) should be five
Thymoquinone is another example of potentiating to ten times higher (without observed toxicity) when the
natural agent of doxorubicin (on leukemia, melanoma, tumor is already present than for preventive administra-
colon, cervix, and breast cancers) (Effenberger-Neidnicht tion (Elegbede et al., 1984). If limonene administration
and Schobert, 2011), 5-fluorouracil (gastric) (Lei et al., is stopped, tumors recur in the presence of the carcinogen.
2012), cisplatin (ovarian) (Nessa et al., 2011), and In vitro results also suggest that limonene is effective
radiotheraphy (human breast carcinoma) (Velho-Pereira against neuroblastoma and leukemia (Gould, 1997). In a
et al., 2011). mouse model in which tumor tissue is implanted intact
(from the base of a human cell line developed in a mouse
model) in the gastric wall of animals, limonene treatment
(15 mL/kg/day for 7 weeks) induced a significant decrease
of the mass of the tumor (1.49 ± 0.09 g vs 2.73 ± 0.23 g,
ANTICANCER ACTION OF TERPENIC AND p < 0.05) and also of the amount of peritoneal metastases
AROMATIC COMPOUNDS IN VITRO AND IN (up to 80.0%) and in liver (70.0%) (Lu et al., 2004).
VIVO WITHOUT ASSOCIATION WITH The same blood metabolites are found for humans
CONVENTIONAL TREATMENTS and rats after ingestion of 100 mg/kg limonene, namely
perillic and dihydroperillic acids (Crowell et al., 1994),
As described earlier, terpenoids and aromatic EO con- and no toxicity has been reported. These data on
stituents can be used to potentiate the action of humans are consistent with its low acute toxicity shown
existing therapies. In addition, hundreds of studies by the animal studies: it has a LD50 of 5–6 g/kg (oral)
in vitro and in vivo in animals also show their effi- in rats and mice (Kim et al., 2013) and is devoid of
ciency when used alone, without conventional chemo- genotoxicity (Whysner and Williams, 1996), mutage-
therapy or radiotherapy treatments. A large number nicity, or carcinogenicity (Khamidulina et al., 2005).
of experimental data suggest that their toxicity is Some carcinogenic and nephrotoxic effects in high doses
focused mainly on cancer cells without affecting healthy have been observed in male rats (Kanerva and Alden,
cells. A description of the effects and mode of action of 1987; Kanerva et al., 1987), but in both cases, these data
13 selected pure EO components is detailed later, and may be inappropriate for interspecies extrapolation and
the structures of these compounds are shown in Fig. 1. human risk assessment (Webb et al., 1990). Dermatolog-
Table 1 summarizes the most significant studies con- ical assays have concluded that limonene is a skin irri-
cerning these compounds. tant, but these effects are in fact due to its oxidation
1426
Table 1. In vitro and in vivo effects of essentials oils constituents on cancer cells and tumors
Model Toxicity data on

Compound cells/animals Cancer type Carcinogenesis Efficient dose Effect healthy cells/animals References
D-Limonene in vivo Mice Stomach Injection BGC-823 15 mL/kg/day for 45% tumor No toxic effect on Lu et al., 2004
cells 7 weeks regression healthy group
(TR) 70–80%
metastases
inhibition
Mice Lung and Nornitrosonicotine In diet 1 h prior Tumor development No toxic effect on Wattenberg and
forestomach (NNK) to NNK inhibition (TDI) healthy group Coccia, 1991
Copyright © 2014 John Wiley & Sons, Ltd.

Rats Breast Ras oncogene 5% limonene in TDI: 135 vs 83 days No toxic effect on Gould et al., 1994
v-Ha-ras+/+ diet three times for controls healthy group
per week
Rats Breast Single dose of NMU, 5% limonene in 34% TDI at No toxic effect on Gould et al., 1994
30 mg/kg i.v. diet three times week 30 healthy group
per week 1 week
after NMU injection
Rats Breast 50 mg/kg MNU i.v. TDI No toxic effect on Asamoto
in Hras128 healthy group et al., 2002
transgenic rats
Rats Breast 7,12-Dimethylbenz[a] 1–10 g/kg in diet 72% TDI No toxic effect on Elegbede
anthracene (DMBA) for 27 weeks healthy group et al., 1993
Rats Breast DMBA 50% TDI at No toxic effect on (Maltzman and
week 23 healthy group Gould, 1991)
Rats Breast DMBA 7.5–10% in diet 100% of TR of Little or no toxicity Haag et al., 1992
J.-F. LESGARDS ET AL.
after 3–5 weeks small tumor is observed

of induction 53% TR of large
tumor at week 11
Rats Breast NMU 7.5–10% in diet 100% TR of small Little or no toxicity Haag et al., 1992
after 3–5 weeks tumor is observed
of induction 78% TR of large
tumor at week 11
Rats Breast DMBA (50 mg/kg) 10% in diet for 87% TR of small Little or no toxicity Jirtle et al., 1993
15 weeks after tumor is observed
tumor development 25% TR of large
tumor
Rats Breast NMU 5–10% in diet for 50–100% TR Little or no toxicity Chander et al., 1994
4 weeks after tumor is observed
development
Geraniol in vitro PC3 Prostate 0.25–0.5 mM ≥65% inhibition Not reported Kim et al., 2011
of cell growth
B16F10 Skin IC50: 160 μM for Inhibition of cell Not reported McAnally Jennifer
geraniol and 5.1 μM growth et al., 2003
(Continues)
Phytother. Res. 28: 1423–1446 (2014)

Table 1. (Continued)
for geranyl-O- Cell cycle arrest

acetylhydroquinone G1 and G2/M
Caco-2 Colon 400 μM 70% inhibition of Not reported Carnesecchi
cell growth et al., 2002
Carnesecchi
et al., 2001
MIA PaCa-2 Pancreas IC50: 200–400 μM Inhibition of cell Wiseman
and BxPC-3 growth et al., 2007

Cell cycle arrest G1
MIA PaCa2 Pancreas IC50: 265 μM 70% inhibition Burke et al., 1997
of cell growth
MCF-7 Breast Inhibition of cell Minimally affection Duncan et al., 2004
growth on normal cells
Cell cycle arrest (MCF-10F)
G0/G1
Geraniol in vivo Mice Prostate Tumor xenograft mice 60 mg/kg by 35% TR No toxic effect on Kim et al., 2011
intratumoral healthy group
injection for
38 days
Rats Kidney DEN injection i.p. 100 and 56% and 79% No toxic effect on Ahmad et al., 2011
and Fe-NTA 2/week 200 mg/kg per TDI, respectively healthy group
for 16 weeks os for 16 weeks
Rats Liver DEN (200 mg/kg), 250 mg/kg for 53% TDI No toxic effect on Cardozo et al., 2011
six intragastric doses 5 weeks healthy group
(30 mg/kg body
weight) 2-AAF
Rats Liver Transplant of Morris 3.5 g/kg of diet 98% TDI No toxic effect on (Yu et al., 1995)
7777 hepatomas for 8 weeks, healthy group
2 weeks before
induction
Mice Colon TC-118 human 150 mg/kg 26% TR No toxic effect on Carnesecchi
tumors transplanted healthy group et al., 2004
in Swiss nu/nu mice
ANTICANCER ACTIVITIES OF ESSENTIAL OILS IN CANCER THERAPY
Rats Colon DEN 250 mg/kg for 35% inhibition No toxic effect on Vieira et al., 2011
9 week of aberrant healthy group
crypt foci
Hamsters Pancreas Transplanted PC-1 20 g/kg for 100% TDI No toxic effect on Burke et al., 1997
hamster pancreatic 4 weeks, 1 week healthy group
adenocarcinomas before
transplantation
Hamsters Mouth, Topical application 100% TDI No toxic effect on Vinothkumar and
pouch 0.5% DMBA three healthy group Manoharan, 2011
Phytother. Res. 28: 1423–1446 (2014)

1427
(Continues)
1428

times a week, for 250 mg/kg by

14 weeks intragastric
administration
Rats Skin Transplant of 1–10 g/kg for 48% TDI No toxic effect on Yu et al., 1995
B16 melanomas 5 weeks, 2 weeks healthy group
before induction
Thymol and B16F10 Skin IC50: 400 μM for Inhibition of cell Not reported Satooka and
carvacrol thymol and growth Kubo, 2012

in vitro 550 μM for
carvacrol
B16F10 Skin IC50: 120–150 μM Inhibition of cell Not reported He et al., 1997
for carvacrol growth
and thymol
MG63 Bones IC50: 200–400 μM, Inhibition of cell Not reported Chang et al., 2011
thymol growth
Apoptosis
DBTRG-05MG Brain IC50: 400 μM, thymol Inhibition of cell Not reported Hsu et al., 2011
growth
Apoptosis
HepG2,Caco-2 Liver, IC50: 350, 600, and Inhibition of cell Not reported Slamenova
and V79 colon, 250 μM, respectively, growth et al., 2007
lung thymol and carvacrol Apoptosis
HL-60 Blood IC50: 25–50 μM, Inhibition of cell No toxic effect on Deb Dipanwita
thymol growth peripheral blood et al., 2011

