**3. Antitumoral activity of EOs and bioactive compounds**

Terpenes (TPs) are usually part of EOs' constituents. Terpenoids (TPNs) are a modified class of terpenes that can be classified according to the number of units of isoprene. Monoterpenes (MTs) are the TPNs with only 2 isoprene units and 10 carbon atoms, sesquiterpenes (STs) have 3 isoprene units and 15 carbon atoms, diterpenes have 4 isoprene units and 20 carbon atoms, triterpenes (TTs) have 6 isoprene units and 30 carbon atoms, and tetraterpenes have 8 isoprene units and 40 carbon atoms [25]. The biosynthesis of terpenoids is shown in **Figure 1**.

Sesquiterpenes (STs) are produced in plants in a way to interact with other plants and as a response to herbivores. These compounds are widely distributed, have been exploited in research for their phytomedicinal potential [26], and are associated with decreasing progression of cancer.

Many plants have demonstrated antiproliferative activity on MCF7 cells and have MT as a major constituent of their EO composition, such as the following : *Schefflera heptaphylla* (β-pinene) [27]; *Heteropyxis dehniae* (linalool) [28]; *Schinus molle* and *Schinus terebinthifolius* (α-phellandrene) [29]; *Melaleuca alternifolia* (terpinen-4-ol) [30]; *Citrus limon*, *Citrus medica*, and *Citrus sinensis* (limonene) [31]; and *Cunila angustifolia* (pulegone and isomenthol) [32], *Satureja khuzistanica* Jamzad (carvacrol) [33], *Satureja intermedia* C.A. Mey (γ-terpinene, thymol, and p-cymene) [34], *Melaleuca armillaris* (Sol Ex Gateau) (1,8-cineole) [35], *Monodora myristica*, *Xylopia aethiopica*, *X. parviflora* [36], *Laurus nobilis*, *Origanum syriacum, O. vulgare*, *Salvia triloba* [37], and berries of *Schinus molle* L. and *S. terebinthifolius* Raddi (more active) (α-phellandrene, β-phellandrene, α-terpineol, α-pinene, β-pinene, and ρ-cymene) [29].

Bisabolene isomers are the main constituents of opoponax (*Commiphora guidotti*); therefore, a ST named β-bisabolene and an alcoholic analogue, α-bisabolol, were tested for their in vitro and in vivo influence on BC. Only β-bisabolene exhibited selective cytotoxic activity for mouse cells MG1361 and human BC cells MCF7, MDA-MB-231, SKBR3, and BT474 with a 37.5% reduction of the growth of transplanted 4T1 mammary tumors [38].

#### *Essential Oils - Bioactive Compounds, New Perspectives and Applications*

**Figure 1.** *Terpeneoids' biosynthesis.*

EO of *Myrcia splendens* (Sw.) DC. (Myrtaceae) from Amazonian Ecuador has its anticancer activity in MCF7 attributed to α-bisabolol in its composition [39], and EO from leaves of *Anaxagorea* mainly composed of β-eudesmol, α-eudesmol, and β-bisabolene showed similar effect [40].

EO from leaves of *Schinus terebinthifolius* Raddi (Anacardiaceae) collected in Brazil, with germacrene D as one of the major compounds, and fractions were tested in vitro against MCF7. All of them had anticancer activity and that may be due to α- and β-pinene structures [41]. EO of *S. molle* made in Costa Rica was active in breast carcinoma EMT-6 cell line and also had beta-pinene and alpha-pinene as major components [42]. Similar results were not found in EO from leaves of *Porcelia macrocarpa* R. E. Fries (Annonaceae), with main compounds germacrene D and bicyclogermacrene, which did not have significant effect on human breast adenocarcinoma SKBr [43].

β-Elemene is the major active component of the EO from a traditional plant from China, *Curcuma wenyujin* Y.H. Chen et C. Ling, and showed significant cytotoxicity in multidrug-resistant cell line MCF7/adriamycin through inhibition of mTOR

**59**

patients [57].

*Essential Oils' Potential in Breast Cancer Treatment: An Overview*

activity, related with cell proliferation and cancer, with the presence of autophagy. However, it only showed effects at high concentrations and the EO had problems

Different parts of the same plant can have different chemical constitution and biological activity. For example, the EO of *Garcinia atroviridis* Griff. ex T. Anders showed different results when different parts of plants were used. The essential oil from stem bark (EO-SB) had 79.8% of fatty acid including palmitoleic acid and palmitic acid, and the leaf oil (EO-L) had 86.3% of STs. While EO-SB did not induce cytotoxic effect, the EO-L stimulated the growth of BEAS-2B normal cells, but not in MCF7 cancerous cells, proving the medicinal effects of STs. But the best result was noticed when EO-L was associated with tamoxifen, which demonstrated better activity than the treatment with the drug alone [45]. The EO of *Pallines spinose* flower (F-PSEO) showed different composition than the leaf EO (L-PSEO). F-PSEO contained 96.39% of STs with 78.63% of the oil as oxygenated derivatives such as acorenone B, α-muurolol, and α-cadinol. The L-PSEO was composed of 51.60% of oxygenated STs and 34.06% of SQ hydrocarbons. F-PSEO had stronger anticancer results for MCF7 and MDA-MB-231 and both EOs induced a caspase-dependent and caspase-independent apoptosis and altered the levels of Bcl-2 and Bax proteins [46]. A component that can optimize the anticancer effects when combined with chemotherapy or reduce side effects of the current treatment is a target for many researches. *Rhizoma curcumae* is a plant known to possess activity against different types of cancer cells [47] and is common in Chinese medicine for the treatment of cancer [48]. Curcumol, a guaiane type ST lactone, is the major component of *R. curcumaeis* and, in combination with doxorubicin, made MDA-MB-231 cells more sensible to the action of doxorubicin through the activation of transcription factor NFAT1 and through the bind of the promoter region of miR-181b-2-3p, which is implicated in motility of BC [49] and less survival in breast cancer patients [50]. Curcumol also demonstrated in

EO of *Blepharocalyx salicifolius* was cytotoxic against the MDA-MB-231 cell not by mechanisms related to apoptosis but by preventing cell metabolism reactions. Its main constituents identified were STs bicyclogermacrene, globulol, viridiflorol,

Leaves of *Garcinia celebica* L, popularly used in Malaysia and known as "manggishutan," provide an ST-rich EO composed of α-copaene (61.25%), germacrene D (6.72%), and β-caryophyllene (5.85%) with antiproliferative action to MCF7 cells [52]. A similar result was found with the leaf of *Phoebe bournei* (Hemsl.) Yang, which is also composed mainly of STs such as α-copaene, α-muurolene, α-cadinene,

A ST isolated from the EO of *Rhizoma curcumae* named Furanodiene (FD) is associated with anticancer activities in various types of cancers in humans. FD also showed action on chemo-resistant breast cancer cells [54]. EO of *R. curcumae* and the main bioactive component FD were assessed on doxorubicin-resistant MCF7 cell line; although it showed inhibitory effects on cell viability it did not work on ABC transporters [47], which promote the efflux of chemotherapeutic compounds from cells leading to reduction of drug levels inside the cancer cells and insensitivity to the treatment associated with resistance [55]. Furthermore, FD induced apoptosis via intrinsic/extrinsic-dependent and NF-κB-independent pathways [54].

Multidrug-resistant human BC cells MCF7/ADR were treated with EO of *Inula japonica* (IJO) or its ST component isoalantolactone (ISO) or *Angelicae dahuricae* EO (ADO). IJO, ISO, and ADO may reverse the cancer cell by down-regulating ABCB1 expression [56]. This gene encodes a transporter that changes the phenotype of the cells into a multidrug resistance type associated with worse prognosis in BC

*DOI: http://dx.doi.org/10.5772/intechopen.91781*

vivo suppress of tumor growth [49].

γ-eudesmol, and α-eudesmol [51].

and 1s-calamenene [53].

regarding stability [44].

#### *Essential Oils' Potential in Breast Cancer Treatment: An Overview DOI: http://dx.doi.org/10.5772/intechopen.91781*

*Essential Oils - Bioactive Compounds, New Perspectives and Applications*

EO of *Myrcia splendens* (Sw.) DC. (Myrtaceae) from Amazonian Ecuador has its anticancer activity in MCF7 attributed to α-bisabolol in its composition [39], and EO from leaves of *Anaxagorea* mainly composed of β-eudesmol, α-eudesmol, and

EO from leaves of *Schinus terebinthifolius* Raddi (Anacardiaceae) collected in Brazil, with germacrene D as one of the major compounds, and fractions were tested in vitro against MCF7. All of them had anticancer activity and that may be due to α- and β-pinene structures [41]. EO of *S. molle* made in Costa Rica was active in breast carcinoma EMT-6 cell line and also had beta-pinene and alpha-pinene as major components [42]. Similar results were not found in EO from leaves of *Porcelia macrocarpa* R. E. Fries (Annonaceae), with main compounds germacrene D and bicyclogermacrene, which did not have significant effect on human breast adeno-

β-Elemene is the major active component of the EO from a traditional plant from China, *Curcuma wenyujin* Y.H. Chen et C. Ling, and showed significant cytotoxicity in multidrug-resistant cell line MCF7/adriamycin through inhibition of mTOR

β-bisabolene showed similar effect [40].