Cell cycle arrest mononuclear cell
G0/G1 (PBMC) up
Apoptosis to 100 μM
Thymoquinone SCC VII and Skin 60 μM Inhibition of cell Inhibition of L929 Ivankovic
in vitro FsaR growth (86% and mouse fibroblast et al., 2006
92%, respectively) growth (62%)
A431 and Skin IC50: 10 μM Inhibition of Not reported Das et al., 2012
Hep2 cell growth
Apoptosis (68%)
HCT116 Colon 60 μM Apoptosis (85%) Not reported Gali-Muhtasib
et al., 2008
MDA-MB-435, Skin, IC50: 50–78 μM Inhibition of Not reported Attoub et al., 2013
HT29, LNM35, colon, cell growth
MCF-7 lung, and Apoptosis (>50%)
breast
HepG2 Liver IC50: 34 μM Inhibition of Not reported Attoub et al., 2013
cell growth
Apoptosis (70%)
Phytother. Res. 28: 1423–1446 (2014)

(Continues)
SaOS-2 Bones Inhibition of cell Not reported Peng et al., 2013

growth
Apoptosis
Thymoquinone Mice Skin SCC VII (squamous 5 mg/kg by intratumoral 52% TDI Ivankovic
in vivo cell carcinoma) and injection at days 3, 4, et al., 2006
FsaR (fibrosarcoma) 5, and 11
Rats Colon DMH (20 mg/kg) 5 mg/kg by i.p. injection 67% TDI and No toxic effect on Jrah-Harzallah
subcutaneous for for 10 weeks 33% TR healthy group et al., 2013

10–20 weeks
Mice Skin Sarcoma 180 cells 10 mg/kg/day (every 75% TR No toxic effect on Das et al., 2012
injected intradermally alternate day for healthy group
into the right flank 18 days) by i.v.
injection after tumor
development
Mice Lung Athymic mice 10 mg/kg/3 days/week 39% TR No toxic effect on Attoub et al., 2013
inoculated with for 18 days by i.p. healthy group
LNM35 cells injection, 1 week after
tumor development
Farnesol MIAPaca2 Pancreas IC50: 39 μM Inhibition of cell Not reported Burke et al., 1997
in vitro growth
CEM-C1 Blood 9.0–31.5 μM Not reported Melnykovych
et al., 1992
Farnesol B16F10 Skin IC50: 45 vs Inhibition of cell Not reported McAnally Jennifer
in vitro 160 μM for geraniol growth et al., 2003
and G2/M
Hamsters Pancreas Transplanted PC-1 20 g/kg for 4 weeks, 100% TDI No toxic effect on Burke et al., 1997
hamster pancreatic 1 week before healthy group
adenocarcinomas transplantation
Rats Liver DEN (200 mg/kg), 250 mg/kg for 87% TDI No toxic effect on Ong et al., 2006
six intragastric 8 weeks healthy group
doses (30 mg/kg
body weight) 2-AAF
(-)-α-Bisabolol KLM1, KP4, Pancreas 5–6.25 μM Inhibition of cell Low toxicity on Seki et al., 2011
in vitro Panc1, MIA growth pancreatic cells
Paca2 Apoptosis (>50%) (ACBRI515)
(18% apoptosis)
HepG2 Liver 10 μM Inhibition of cell Not reported Chen et al., 2010
growth
Apoptosis (70%)
K-562 Blood IC50: 6.37 μM Not reported da Silva et al., 2010
Phytother. Res. 28: 1423–1446 (2014)

1429
(Continues)
1430

Inhibition of cell
growth
T67, U87 Brain 2 and 4 μM, Apoptosis (50%), No toxicity on rat Cavalieri et
respectively 100% at 10 μM astroglial cells al., 2004
(-)-α-Bisabolol Mice Pancreas Subcutaneous 1 g/kg once a week 70% TDI No toxic effect on Seki et al., 2011
in vivo inoculation of either for 3 weeks by healthy group
KLM1 or KP4 cells intragastric
administration,

1 week after cells
inoculation
HER-2/neu Breast 10 mg per mouse TDI No toxic effect on Costarelli
transgenic two times per healthy group et al., 2010
mice intramammary
infusion
(-)-α-Bisabolol Blood cells Blood IC50: 14 μM in acute Inhibition of cell IC50: 95 and 62 μM Cavalieri et al., 2011
+ +
ex vivo from patients lymphoid leukemia growth CD33 and CD34 ,
with leukemia Apoptosis respectively
Blood cells Blood IC50: 45–65 μM for Inhibition of cell IC50: 95 and 62 μM Cavalieri et al., 2011
+ +
from patients acute myeloid growth CD33 and CD34 ,
with leukemia leukemia Apoptosis respectively
(-)-β-Elemene U87 and C6 Brain IC50: 60 μM Inhibition of cell Not reported Zhu et al., 2011
in vitro growth
Cell cycle arrest
G0/G1
A2780 Ovaries IC50: 330 μM Inhibition of cell IC50:114 μg/mL for Li et al., 2005
growth normal cells
Cell cycle arrest G2 (IOSE-397)
MG63 and Bones IC50: 70 and Inhibition of cell Not reported Liang and Lu, 2012
SaOS-2 62 μM, respectively growth
Apoptosis
MCF-7, MCF Breast 30 μM Increase the Not reported Xu et al., 2012
7/DOX cytotoxicity
of doxorubicin
H22 Liver Inhibition of cell Not reported Bao et al., 2012
growth
C6 and Brain 80 μM Apoptosis (40%) Not reported Zhao et al., 2012
U87MG
SGC7901 Stomach IC50: 100 μM Inhibition of cell Not reported Liu et al., 2011
growth
Apoptosis
DU145 and Prostate IC50: 340 and Inhibition of cell Not reported Li et al., 2010
PC-3 500 μM, respectively growth
Phytother. Res. 28: 1423–1446 (2014)

(Continues)

Apoptosis
CCL-222 Colon IC50: 230 μM Inhibition of cell Not reported Li et al., 2010
growth
Apoptosis
B16BF10 Skin IC50: 469 μM Inhibition of cell Not reported Chen et al., 2011a
growth
Inhibition of VEGF

(from 20 μM)
(-)-β-Elemene Mice Skin B16F10 cells injected 20–50 mg/kg once 50% TDI for No toxic effect on Chen et al., 2011a
in vivo subcutaneously a day for 3 weeks, 20 mg/kg healthy group
C57BL/6 mice 1 day after injection 60% TDI for
50 mg/kg
Mice Liver H22 cells HCC TDI No toxic effect on Bao et al., 2012
xenograft healthy group
transplantation
Mice Lung A549 lung 45 mg/kg Tumor No toxic effect on Li et al., 2012
adenocarcinoma regrowth delay healthy group
xenograft
Mice Brain Subcutaneous 50 mg/kg for 50% TDI No toxic effect on Zhao et al., 2012
injection of 1 week by i.p. healthy group
U87 cells injection
(-)-β-Caryophyllene PC-3 and Prostate (-)-β-Caryophyllene 30–50 μM Inhibition of cell Not reported Park et al., 2011
in vitro MCF-7 and breast (oxide) growth
Apoptosis
α-Humulene A-549 and Lung and IC50: 55 μM Inhibition of cell Not reported Sylvestre
in vitro DLD-1 colon growth et al., 2007
LNCaP Prostate IC50: 55 μM Inhibition of cell Not reported Loizzo et al., 2007
growth
MCF-7 Breast IC50: 157 μM Inhibition of cell Not reported Legault and
growth Pichette, 2008
Nerolidol in vitro A-549 and Lung and Inhibition of cell Not reported Sylvestre
DLD-1 colon growth et al., 2007

Germacrone MDA-MB-231 Breast IC50: 200–300 μM Inhibition of cell Not reported Zhong et al., 2011
in vitro growth
Cell cycle arrest
G0/G1
and G2-M
Apoptosis (35%)
(Continues)
Phytother. Res. 28: 1423–1446 (2014)

1431
1432
MCF-7 Breast IC50: 200 μM Inhibition of cell Not reported Chen et al., 2011b
growth
Cell cycle arrest

G0/G1
and G2-M
Apoptosis (45%)
Eugenol HL-60 and Blood IC50: 24 and 39 μM, Inhibition of cell Not reported Yoo et al., 2005
in vitro U-937 respectively growth
Apoptosis
HepG2 Liver IC50: 119 μM Inhibition of cell Not reported Yoo et al., 2005
growth
Apoptosis
HCT-15 and Colon IC50: 300 and Inhibition of cell Not reported Jaganathan
HT-29 500 μM, growth et al., 2011
respectively Cell cycle arrest
sub-G1
Apoptosis
MCF-7 Breast IC50: 500 μM Inhibition of cell Not reported Vidhya and
growth Devaraj, 2011

Apoptosis (65%)
Sbcl2 and Skin IC50: 0.5 μM Inhibition of cell Not reported Ghosh et al., 2005
WM3211 growth
Eugenol Mice Skin B16 melanoma model 125 mg/kg twice 40% TDI No toxic effect on Ghosh et al., 2005
in vivo per week i.p. 50% reduction in healthy group
metastasis
Mice Skin DMBA 1.25 mg/kg twice No toxic effect on Pal et al., 2010
per week healthy group
Rats Stomach MNNG (150 mg/kg 100 mg/kg three Apoptosis and No toxic effect on Manikandan
body weight) by times/week for inhibition healthy group et al., 2010
intragastric intubation 26 weeks, from of invasion and
the beginning angiogenesis
Phytother. Res. 28: 1423–1446 (2014)

products (Kim et al., 2013). In conclusion, most of the carvacrol (Jenner et al., 1964). In dogs, intravenously
studies prove the harmlessness of limonene, which is injected lethal doses were 0.15 g/kg for thymol and
besides included in the GRAS (generally recognized as 0.31 g/kg for carvacrol (Caujolle and Franck, 1944). A
safe) list (Burdock et al., 1990). mutagenicity study of thymol gave negative results with
the Ames tester strain TA97 (Azizan and Blevins, 1995)
while the mutagenic potential of carvacrol was never
Geraniol investigated (De Vincenzi et al., 2004). Further toxico-
logical studies are needed on these compounds to fully
Geraniol is a widespread unsaturated monoterpenic appreciate their pharmacological potential, because a
alcohol. It is a major constituent of rose and palmarosa promising result was given by a metabolic study where
EO (85%). It is also present in the EOs of geranium carvacrol was shown to be excreted with urine after
species (25–50%) and lemongrass (30%). As limonene, 24 h in large quantities or unchanged, or as glucuronide
geraniol shows interesting anticancer properties and sulfate conjugates (De Vincenzi et al., 2004).
(Crowell, 1999). The efficacy of geraniol has been dem-
onstrated by numerous studies in vitro and in vivo on
many cancers including prostate (Kim et al., 2011), Thymoquinone
kidney (Ahmad et al., 2011), liver (Cardozo et al., 2011;
Ong et al., 2006; Polo et al., 2011), colon (Carnesecchi This compound is predominantly found in the EO of
et al., 2004; Carnesecchi et al., 2001; Carnesecchi et al., Nigella seeds (24%) (Nigella sativa F., Ranunculaceae)
2002; Vieira et al., 2011), pancreas (Burke et al., 1997; also called black cumin. The biosynthesis of this quin-
Wiseman et al., 2007), breast (Duncan et al., 2004), onic compound probably involves the oxidation of
mouth (Vinothkumar and Manoharan, 2011), and skin thymol or carvacrol. This is a highly promising compo-
(Yu et al., 1995). Geraniol at 100 μM induced an inhibi- nent that is effective in cellular models as well as on
tion of proliferation in cultured cells of colon cancer animal tumor (fibrosarcoma models) with a 52% inhibi-
(Carnesecchi et al., 2001) and reduced tumor volume tion of tumor growth (one to four injections of doses of
by 26% with 150 mg/kg (Carnesecchi et al., 2004). Gera- 5 mg/kg) (Ivankovic et al., 2006). The results were dose
niol causes cell significant cycle arrest (G1) at 0.25 mM dependent, and in vivo activity was better than in vitro.
and apoptosis both in cultured cells and animal tumors Thymoquinone also activates apoptosis in colon cancer
(60 mg/kg) in prostate cancer (Kim et al., 2011). An ester cells (Gali-Muhtasib et al., 2008); it reduced tumor
derivative of geraniol, geranyl-O-acetylhydroquinone, incidence (67%) in 1,2-dimethylhydrazine-induced colonic
seems to have superior properties to geraniol itself carcinogenesis (Jrah-Harzallah et al., 2013). Thymo-
(McAnally Jennifer et al., 2003). quinone is also active in lung, liver, melanoma, and breast
Antitumoral effects of geraniol can be significantly cells (Attoub et al., 2013). In this last work, the anticancer
increased by co-administration of conventional treatment activity of the compound was also investigated in athymic
such as 5-fluorouracil as described earlier (McAnally mice inoculated with the LNM35 lung cells. Administra-
Jennifer et al., 2003). Geraniol has rather low acute and tion of thymoquinone (10 mg/kg i.p.) for 18 days inhibited
chronic toxicities, with oral, dermal, and intramuscular the LNM35 tumor growth by 39%. Thymoquinone is also
LD50 around 4 g/kg in rodents. No mutagenic or active on skin tumors (Das et al., 2012) and osteosarcoma
genotoxic properties were ever recorded in the published (Peng et al., 2013). Finally, other quinones from EO
studies, and human tests showed no skin irritant proper- may have potential anticancer effects such as juglone
ties (Lapczynski et al., 2008b). and β-lapachol (Lu et al., 2012).
The antitumor activity of monoterpenoids is related
to their chemical structures and functions although this
Thymol and carvacrol is not clearly defined. Acyclic and bicyclic compounds
seem to have no significant activity compared with
Thymol is a monoterpenic phenol also associated with monocyclic ones, and hydroxylation of monoterpenes
cancer cell death related to various organs: melanoma increases their anticancer activity (Loza-Tavera, 1999).
(He et al., 1997; Satooka and Kubo, 2012), osteosarcoma Thymoquinone is somewhat more toxic than the
(Chang et al., 2011), glioblastoma (Hsu et al., 2011), lung other compounds described in this review and showed
cancer (Slamenova et al., 2007), breast cancer (El Babili cytotoxic and genotoxic effects on primary rat hepato-
et al., 2011), leukemia (Deb Dipanwita et al., 2011), cyte cultures (Khader et al., 2009). Its toxicity mecha-
hepatoma (Slamenova et al., 2007), and colon cancer nism seemed dependent of the route of administration
(Slamenova et al., 2007). Like for the action of most (Abukhader, 2012). In rats, the oral LD50 was deter-
terpenoids, DNA strand breaks and cell cycle block in mined to be 794.3 mg/kg, and it is 57.5 mg/kg after
G0/G1 phase were observed (Deb Dipanwita et al., intraperitoneal injection. Slightly higher values were
2011). Carvacrol is an isomer of thymol, and these two observed in mice (Al-Ali et al., 2008). As pointed out
compounds are often tested in parallel in activity by the authors of this study, these values are 10–15 times
studies. They are also often found in the same plants (i.p.) and 100–150 times (oral) higher than doses of
as in oregano EO (Origanum compactum Bentham, thymoquinone reported for its antiinflammatory, anti-
Lamiaceae). These two compounds show similar cura- oxidant, and anticancer effects. In another study, the
tive properties on several cancers including liver, colon, oral LD50 in mice was 2.4 g/kg. The high doses pro-
and lung (Slamenova et al., 2007). Despite their wide- duced hypoactivity and difficulty in respiration, and
spread occurrence (especially as spice constituents), several metabolic changes on various organs, but no
toxicity studies on thymol and carvacrol are scarce. toxic effects were noticed with subchronic doses previ-
The acute oral LD50 in mg/kg was determined as 980 ously shown to have cytoprotective activity (Badary
(rat) and 880 (guinea pig) for thymol and 810 (rat) for et al., 1998).
Farnesol α-Bisabolol derivatives (thiosemicarbazones) also have