**58**

**Figure 1.**

*Terpeneoids' biosynthesis.*

carcinoma SKBr [43].

activity, related with cell proliferation and cancer, with the presence of autophagy. However, it only showed effects at high concentrations and the EO had problems regarding stability [44].

Different parts of the same plant can have different chemical constitution and biological activity. For example, the EO of *Garcinia atroviridis* Griff. ex T. Anders showed different results when different parts of plants were used. The essential oil from stem bark (EO-SB) had 79.8% of fatty acid including palmitoleic acid and palmitic acid, and the leaf oil (EO-L) had 86.3% of STs. While EO-SB did not induce cytotoxic effect, the EO-L stimulated the growth of BEAS-2B normal cells, but not in MCF7 cancerous cells, proving the medicinal effects of STs. But the best result was noticed when EO-L was associated with tamoxifen, which demonstrated better activity than the treatment with the drug alone [45]. The EO of *Pallines spinose* flower (F-PSEO) showed different composition than the leaf EO (L-PSEO). F-PSEO contained 96.39% of STs with 78.63% of the oil as oxygenated derivatives such as acorenone B, α-muurolol, and α-cadinol. The L-PSEO was composed of 51.60% of oxygenated STs and 34.06% of SQ hydrocarbons. F-PSEO had stronger anticancer results for MCF7 and MDA-MB-231 and both EOs induced a caspase-dependent and caspase-independent apoptosis and altered the levels of Bcl-2 and Bax proteins [46].

A component that can optimize the anticancer effects when combined with chemotherapy or reduce side effects of the current treatment is a target for many researches. *Rhizoma curcumae* is a plant known to possess activity against different types of cancer cells [47] and is common in Chinese medicine for the treatment of cancer [48]. Curcumol, a guaiane type ST lactone, is the major component of *R. curcumaeis* and, in combination with doxorubicin, made MDA-MB-231 cells more sensible to the action of doxorubicin through the activation of transcription factor NFAT1 and through the bind of the promoter region of miR-181b-2-3p, which is implicated in motility of BC [49] and less survival in breast cancer patients [50]. Curcumol also demonstrated in vivo suppress of tumor growth [49].

EO of *Blepharocalyx salicifolius* was cytotoxic against the MDA-MB-231 cell not by mechanisms related to apoptosis but by preventing cell metabolism reactions. Its main constituents identified were STs bicyclogermacrene, globulol, viridiflorol, γ-eudesmol, and α-eudesmol [51].

Leaves of *Garcinia celebica* L, popularly used in Malaysia and known as "manggishutan," provide an ST-rich EO composed of α-copaene (61.25%), germacrene D (6.72%), and β-caryophyllene (5.85%) with antiproliferative action to MCF7 cells [52]. A similar result was found with the leaf of *Phoebe bournei* (Hemsl.) Yang, which is also composed mainly of STs such as α-copaene, α-muurolene, α-cadinene, and 1s-calamenene [53].

A ST isolated from the EO of *Rhizoma curcumae* named Furanodiene (FD) is associated with anticancer activities in various types of cancers in humans. FD also showed action on chemo-resistant breast cancer cells [54]. EO of *R. curcumae* and the main bioactive component FD were assessed on doxorubicin-resistant MCF7 cell line; although it showed inhibitory effects on cell viability it did not work on ABC transporters [47], which promote the efflux of chemotherapeutic compounds from cells leading to reduction of drug levels inside the cancer cells and insensitivity to the treatment associated with resistance [55]. Furthermore, FD induced apoptosis via intrinsic/extrinsic-dependent and NF-κB-independent pathways [54].

Multidrug-resistant human BC cells MCF7/ADR were treated with EO of *Inula japonica* (IJO) or its ST component isoalantolactone (ISO) or *Angelicae dahuricae* EO (ADO). IJO, ISO, and ADO may reverse the cancer cell by down-regulating ABCB1 expression [56]. This gene encodes a transporter that changes the phenotype of the cells into a multidrug resistance type associated with worse prognosis in BC patients [57].