interesting antitumor properties on different cancer cell
With five additional carbons in their skeleton, sesquiter- lines, especially leukemia at relatively low concentrations
penes and their derivatives display a structural diversity between 0.01 and 4.22 μM (da Silva et al., 2010).
far superior to monoterpenoids, while still keeping The toxicity of α-bisabolol has been investigated in
physicochemical properties that ensure a good biodis- several animal models, and its acute toxicity is generally
ponibility. Consequently, they constitute a very promis- very low (Bhatia et al., 2008; Habersang et al., 1979). It is
ing class of natural compounds in the search for new not toxic for the reproduction at any dose level tested,
anticancer agents. Many sesquiterpenoids have indeed and mutagenicity and genotoxicity studies did not show
shown such potential (Modzelewska et al., 2005). any problematic properties for this material (Bhatia
Farnesol has capabilities equivalent to its mono- et al., 2008).
terpenic homologue geraniol in pancreatic cancer.
Complete inhibition of tumor growth was observed for
each of these two compounds with 20 g/kg in the diet (-)-β-Elemene
1 week before tumor induction and during the 5 weeks
of the experiment (Burke et al., 1997). In certain Elemane derivatives are found in a wide variety of
animals, tumor regressions have been also observed plants. The sesquiterpenes α-, β-, γ-, and δ-elemenes
when both compounds were administered after an onset are structural isomers, and β-elemene in particular
of the tumor larger than 2 mm in diameter. In the initia- shows significant antitumor properties. It blocks cells
tion phase of liver tumors in rats, doses of 250 mg/kg in the G0/G1 (Zhu et al., 2011) and G2 phases (Li et al.,
body weight reduced the appearance of nodules (13% 2005) and leads to an inhibition of tumor growth and
against 100% for control animals), and tumor size was induction of apoptosis. β-Elemene is effective against
divided by 2 (Ong et al., 2006). In cell cultures, farnesol various cancers: osteocarcinoma (Liang and Lu, 2012),
was more effective than geraniol (60–90% of inhibition lung (Li et al., 2012; Li et al., 2009) and mammary tumors
of cellular growth with 25 μM farnesol and 100 μM resistant to doxorubicin (Xu et al., 2012), liver cells and
geraniol) (Burke et al., 1997). Farnesol is also effective tumors in animals (Bao et al., 2012), glioblastoma (Zhao
on leukemia cells growth at concentrations from 9 to et al., 2012), gastric cancer (Liu et al., 2011), prostate
31.5 μM (Melnykovych et al., 1992). cancer (Li et al., 2010), melanoma (Chen et al., 2011a),
All of the toxicology studies on farnesol showed a and ovarian cancer (Li et al., 2005). Using in silico models,
very low toxicity, either by oral or dermatological β-elemene was predicted to be mutagen on rat, but not on
routes, with an oral LD50 of >5 g/kg in rats (Lapczynski mice and devoid of hepatotoxicity on rodents (Balaji and
et al., 2008c). Chempakam, 2010).
(-)-β-Caryophyllene
(-)-α-Bisabolol
(-)-β-Caryophyllene is one of the most widespread
α-Bisabolol is a sesquiterpenic alcohol present in a large
sesquiterpenes. It is present in large amounts (75%) in
number of EO, with stereoisomere (6S, 7S)-α-(-)-
the EO of clove bud (Syzigium aromaticum or Eugenia
bisabolol being the most common. It also ranks among
caryophyllata, (L.) Merr. and L.M. Perry, Myrtaceae),
this class of sesquiterpenes potentially active against
hemp (Cannabis sativa L., Cannabaceae), black pepper
cancer and is the major component of the EO of
(Piper nigrum, L., Piperaceae) (35%), Ylang-ylang
chamomile (Matricaria chamomilla L., Asteraceae),
(Cananga odorata (Lam.) Hook. f. and Thomson,
poplar buds of North American Populus deltoides (Bartr.
Annonaceae) (30%), and guava leaves (Psidium
And Marsh., Salicaceae), and Artemisia desertorum
cattleianum Sabine, Myrtoideae) (60%).
(L., Asteraceae), a sagebrush from Siberia and China
β-Caryophyllene has shown antitumor properties in
(in typical amounts of 13%, 25%, and 55%, respec-
particular against prostate cancer and breast cancer
tively). Many studies have demonstrated its effectiveness
(Park et al., 2011) and several types of solid tumors (Kubo
against the development of various cancers: pancreas
et al., 1996). It also induces apoptosis in lymphoma cell
(Seki et al., 2011), liver (Chen et al., 2010), brain
lines (Amiel et al., 2012).
(Cavalieri et al., 2004), and breast in mice (Costarelli
et al., 2010), or against leukemia [ex vivo blasts from 42
acute leukemia, Ph /Ph+B-acute lymphoid leukemia and α-Humulene
acute lymphoid leukemia (AML)] (Cavalieri et al., 2011).
Low doses can be effective: a 24-h treatment with This sesquiterpene is present in hops (Humulus lupulus
2.5–3.5 μM α-bisabolol reduced by 50% cell viability L., Cannabinaceae) (36%) and sages EO (Salvia spp.)
of rat glial tumor and by 100% with 10 μM (Cavalieri (15%) and has shown antitumor activity in lung and
et al., 2004). colon cancers with IC50 values for growth inhibition of 66
These results were observed in different cell lines and and 46 μg/mL, respectively (Sylvestre et al., 2007) as well
pancreatic tumors in mice with 1 g/kg once a week for as in prostate cancer (IC50 of 11.24 μg/mL) (Loizzo et al.,
3 weeks (Seki et al., 2011). Mammary tumors established 2007) and breast cancer (Legault and Pichette, 2008).
in mice (HER-2/neu transgenic animals) decreased
significantly with doses of 10 mg per animal (Costarelli
et al., 2010). On blood cells taken from 42 patients with Nerolidol
leukemia, IC50 was 14 ± 5 μM after 24 h of exposure in
chronic myeloid leukemia and 45 ± 7 and 65 ± 5 μM for Some compounds have been less studied but have inter-
AML (Cavalieri et al., 2011). esting properties that remain to be clarified. This is the
case of nerolidol contained in Niaouli EO (Melaleuca and is widely used as a food additive (Kamatou et al.,
quinquenervia (Cav.) S.T. Blake, Myrtaceae) (25%) 2012). Its toxicity should however be better defined for
and mugwort leaf chamomile (Artemisia chamaemeli- other applications, because even if it seems to have a
folia, Vill., Asteraceae) (22%). This compound is a rather low acute toxicity on rats (Clark, 1988), some
sesquiterpenic alcohol, which has shown antitumor hepatotoxic (Soundran et al., 1994; Thompson et al.,
activity in lung cancer cell lines and colon with IC50 1998) and genotoxic effects (Minet Emmanuel et al.,
values for growth inhibition of 66 and 46 μg/mL, respec- 2012) have been reported for this compound.
tively (Sylvestre et al., 2007). The LD50 of nerolidol was
determined to be superior to 5 g/kg in rats, mice, and
rabbits (Lapczynski et al., 2008a). Up to now, no data Whole essential oils or essential oils mixture
are available on the other types of toxicity such as
chronic, reproductive, and developmental toxicities, Several teams have also evaluated EO globally for their
mutagenicity, genotoxicity, and carcinogenicity. anticancer activity. Table 2 summarizes the most signifi-
cant studies concerning these EO. This is the case of
plants from the family of Labiatae and Lauraceae such
Germacrone as sage (Salvia officinalis L., Lamiaceae) and bay tree
(Laurus nobilis L., Lauraceae) (Loizzo et al., 2007)
Germacrone is also one of these promising sesquiter- against prostate carcinoma LNCaP, MCF-7 breast
penoids whose effects have been discovered very re- cancer, renal cell adenocarcinoma ACHN, and mela-
cently (Lu et al., 2012). It is present in significant noma C32 cell lines. L. nobilis fruit oil exerted the
amounts (2–10%) in turmeric EO (Curcuma longa L., highest activity with IC50 values on C32 and ACHN of
Zingiberaceae) and induces cell cycle arrest and 75.45 and 78.24 μg/mL, respectively. Oregano EO (O.
apoptosis (between 50 and 200 μM) (Chen et al., 2011b; compactum Bentham, Lamiaceae) exhibited an IC50 of
Zhong et al., 2011). 34 μg/mL against human breast cancer cells (MCF7)
(El Babili et al., 2011). Different fractions can be identi-
fied to clarify the bioactive compounds, and another
Eugenol study on oregano EO showed that carvacrol was the
most active oil component (Mezzoug et al., 2007).
Together with the terpenic constituents, EOs often contain Many other EOs have been tested as Helichrysum
also aromatic components coming from a distinct bio- gymnocephalum ((DC.) Humb., Asteraceae) (Afoulous
synthetic pathway. Eugenol (4-allyl-2-methoxyphenol) is et al., 2011), some species of wormwood (Artemisia
a member of the phenylpropanoid family. It is present in capillaris Thunb, Asteraceae) (Cha et al., 2009), rosewood
many EOs: leaf and stem of clove (over 90%) (S. (Aniba rosaeodora Ducke, Lauraceae) (Soeur et al.,
aromaticum or E. caryophyllata, (L.) Merr. and L.M. Perry, 2011), sweetfern (Comptonia peregrina (L.) J.M. Coulter,
Myrtaceae), cinnamon leaves (Cinnamomum zeylanicum Myricaceae) (Sylvestre et al., 2007), nutmeg (Myristica
Nees, Lauraceae) (80%), allspice (Pimenta dioica (L.) fragrans Houtt, Myristicaceae) and nono or apple dog
Merr., Myrtaceae), berries from Indian wood (Pimenta tree (Morinda citrifolia L., Rubiaceae) (Piaru et al.,
racemosa (Mill.) J.W.Moore, Myrtaceae) (50%), and 2012), balsam fir (Abies balsamea (L.) Mill. Pinaceae),
leaves of basil (Ocimum basilicum L., Lamiaceae) (20%). clove (Eugenia caryophyllus (L.) Merr. and L.M. Perry,
Literature has brought increasing data about eugenol’s an- Myrtaceae) (Park et al., 2011), Nigella (N. sativa L.,
tioxidant, antiinflammatory, antimutagenic, antigenotoxic, Ranunculacea) (Ait Mbarek et al., 2007; Edris, 2009;
and anticancer activities. Molecular mechanisms of Randhawa and Alghamdi, 2011; Salomi et al., 1991), and
apoptosis induced by eugenol in skin tumors, osteosar- eastern lemongrass (Cymbopogon flexuosus (Nees ex
coma (Shin et al., 2007), leukemia (Yoo et al., 2005), cells Steud.) W. Watson, Poaceae) (Sharma et al., 2009).
and gastric tumors (Manikandan et al., 2010), and colon In the work on H. gymnocephalum ((DC.) Humb.,
(Jaganathan et al., 2011) and breast cancers (Vidhya and Asteraceae) (Afoulous et al., 2011), 23 compounds
Devaraj, 2011) are documented. Eugenol at a concentra- were identified. β-Selinene (R2 = 0.76), α-terpinolene
tion of 0.5 μM inhibited cell growth by 50% after 24 h in (R2 = 0.88), and aromadendrene (R2 = 0.90) presented
melanoma cell lines (Sbcl2 and WM3211), and administra- a higher relationship with the anticancer activity of
tion of 125 mg/kg twice a week intraperitoneally in mice the whole oil thus showing that many other EO con-
(melanoma xenograft model) (Ghosh et al., 2005) reduces stituents may potentially have anticancer activity even
the size of tumors by 40% compared with control animals. though they have not been yet studied.
This extended the survival median of 20% with a 50% Lemon balm (Melissa officinalis L., Lamiaceae) was
reduction in metastasis. Other researchers have observed effective against a series of human and animal cancer
a 42% decrease in the number of mice developing cell lines related to lung, breast, colon, blood, and skin
melanoma induced by DMBA (Pal et al., 2010) with oral cancers (De Sousa et al., 2004).
administration of 1.25 mg/kg eugenol twice per week. Among ten EO tested [mint (Mentha spicata L.,
The administration of 100 mg/kg of eugenol in rats Lamiaceae), ginger (Zingiber officinale Rosc., Zingi-
developing gastric carcinomas induced by N-methyl-N beraceae), lemon (Citrus limon Burm. F., Rutaceae),
(′)-nitro-N-nitrosoguanidine (MNNG) (three times per grapefruit (Citrus paradisi Macf., Rutaceae), jasmine
week from the beginning of exposure of MNNG until (Jasminum grandiflora L., Oleaceae), lavender (Lavan-
the end of the study, 26 weeks) leads to apoptosis in dula angustifolia Mill., Lamiaceae), chamomile (Matri-
tumor cells and did not affect healthy cells (not treated caria chamomilla L., Compositae), thyme (Thymus
with MNNG) (Manikandan et al., 2010). vulgaris L., Lamiaceae), rose (Rosa damascena Mill.,
Eugenol has been classified as “generally recognized as Rosaceae), and cinnamon (C. zeylanicum N., Lauraceae)],
safe (GRAS)” by the US Food and Drug Administration thyme EO showed the highest cytotoxicity against three
1436
Table 2. In vitro and in vivo effects of whole essential oils (EO) or EO mixture on cancer cells and tumors

EO cells/animals Cancer type Carcinogenesis Efficient dose Effect healthy cells/animals References
Crude extracts
Sage (Salvia In vitro C32 and ACHN Kidney IC50: 367 and Inhibition of cell growth Not reported Loizzo et al., 2007
officinalis) 109 μg/mL
Bay tree In vitro C32 and ACHN Kidney IC50: 75 and Inhibition of cell growth Not reported Loizzo et al., 2007
(Laurus nobilis) 78 μg/mL,
respectively
ACHN Prostate IC50: 78 μg/mL Inhibition of cell growth Not reported Loizzo et al., 2007
Oregano (Origanum In vitro MCF7 Breast IC50: 34 mg/mL Inhibition of cell growth No toxic effect El Babili et al., 2011

compactum) on healthy cells
Ex vivo Drosophila URE; MMS Coadministration Antimutagenic effect Ames assay showed Mezzoug
melanogaster with mutagens against URE and MMS no mutagenic effect et al., 2007
Helichrysum In vitro MCF-7 Breast IC50: 16 mg/mL Inhibition of cell growth Not reported Afoulous
gymnocephalum et al., 2011
Wormwood (Artemisia In vitro KB Nasopharynx Inhibition of cell growth Not reported Cha et al., 2009
capillaris) Apoptosis
Rosewood In vitro A431 and Skin IC50: 0.3 μL/mL Inhibition of cell growth Minor toxicity on Soeur et al., 2011
(Aniba rosaeodora) HaCaT Apoptosis transformed normal
keratinocytes HEK001
and primary normal
keratinocytes (>80%
viability)
Sweetfern (Comptonia In vitro A-549 Lung IC50: 66 mg/mL Inhibition of cell growth Not reported Zu et al., 2010
peregrina)
DLD-1 Colon IC50: 46 mg/mL Inhibition of cell growth Not reported Zu et al., 2010
Nutmeg Ex vivo Rat aortic IC50: 77.64 μg/mL Antiangiogenic Not reported Piaru et al., 2012
(Myristica fragrans) rings activities
Nigella sativa P815 Mastocytoma IC50: 6 μL/mL Inhibition of cell growth Not reported Ait Mbarek
et al., 2007
In vivo Mice DBA2/P815 model, Six intratumoral 95% TR No toxic effect on Ait Mbarek
subcutaneous injection injections healthy group et al., 2007
(1/2 days) of 50 μL
(47.5 mg)/mouse
at day
In vitro and Reviews on inhibition Randhawa and
In vivo of cell growth and Alghamdi, 2011
apoptosis in Edris, 2009
different cell lines
In vivo Skin DMBA/croton oil 100 mg/kg TDI No toxic effect on Salomi et al., 1991
healthy group
Sarcoma 33% TR No toxic effect on Salomi et al., 1991
healthy group
(Continues)
Phytother. Res. 28: 1423–1446 (2014)

EO cells/animals Cancer type Carcinogenesis Efficient dose Effect healthy cells/animals References
MCA (745 100 mg/kg per os

nmol × 2 days) 30 days after
subcutaneously induction
Eastern in vitro 502713 Colon IC50: 4 μg/mL Inhibition of cell growth Not reported Sharma et al., 2009
lemongrass Apoptosis
(Cymbopogon
flexuosus)
IMR-32 Extracranial cancer IC50: 5 μg/mL Inhibition of cell growth Not reported Sharma et al., 2009

Apoptosis
SiHa Cervix IC50: 7 μg/mL Inhibition of cell growth Not reported Sharma et al., 2009
Apoptosis
Hep-2 Liver IC50: 5 μg/mL Inhibition of cell growth Not reported Sharma et al., 2009
Apoptosis
In vivo Mice Ehrlich carcinoma 200 mg/kg from day 98% and 58% TDI of Not reported Sharma et al., 2009
1 to 9 by i.p. ascitic and solid forms
administration of Ehrlich and sarcoma-
180 tumor, respectively
Mice Sarcoma-180 200 mg/kg from day 94% and 37% TDI of Not reported Sharma et al., 2009
1 to 9 by i.p. ascitic and solid forms
administration of sarcoma-180 tumor,
respectively
Lemon balm In vitro A549, MCF-7, De Sousa et al., 2004
(Melissa Caco-2, HL-60,
officinalis) K562
Thyme (Thymus In vitro PC-3, A549, Prostate, lung, IC50: 0.1, 0.1, and Inhibition of cell growth Not reported Zu et al., 2010
vulgaris) and MCF-7 and breast 0.3 μL/mL, respectively
Cinnamon In vitro PC-3, A549, Prostate, lung, IC50: 0.1, 0.2, and Inhibition of cell growth Not reported Zu et al., 2010
(Cinnamomum and MCF-7 and breast 0.7 μL/mL, respectively
zeylanicum)
Chamomile In vitro PC-3, A549, Prostate, lung, IC50: 0.7, 0.7, and Inhibition of cell growth Not reported Zu et al., 2010
(Matricaria and MCF-7 and breast 0.7 μL/mL, respectively
chamomilla)
Jasmine In vitro PC-3, A549, Prostate, lung, IC50: 0.2, 0.1, and Inhibition of cell growth Not reported Zu et al., 2010
(Jasminum and MCF-7 and breast 0.7 μL/mL, respectively

grandiflora)
Lemon (Citrus In vitro PC-3, A549, Prostate, lung, IC50: 0.8, 0.6, and Inhibition of cell growth Not reported Zu et al., 2010
limon) and MCF-7 and breast 0.15 μL/mL,
respectively
Mint (Mentha In vitro PC-3 Prostate IC50: 0.8 μL/mL Inhibition of cell growth Not reported Zu et al., 2010
spicata)
Ginger (Zingiber In vitro PC-3, A549 Prostate and lung IC50: 0.8 and Inhibition of Not reported Zu et al., 2010
officinale) 0.8 μL/mL, respectively cell growth
Phytother. Res. 28: 1423–1446 (2014)

1437
(Continues)
human cancer cell lines. The median inhibitory concen-

tration (IC50) of cell lines PC-3 (prostate), A549 (lung),
References
Zu et al., 2010
Zu et al., 2010
Zu et al., 2010
Zu et al., 2010
Zu et al., 2010
and MCF-7 (human mammary carcinoma) were respec-
tively 0.010% (v/v), 0.011% (v/v), and 0.030% (v/v) (Zu
et al., 2010).
In another study realized on 17 Thai medicinal plants
TDI, tumor development inhibition; TR, tumor regression; DMBA: 7,12-dimethylbenz[a]anthracene; URE, urethane; MMS, methyl methanesulfonate; MCA, 20-methylcholanthrene.
on human mouth epidermal carcinoma (KB) and
murine leukemia (P388) cell lines (104 cells/well of KB
cell line and 1 × 105 cells/well of P388 cell line), guava
healthy cells/animals
Toxicity data on
(Psidium guajava L., Myrtaceae) leaf oil showed the