EO of *Lycopus lucidus* Turcz. var. hirtus Regel was mainly composed of STs α-humulene, β-caryophyllene, and humulene epoxide II, which resulted in a significant dose-dependent inhibition of cell growth human BC cell lines MDA-MB-435S and ZR-75-30, possibly due to the presence of STs in its composition [58].

A primary alcohol named 2-phenylethanol was the main constituent in the EO of *Magnolia virginiana,* while in *M. grandiflora* oil sample the main compounds were ST alcohol (E,E)-farnesol (18%) and 2-phenylethanol (10%). Both EOs were active against MDA-MB231 cell [59]. Similar action was found with EO of *Eryngium campestre* and *E. amethystinum* from central Italy, rich in ST hydrocarbons like germacrene D, allo-aromadendrene, β-elemene, spathulenol, and ledol against human breast adenocarcinoma cells [60].

In the Amazon Rain Forest, climate changes seem to influence *Iryanthera polyneura* Ducke trees. EOs obtained from leaves collected in the rainy season were more active against MCF7. STs spathulenol, α-cadinol, and τ-muurolol were identified as the main compounds [61]. Some seasonal variation was also found in EO of *Mentha* species, *M. arvensis*, *M. piperita*, *M. longifolia,* and *M. spicata*, and they all stimulated the decrease of MCF7 proliferation. Their major compounds were MTs such as menthol, menthone, piperitenone oxide, and carvone, respectively [62].

STs represent 88.57% of all the compounds detected in *Hedyosmum sprucei* EO (Chloranthaceae), collected in the Amazonian region of Pastaza, which led to cytotoxic effects on MCF7 [63]. Similar effect was observed in STs from EO of *Ballota undulata, B. saxatilis, B. nigra* [64], *Convolvulus althaeoides* [65], *Talauma gloriensis* [66], *Cedrelopsis grevei* [67] and *Feronia elephantum* Correa [68].

*Pinus roxburghii* Sarg. is a Nepal pine used for skin injuries. Its needle EO can inhibit up to 70% of MCF7 cells due to high concentrations of STs such as (E)-caryophyllene and α-humulene and of MT alcohols terpinen-4-ol and α-terpineol [69]. *P. sylvestris* showed cytotoxic selectivity to ER-negative BC cells MDA-MB-231 compared to ER-positive cell line (MCF7) but its chemical composition was not elucidated [70].

Volatile oil from *Saussurea lappa* root (VOSL) showed better anti-breast cancer efficacy and lower side effects than its isolated STs named costunolide (Cos) and dehydrocostuslactone (Dehy), although when combined Cos and Dehy induced apoptosis with regulation of the c-Myc/p53 and AKT/14-3-3 signaling pathways in MCF7 cells or MDA-MB-231 [71].

Thymoquinone (TQ ) is a MT and the main constituent of the EO from the seed of *Nigella sativa*. It can optimize chemotherapeutic agents and reduce its toxic side effects, proving to affect the modulation of signaling pathways and molecules with important participation in oncogenic processes such as initiation, progression, invasion, metastasis, and angiogenesis [1]. TQ encapsulated in poly(d,l-lactide-coglycolide) nanoparticles inhibits the proliferation of MDA-MB-231cells [72], and same effect was obtained with TQ loaded with liposomes in MCF7 and T47D [73]. TQ derivates decreased the growth of MCF-7/Topo [74]. TQ improved the growth inhibition of reference drug doxorubicin in multidrug-resistant MCF-7/TOPO cells, which may be a good source for a booster in the treatment [75]. TQ also showed apoptotic effect in BC cell line (T47D) in combination with gemcitabine as well as alone [76].

TQ was not only active in BC cells but also in vivo by reduction of tumor cell growth, invasion, and migration. These actions seem to be related to the activation of peroxisome proliferator-activated receptor (PPAR)-γ, which acts to inhibit cell growth and proliferation. It also increases ROS, leading to the phosphorylation of p38, a mitogen-activated protein kinase (MAPK), which leads to an antiproliferative and proapoptotic efficacy of TQ in BC [77].

**61**

leaves [90].

*Essential Oils' Potential in Breast Cancer Treatment: An Overview*

XIAP, survivin, Bcl-xL, and Bcl-2 antiapoptotic proteins [78].