Not reported
Not reported
Not reported
Not reported
Not reported
highest antiproliferative activity with the IC50 value of
37.9 μg/mL (4.37 times more potent than vincristine),
whereas sweet basil (Ocimum basilicum L., Lamiaceae)
oil gave the highest antiproliferative activity with the
IC50 value of 36.2 μg/mL (12.7 times less potent than
5-FU) in P388 cell line (Manosroi et al., 2006). Moreover,
Inhibition of cell growth
EOs may have some synergistic effects when tested to-

gether. This is the case of the Immortelle (Helichrysum
italicum (Roth) G. Don, Asteraceae), Greenland rosemary
Effect
(Ledum groenlandicum (Oeder) Kron & Judd, Ericaceae),

and Ravensara aromatica (Sonn., Lauraceae) (Idaomar
et al., 2002). This study indicates that these EOs possess
an antigenotoxic activity in Drosophila wing spot test.
The choice of these oils was based on a previous patent
(Giraud, 2002).
0.95 μL/mL, respectively

IC50: 0.4, 0.55, and
Efficient dose
IC50: 0.5, 1.3, and
IC50: 37.9 μg/mL
IC50: 36.2 μg/mL

IC50: 0.95 and
CLINICAL STUDIES
Very few clinical studies have been conducted so far

despite many in vitro and in vivo promising data have
been published. These studies have focused especially
on limonene and perillyl alcohol, which is structurally
very close to limonene (alcohol function) and leads
Carcinogenesis
in vivo to the same metabolites, namely perillic and

dihydroperillic acids.
A phase I clinical study showed that doses of 8 g/m2
per day of limonene can be used in humans without
toxicity, except slight gastrointestinal symptoms (irrita-
tion, nausea, and diarrhea in a few cases) (Vigushin
et al., 1998). This study enrolled a group of 32 patients
Prostate and lung
with refractory solid tumors who were administered

Cancer type
Prostate, lung,
Prostate, lung,
Nasopharynx
limonene orally in 21-day cycles. Partial response (defined

and breast
and breast
as 50% reduction in tumor size) was observed in a patient

with breast cancer, and stabilization (defined as <50%
Blood
tumor regression or <25% progression) of more than

6 months was observed in three patients with colorectal
cancer (0.5–1 g/m2). Only six patients received two cycles
cells/animals
PC-3, A549,
PC-3, A549,
of the treatment, and six others received five or more

PC-3, A549
and MCF-7
and MCF-7
Model
cycles. Except these positive cases, the results of this

study do not bring evidence of a significant benefit
P388
of D-limonene. Ten additional breast cancer patients

KB
with locally advanced or metastatic disease, heavily

pretreated and refractory to conventional hormonal
and cytotoxic treatment, received 8 g/m2 per day.
In vitro
In vitro
In vitro
In vitro
In vitro
Seven patients completed one or more cycles of treat-

ment, but no additional responses were observed.
A very recent study involved 43 women with newly

diagnosed operable breast cancer electing to undergo
surgical excision (Miller Jessica et al., 2013). They
Grapefruit (Citrus
Guava (Psidium
received orally 2 g of limonene daily for 2–6 weeks

angustifolia)
damascena)
(Lavandula
basilicum)
Sweet Basil
before surgery. Limonene was found to preferentially

(Ocimum
Rose (Rosa
paradisi)
guajava)
Lavender
concentrate in the breast tissue, reaching high tissue

concentration (mean = 41.3 μg/g tissue), whereas the
EO
major active circulating metabolite, perillic acid, did

not concentrate in the breast tissue. They also observed

BIOCHEMICAL MODE OF ACTION OF
a 22% reduction in cyclin D1 expression (p = 0.002) in
tumor tissue that may lead to cell cycle arrest and BIOACTIVE COMPOUNDS
reduced cell proliferation. But no significant changes
in serum leptin, adiponectin, TGF-β1, IGFBP-3 and Essential oils terpenoids and phenylpropanoids com-
IL-6, and caspase 3 levels were observed. pounds are particularly lipophilic and are well absorbed
Perillyl alcohol, which has also shown antitumoral by the body. Several biochemical processes have been
activities in cells and animals (Belanger, 1998), has been proposed to explain the anticancer effects of EO and
also tested in clinical protocols. In a phase I study, 16 their constituents. The main biochemical pathways con-
evaluable patients with advanced refractory malignan- tributing to the promising potential of these compounds
cies (cancer site: four prostate, three ovaries, two adeno- are exposed here and are summarized in Fig. 2. Even
carcinoma, two colorectal and others) were treated at though most of the studies report specific toxicity on
the following doses: level 1 (L1), 800 mg/m2/dose; L2, cancer cells and no toxicity on healthy control cells,
1200 mg/m2/dose; and L3, 1600 mg/m2/dose (Ripple some compounds such as safrole or isoeugenol are
et al., 2000). The maximum tolerated dose of perillyl well-known hazardous molecules, and the evaluation
alcohol given continuously four times a day was of toxicity of EO constituents in vitro and especially
1200 mg/m2/dose (gastrointestinal symptoms and nausea in vivo is of crucial importance (Bakkali et al., 2008).
and vomiting for a few patients at levels 1 and 2).
Evidence of antitumor activity was seen in a patient with
metastatic colorectal cancer who has an ongoing near- Inhibition of inflammation and oxidative stress
complete response after 10 months duration at L3 dose.
Three other patients were on study for >6 months with Inflammation and oxidative stress are phenomena
stable disease. Two patients with hormone-refractory associated with cancer progression but are also probably
prostate cancer were treated at L1 with stable disease associated with its genesis (Kundu and Surh, 2012;
for 13 and 10 months, respectively. The third patient, Nowsheen et al., 2012; Valko et al., 2004). Oxidative
with adenoid cystic carcinoma of the salivary gland, stress and antioxidant status, which can be assessed in
was treated at L2 for 8 months before the disease humans, have been shown to be linked to several life-
progressed. No significant hepatic, renal, or neurologi- style factors such as nutrition or smoking habits
cal toxicities thought to be related to the drug were seen (Lesgards et al., 2002). Many studies showed that the an-
in this study. ticancer effects of some EO compounds are associated
Another phase I trial (Hudes et al., 2000) with 17 with a decrease in inflammation and oxidative stress.
patients (cancer site: nine colon, three kidney, two Limonene, for example, restores the level of reduced
lungs, two parotid, and one unknown) confirms the GSH, glutathione peroxidase, catalase, and glutathione
range of the maximum tolerated dose observed for reductase (Chaudhary et al., 2012). Eugenol also restores
perillyl alcohol in the last study. The patients took GSH levels in the skin subjected to the carcinogen
perillyl alcohol per os three times daily for 14 days DMBA (Kaur et al., 2010). Geraniol inhibits the produc-
of each 28-day cycle. The starting dose of perillyl tion of nuclear factor-kappa B (NF-κB), which is a key
alcohol (POH) was 1600 mg/m2/dose, with escalations proinflammatory protein in the body (Ahmad et al.,
to 2100 and 2800 mg/m2/dose in subsequent cohorts. 2011). The link between the inflammatory action of
Chronic nausea and fatigue were dose-limiting toxic NF-κB and cancer development, therapeutic resistance
effects at 2800 mg/m2. Grade 1–2 hypokalemia was in tumor development, angiogenesis, and metastasis in
common at 2100 and 2800 mg/m2. cancer is established and increasingly described (Brown
Figure 2. Biochemical pathways of anticancer activity of essential oils (EO) constituents. Activation of proapototic pathways by EO constit-
uents through mitochondria in cancer cells. Inhibition of tumor-inducing genes and angiogenesis. Protection of healthy cells.
et al., 2008). Eugenol also reduces the NF-κB in the treat- prostate cancer cells with 0.25 mM for 24–48 h (Kim
ment of gastric carcinomas induced in rats (100 mg/kg, et al., 2011). Cancer cells are often hyperpolarized, and
three times per week throughout the study) (Manikandan their terpene-induced depolarization helps to restore
et al., 2011). Moreover, compounds such as eugenol normal processes in the cell including apoptosis.
decrease inflammation by influencing other factors such α-Bisabolol is also efficient against leukemia (AML
as cyclooxygenase 2 (COX2), cytokines, and inflammatory and chronic myeloid leukemia) by depolarizing the
factors such as IL-1β, IL-6, TNF-alpha, and PGE2 mitochondrial membrane), among other processes
(Hussain et al., 2011). (Cavalieri et al., 2011), as thymol on the same type of can-
Thymoquinone pre-treatment also restored com- cer (Deb Dipanwita et al., 2011). Germacrone also seems
pletely 1,2-dimethylhydrazine-induced oxidative stress to depolarize the mitochondrial membrane of cancer cells
at initiation as well as established histological changes in breast cancer (Chen et al., 2011a). Geraniol induces
and tumor development. It abrogated oxidative status membrane depolarization of colon cells (Caco-2) from
aggravation at promotion and significantly reduced 0.1 mM (Carnesecchi et al., 2001; Carnesecchi et al.,
tumor incidence (67%) (Jrah-Harzallah et al., 2013). 2002). Other terpenes such as β-elemene also alter
the membrane of cancer cells (Zhao et al., 2007).
Under the action of terpenoids, cancer cells mito-
Reactive oxygen species production in the cancer cell chondria release cofactors such as cytochrome C, which
will activate apoptosis (through caspases activation).
Oxidative stress and inflammation are detrimental at a One of the pathways is the opening of the mitochondrial
global and uncontrolled level in the body (Lesgards permeability transition pore, which enables a sudden
et al., 2011). However, a specific increase of free radicals increase in the permeability of the mitochondrial inner
and oxidative stress in cancer cell has an antitumor membrane to water and molecules smaller than 1.5 kDa.
effect. Several terpenic EO constituents such as Terpenoids such as α-bisabolol seem to target this system
β-caryophyllene (Park et al., 2011) can specifically induce (Cavalieri et al., 2009; Darra et al., 2008).
the production of ROS in the mitochondria of cancer cells The change in membrane potential can modulate the
without increasing oxidative stress in normal cells. opening or closing of ion channels (which may alter
Thymol seems to produce a stable phenoxy radical intracellular pH) and induce multiple reactions in the
intermediate that generates free radicals and oxidized cell. For example, thymol and carvacrol at 200 μM seem
derivatives of quinones, which are associated with death to induce apoptosis by mitochondrial pathway and
of melanoma cells (IC50 reached to 400 μM) (Satooka opening of calcium channels that produces the release
and Kubo, 2012) and osteosarcoma cells (200–400 μM) of Ca2+ in the endoplasmic reticulum of cancer cells:
(Chang et al., 2011). Thymol in particular increases osteosarcoma (MG63) (Chang et al., 2011) and glioblas-
the production of hydrogen peroxide in the mitochon- toma (Hsu et al., 2011; Liang et al., 2012).
dria of cancer cells (Deb Dipanwita et al., 2011).
Eugenol also produces oxidative stress in cancer cells
and decreases glutathione levels (Vidhya and Devaraj, Activation of apoptosis by caspases
2011; Yoo et al., 2005).
Apoptosis of cancer cells occurs through the activation
of certain proteins of the caspase family. All terpenes
Overexpression and regulation of liver detoxification quoted in this review have shown to activate caspases.
enzymes Caspases 3 and 9 are activated in leukemic cells
cultured in the presence of limonene (Ji et al., 2006) or
Blocking the initiation phase of carcinogenesis by some geraniol (caspase 3) in many cancers (on cells and
terpenoids is probably also associated with the induction tumors), especially in prostate (Kim et al., 2011) or
of phase I and phase II enzymes that metabolize carcin- kidney cancers (caspases 3, 8, and 9) (Ahmad et al.,
ogens and reduce their impact on DNA and, therefore, 2011). Other terpenes such as β-caryophyllene also acti-
the occurrence of cancer. Glutathione S-transferase vate caspases (caspase 3) (Park et al., 2011), α-bisabolol
(Chaudhary et al., 2012; Elegbede et al., 1993; Uedo (caspase 3, 8, and 9) (Chen et al., 2010), or β-elemene
et al., 1999; van Lieshout et al., 1998) and cytochrome (caspases 3,7, 9, and 10) in different cancer cell lines
P-450 (Austin et al., 1988) are among the most impor- (prostate, glioma, breast, colon, and lung) with average
tant enzymes whose activity is increased (30%) by doses of 300 μM (Li et al., 2009) and thymol (caspase 3, 8,
terpenoids such as limonene, in human studies with doses and 9) in leukemia (Deb Dipanwita et al., 2011). The
of 400 mg/kg/day for 30 days (Ariyoshi et al., 1975). germacrone activates caspases 3, 7, and 9 (Zhong et al., 2011).
From a biochemical point of view, this requires the
phosphorylation and activation of different proteins
Modification of membrane potential of cancer cells and (p53, Bax, and p21/waf) involved in the cascade of
mitochondria events that ultimately leads to the activation of these
caspases, which will eventually give the signal to destroy
An increasing number of studies demonstrate that the cancer cells, and to cell proliferation. Our laboratory has
beneficial effects of terpenoids against cancer are associ- a significant experience on p53 activation and its targets
ated with a change in the polarization of the membrane such as TP53INP1, which is an antiproliferative and
of cancer cells and especially in the membrane of proapoptotic protein involved in cell stress response
mitochondria. Terpenoids are indeed very lipophilic (Cano et al., 2009). We have shown that p53 and
and have a high affinity for cell membranes. Induction TP53INP1 were closely linked with ROS regulation
of apoptosis by geraniol in prostate cancer is associated and apoptosis in colorectal cancer (Gommeaux et al.,
with a membrane depolarization of mitochondria in 2007) and in thymus cells (N’Guessan et al., 2011).
This pathway also implies a decrease in the expres- regulation of energy metabolism. If its positive role is
sion of genes bcl-2 (antiapoptotic) and related proteins mainly described for type II diabetes, its function in
in cancer cells. The variation of these markers changes cancer cells generates also an increasing interest. This
significantly with geraniol from 0.25 mM in cell cultures protein is a mediator of the tumor suppressor LKB1,
and 60 mg/kg in animal tumor (Kim et al., 2011). and its stimulation reprograms the cellular metabolism
α-Bisabolol acts on bcl-2 protein in leukemia (Cavalieri and acts on the biochemical pathway of p53, which is
et al., 2011). β-Elemene is also linked to P53 and bcl-2 involved in the cascade of events leading to caspase
pathways (Li et al., 2005) as well as eugenol (Pal et al., activation and apoptosis in cancer cells (Luo et al.,
2010). Most of these biochemical processes are clearly 2010). Studies suggest that activation of AMPK by
described in a study in rats developing gastric carcino- some terpenoids such as geraniol (Kim et al., 2012) and
mas induced by MNNG (Manikandan et al., 2010). β-caryophyllene (Park et al., 2011) contributes to the
Administration of 100 mg/kg eugenol (three times per inhibition of growth and the apoptosis of human cells in
week from the beginning of MNNG exposure until the various cancers including bladder, prostate, or breast.
end of the 26 weeks study) induces apoptosis in tumor
cells and does not affect healthy cells (not treated with
MNNG). This has also been observed with global EO MAPK/ERK pathway
extract as Artemisia capillaries (Cha et al., 2009) with
changes in Bcl-2 and Bax levels. MAPK/ERK proteins belong to a chain of proteins in
cells that communicate a signal from a receptor on the
surface of the cell to the DNA in the nucleus. The signal
Inactivation of PI3K/Akt/NF-κB pathway starts when a signaling molecule binds to a receptor on
the cell surface and stimulates DNA in the nucleus,
Inactivation of PI3K/Akt/NF-κB pathway is also a which leads to the expression of proteins, and changes
way of controlling the development of cancer. The in the cell, such as cell division. These proteins are
expression of genes leading to the activation of kinases that communicate by adding phosphate
phosphoinositide 3-kinase (PI3K)/Akt pathway has groups to a neighbor protein. These phosphorylation–
been observed in many cancers, including leukemia, dephosphorylation reactions act as a switch “on” or
which makes this route a central target for the treatment “off”. Some substances such as limonene act in this
of cancer. Signaling pathway of PI3K is involved both in way to induce apoptosis in cancer cells lines such as
the control of cell growth and in glucose metabolism. It lymphoma (Manuele et al., 2010). β-elemene also
influences protein synthesis via mTOR enzyme and also modulates MAPK pathway (Manuele et al., 2010).
acts on uptake and utilization of glucose. Even in non-
insulin-dependent tissue, Akt via PI3K can regulate
the expression of glucose transporters and activity of Inhibition of other factors implicated in tumor-inducing
glycolytic enzymes such as hexokinase and phospho- genes
fructokinase (DeBerardinis et al., 2007). Activation of
the PI3K pathway makes cancer cells dependent on Some monoterpenoids contained in EO inhibit a
high levels of glucose flux (Buzzai et al., 2005). Thus, chemical reaction called “isoprenylation” accomplished
by limiting this pathway, some EO components such by several cells on certain proteins (reaction realized
as geraniol can affect the metabolic aspect of cancers, by enzymes such as farnesyl protein transferase). The
which requires large amounts of glucose to grow and prenylated proteins activate certain genes promoters of
generate energy, such as prostate cancer (Kim et al., cell growth and proliferation, and these monoterpenoids
2012). Indeed, cancer cells preferentially use aerobic compete with these reactions, thus slowing down or
glycolysis in the cytoplasm of the cell (fermentation of blocking the function of cellular signaling proteins
pyruvate to lactate: it produces only two ATP molecules leading to the growth of cancer cells (Gould, 1997;
per molecule of glucose) rather than oxidative phos- Loza-Tavera, 1999). The action of such components
phorylation in the mitochondria (production of 36 (such as limonene or perillyl acid) also leads to the
molecules of ATP/molecule of glucose). This metabolic decrease of growth factors such as “mitogen IGF II”
diversion was described by Otto Warburg in 1924 and is and the active cell stabilizing factor TGF-β (Loza-
called “Warburg effect” (Vander Heiden et al., 2009; Tavera, 1999). In mammary tumors cells, these phenom-
Warburg, 1956; Warburg, 1930). ena induce, for example, the shutdown of the division
Inhibition of mTOR by geraniol and other terpenes in cycle (in G1 phase), followed by cell death and tumor
cancer cells can also reactivate a process called regression (Gould, 1997). On the other hand, the pro-
“autophagy” that will lead to the death of these cells teins of the Ras family (from “rat sarcoma”: cancer
(Kim et al., 2012). Derivatives of β-caryophyllene also tissue in rats) and associated genes have a role in pro-
seem to act by this biochemical pathway to exert their moting cancer growth by activating cancer cells through
anticarcinogenic effect particularly in breast and prostate the acceleration of their division (Goodsell, 1999). Many
(Park et al., 2011) as well as α-bisabolol in pancreatic EO constituents inhibit this pathway and thereby block
cancer (Seki et al., 2011) or β-elemene in lung (Liu et al., the development of cancer. This is the case of limonene
2012) and stomach cancers (Liu et al., 2011). (Chaudhary et al., 2012). Another example of important
genes and proteins on which terpenoids may have an
effect is the hypoxia-inducible factor-1α (HIF)-1α. Re-
AMPK pathway cent research has highlighted the active participation
of (HIF)-1α in human cancer tumors. Several mecha-
The AMP-activated protein kinase (AMPK) is a sensor nisms may be responsible for its overexpression such
of the energy status of the cell and plays a key role in the as the creation of an intratumoral hypoxic region that
stabilizes HIF-1α and induces complex (HIF)-1α.