In breast tumor xenograft mouse model, TQ was able to reduce the tumor growth and act synergistically with doxorubicin with antiproliferative and proapoptotic effects [78]. Similar result was found with mice injected with triple negative BC (MDA-MB-231 and MDA-MB-436 cells), probably due to the inhibition of eukaryotic elongation factor 2 kinase (EEF2K) signaling [79], which downregulates steps in protein synthesis and increases solid tumor size in vivo [80]. On mice transplanted with breast cancer with EMT6/P cells, the synergic action of TQ and resveratrol decreased the tumor size and led to the cure of 60% animals with no liver or kidney toxicity. The combination also induced apoptosis in EMT6/p and human epithelial BC cell lines MCF7 and T47D [81]. In the xenograft mouse model, TQ increased expression of p-p38 protein in tumors, and led to a decrease in the

Eugenol (Eu), an oxygenated MT, is an important volatile constituent of clove EO mainly obtained from *Syzygium*, which has promising results in vitro for the prevention of the progression of BC, with alteration in cellular energy metabolism of MCF10A-ras [82]. For MCF-7 cell, there were cytotoxicity of cinnamon, thyme, chamomile, and jasmine EOs. MT eugenol seems to play an important role in cinnamon action [83]. EO rich in MT eucalyptol from *Cinnamomum glanduliferum* from Egypt and *Nepeta menthoides* from Iran inhibited respectively, MCF7 [84] and MCF7, T47D

The EO from *Hedychium spicatum* from different regions of western Himalaya where collected and the samples from Almora, Binsar and Uttarakhand were rich in MT and ST and showed cytotoxicity action in MCF7 [86]. Similar effect was observed with EOs obtained from mint (*Mentha spicata*), ginger (*Zingiber officinale*), lemon (*Citrus limonum*), grapefruit (*Citrus paradisi*), jasmine (*Jasminum grandiflora*), lavender (*Lavandula stoechas*), chamomile (*Anthemis nobilis*), thyme (*Thymus vulgaris*), rose (*Rosa centifolia*) and cinnamon (*C. zeylanicum*) from a commercial source in China, composed by elements such as MTs limonene and menthol [83]. *Protium heptaphyllum* (Aubl.) EO was collected during 3 years and did not exhibit significant cytotoxicity against MCF7 cancer cells, with no change in caspase-3 and TNF-α levels. The major compounds were MT such as terpinolene and p-cymene-8-ol, and p-cymene. However, the EO had antimutagenic activity, which

The fruit of *Angelica archangelica* L. growing in Iceland provides MT-rich α-pinene EOs differing mainly in the absence or presence of the MT β-phellandrene. However the cytotoxic activity in Crl mouse-BC-cells was independent of the

The method of preparation affected the composition of EO from *Pituranthos tortuosus* (Desf.) Benth and Hook (Apiaceae). The EO was rich in MT and the major components of the sample prepared by hydrodistillation (HD) were MT β-myrcene, MT sabinene, phenylpropanoids trans-iso-elemicin and MT alcohol terpinen-4-ol. The mayor components from the sample prepared by simultaneous hydrodistillation solvent (n-pentane) (DE) were MTs terpinen-4-ol, sabinene, gamma-terpinene and beta-myrcene. And the mayor components from the sample prepared by conventionalvolatile-solvent extraction (SE) were MT terpinen-4-ol, phenylpropanoid dillapiole, and MT allo-ocimene. The DE sample was the most potent against MCF7 [89]. *Solanum erianthum* leaf volatile oil demonstrated potent inhibitory activity against Hs 578T characterized by the abundance of MT α-terpinolene (17.8%), MT α-phellandrene (17.5%), MT ρ-cymene (15.7%), and MT β-pinene (11.7%) in the

The EO from *Myristica fragrans* (nutmeg) was composed of MT, oxygenated MT, SQ, phenolic ether, and phenylpropanoids, while *Morinda citrifolia* (mengkudu) had mostly carboxylic acids, esters, and isothiocyanate. Both Eos decreased MCF7 cells

*DOI: http://dx.doi.org/10.5772/intechopen.91781*

and MDA-MB-231 [85].

might provide a chemo-preventive effect [87].

quantity of their main components [88].

#### *Essential Oils' Potential in Breast Cancer Treatment: An Overview DOI: http://dx.doi.org/10.5772/intechopen.91781*

*Essential Oils - Bioactive Compounds, New Perspectives and Applications*

breast adenocarcinoma cells [60].

respectively [62].

tion was not elucidated [70].

MCF7 cells or MDA-MB-231 [71].

and proapoptotic efficacy of TQ in BC [77].