CONCLUSION
Studies show that β-elemene, for example, at 45 mg/kg
significantly inhibited the expression of these proteins
(Li et al., 2012). The antitumor action of terpenoids and phenyl-
propanoids is linked to the activation of the phenomena
of cell death (apoptosis) in cancer cells without affecting
normal cells. A very large number of studies suggest that
Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A natural terpenoids such as limonene constitutes a new
class of anticancer drugs with the potential to cause
The enzyme 3-hydroxy-3-methylglutaryl coenzyme A tumor regressions with limited toxicity. In addition,
reductase catalyzes the formation of mevalonate, a several studies have also shown that EO terpenoids
precursor of cholesterol necessary for cell proliferation. could act in synergy with conventional chemotherapy.
The depletion of mevalonate produces a stop in G1 Despite the promising results obtained over 35 years
phase of the cell cycle. The inhibition of mevalonate on the beneficial effect of these compounds, very few
synthesis may therefore be a useful strategy to reduce clinical studies in humans have been conducted in the
the growth of malignant cells. Some particular terpe- field. The only existing studies (mainly on phases I and
noids possess this property (Elson and Yu, 1994). II) have been performed on limonene and its derivatives
Farnesol appears to act in this way also in liver cancer with some encouraging results. Many other EO constit-
in rats (Ong et al., 2006). This is also the case of β-ionone uents seem even more promising as anticancer agents,
(treatment of 160 mg/kg for 5 weeks in rats) that reduces but their toxicological profile is often poorly understood,
cholesterol synthesis (Cardozo et al., 2011). if not totally unknown for some of the constituents de-
scribed in this review (α-humulene, β-caryophyllene, and
germacrone). Up to now, no study has been conducted
Antiangiogenesis with an EO or a mixture of crude oils. One of the main
difficulty in such works is linked with the rationalization
In addition, it is well known that tumors are irrigated by of the effect: because EOs are complex mixtures of
blood capillaries (angiogenesis), which provide nutri- hundreds of constituents, their action on cancer cells is
ents. EO compounds such as terpenes and certain the sum of each individual activity, modulated by all the
polyphenols may reduce and prevent the formation of potential synergies. However, this point should not dis-
the network supplying the tumor with blood. This is courage the studies on the use of whole EO, particularly
the case with limonene (Lu et al., 2004). The density of in the combination with conventional chemotherapies,
microvessels was 5.32 ± 4.26 in the group supplemented because these mixtures can be considered as promising
with limonene versus 18.64 ± 2.81 for the control group. sources of new antitumoral agents. Besides, EOs and
The expression of vascular endothelial growth factor crude natural extracts are in general positively considered
(VEGF) was 29.71 ± 8.92 in the limonene group versus by patients, although their good reputation (due to the
45.77 ± 4.79 for the control group. β-Elemene (Chen common popular belief that their naturalness is a guaranty
et al., 2011a) also significantly reduces VEGF at 20 μM of safety) can hide occasional toxicity problems due to the
in vitro and in vivo. Administration of 100 mg/kg presence of peculiar compounds. Hence, the exploration of
eugenol (three times per week from the beginning of the antitumor properties of EO is now clearly a research
MNNG exposure until the end of the study, 26 weeks) axis that should receive the same interest than the more
induces apoptosis in tumor cells and significantly reduces conventional chemotherapy treatments with synthetic anti-
VEGF and matrix metalloproteinases, clearly demonstrat- cancer agents.
ing an antiangiogenic effect (Manikandan et al., 2010).
Acknowledgements
Histone This work was supported by the Centre National de la Recherche
Scientifique and by grants from IPSEN-Institut Henri Beaufour. The
Histones are essential proteins in the body because they authors thank Drs Katy Drieu and F. V. DeFeudis for constructive
wrap around DNA to form structures called nucleo- initial discussion. Nicolas Vidal acknowledges the SARL YELEN,
somes. The positive charges of basic histones allow a Ensuès-La-Redonne, France, for the financial support.
strong interaction with the phosphate groups of DNA
that carry negative charges. The inhibition of cancer cell
growth by some terpenes such as β-elemene could be Conflict of Interest
associated with the increase of histone H1, considered
as a transcription inhibitor (Bao et al., 2012). We declare no conflicts of interest.
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PHYTOTHERAPY RESEARCH

Phytother. Res. 28: 1423–1446 (2014)

Jean-François Lesgards,1* Nicolas Baldovini,2 Nicolas Vidal1 and Sylvia Pietri1

Keywords: essential oils; terpenoids; apoptosis; membrane potential; oxidative stress.

with an inhibition of free radical formation rather than

Terpenoids are generally well absorbed by the body

tumor size by 26% (Carnesecchi et al., 2004). Other D-Limonene

Model Toxicity data on

Copyright © 2014 John Wiley & Sons, Ltd.

after 3–5 weeks small tumor is observed

Phytother. Res. 28: 1423–1446 (2014)

for geranyl-O- Cell cycle arrest

Copyright © 2014 John Wiley & Sons, Ltd.

Phytother. Res. 28: 1423–1446 (2014)

Model Toxicity data on

times a week, for 250 mg/kg by

Copyright © 2014 John Wiley & Sons, Ltd.

thymol growth peripheral blood et al., 2011

Phytother. Res. 28: 1423–1446 (2014)

SaOS-2 Bones Inhibition of cell Not reported Peng et al., 2013

Copyright © 2014 John Wiley & Sons, Ltd.

Phytother. Res. 28: 1423–1446 (2014)

Model Toxicity data on

Copyright © 2014 John Wiley & Sons, Ltd.

Phytother. Res. 28: 1423–1446 (2014)

Model Toxicity data on

Copyright © 2014 John Wiley & Sons, Ltd.

DLD-1 colon growth et al., 2007

Phytother. Res. 28: 1423–1446 (2014)

Copyright © 2014 John Wiley & Sons, Ltd.

growth Devaraj, 2011

Phytother. Res. 28: 1423–1446 (2014)

Farnesol α-Bisabolol derivatives (thiosemicarbazones) also have

Model Toxicity data on

Copyright © 2014 John Wiley & Sons, Ltd.

Phytother. Res. 28: 1423–1446 (2014)

MCA (745 100 mg/kg per os

Copyright © 2014 John Wiley & Sons, Ltd.

(Jasminum and MCF-7 and breast 0.7 μL/mL, respectively

Phytother. Res. 28: 1423–1446 (2014)

human cancer cell lines. The median inhibitory concen-

(Psidium guajava L., Myrtaceae) leaf oil showed the

Inhibition of cell growth

Inhibition of cell growth

Inhibition of cell growth

Inhibition of cell growth

EOs may have some synergistic effects when tested to-

(Ledum groenlandicum (Oeder) Kron & Judd, Ericaceae),

0.7 μL/mL, respectively

IC50: 0.5, 1.3, and

IC50: 37.9 μg/mL

IC50: 36.2 μg/mL

Very few clinical studies have been conducted so far

in vivo to the same metabolites, namely perillic and

with refractory solid tumors who were administered

limonene orally in 21-day cycles. Partial response (defined

as 50% reduction in tumor size) was observed in a patient

tumor regression or <25% progression) of more than

of the treatment, and six others received five or more

cycles. Except these positive cases, the results of this