EO of *Lycopus lucidus* Turcz. var. hirtus Regel was mainly composed of STs α-humulene, β-caryophyllene, and humulene epoxide II, which resulted in a significant dose-dependent inhibition of cell growth human BC cell lines MDA-MB-435S

A primary alcohol named 2-phenylethanol was the main constituent in the EO of *Magnolia virginiana,* while in *M. grandiflora* oil sample the main compounds were ST alcohol (E,E)-farnesol (18%) and 2-phenylethanol (10%). Both EOs were active against MDA-MB231 cell [59]. Similar action was found with EO of *Eryngium campestre* and *E. amethystinum* from central Italy, rich in ST hydrocarbons like germacrene D, allo-aromadendrene, β-elemene, spathulenol, and ledol against human

In the Amazon Rain Forest, climate changes seem to influence *Iryanthera polyneura* Ducke trees. EOs obtained from leaves collected in the rainy season were more active against MCF7. STs spathulenol, α-cadinol, and τ-muurolol were identified as the main compounds [61]. Some seasonal variation was also found in EO of *Mentha* species, *M. arvensis*, *M. piperita*, *M. longifolia,* and *M. spicata*, and they all stimulated the decrease of MCF7 proliferation. Their major compounds were MTs such as menthol, menthone, piperitenone oxide, and carvone,

STs represent 88.57% of all the compounds detected in *Hedyosmum sprucei* EO (Chloranthaceae), collected in the Amazonian region of Pastaza, which led to cytotoxic effects on MCF7 [63]. Similar effect was observed in STs from EO of *Ballota undulata, B. saxatilis, B. nigra* [64], *Convolvulus althaeoides* [65], *Talauma gloriensis*

*Pinus roxburghii* Sarg. is a Nepal pine used for skin injuries. Its needle EO can inhibit up to 70% of MCF7 cells due to high concentrations of STs such as (E)-caryophyllene and α-humulene and of MT alcohols terpinen-4-ol and α-terpineol [69]. *P. sylvestris* showed cytotoxic selectivity to ER-negative BC cells MDA-MB-231 compared to ER-positive cell line (MCF7) but its chemical composi-

Volatile oil from *Saussurea lappa* root (VOSL) showed better anti-breast cancer efficacy and lower side effects than its isolated STs named costunolide (Cos) and dehydrocostuslactone (Dehy), although when combined Cos and Dehy induced apoptosis with regulation of the c-Myc/p53 and AKT/14-3-3 signaling pathways in

Thymoquinone (TQ ) is a MT and the main constituent of the EO from the seed of *Nigella sativa*. It can optimize chemotherapeutic agents and reduce its toxic side effects, proving to affect the modulation of signaling pathways and molecules with important participation in oncogenic processes such as initiation, progression, invasion, metastasis, and angiogenesis [1]. TQ encapsulated in poly(d,l-lactide-coglycolide) nanoparticles inhibits the proliferation of MDA-MB-231cells [72], and same effect was obtained with TQ loaded with liposomes in MCF7 and T47D [73]. TQ derivates decreased the growth of MCF-7/Topo [74]. TQ improved the growth inhibition of reference drug doxorubicin in multidrug-resistant MCF-7/TOPO cells, which may be a good source for a booster in the treatment [75]. TQ also showed apoptotic effect in BC cell line (T47D) in combination with gemcitabine as well as

TQ was not only active in BC cells but also in vivo by reduction of tumor cell growth, invasion, and migration. These actions seem to be related to the activation of peroxisome proliferator-activated receptor (PPAR)-γ, which acts to inhibit cell growth and proliferation. It also increases ROS, leading to the phosphorylation of p38, a mitogen-activated protein kinase (MAPK), which leads to an antiproliferative

[66], *Cedrelopsis grevei* [67] and *Feronia elephantum* Correa [68].

and ZR-75-30, possibly due to the presence of STs in its composition [58].

**60**

alone [76].

In breast tumor xenograft mouse model, TQ was able to reduce the tumor growth and act synergistically with doxorubicin with antiproliferative and proapoptotic effects [78]. Similar result was found with mice injected with triple negative BC (MDA-MB-231 and MDA-MB-436 cells), probably due to the inhibition of eukaryotic elongation factor 2 kinase (EEF2K) signaling [79], which downregulates steps in protein synthesis and increases solid tumor size in vivo [80]. On mice transplanted with breast cancer with EMT6/P cells, the synergic action of TQ and resveratrol decreased the tumor size and led to the cure of 60% animals with no liver or kidney toxicity. The combination also induced apoptosis in EMT6/p and human epithelial BC cell lines MCF7 and T47D [81]. In the xenograft mouse model, TQ increased expression of p-p38 protein in tumors, and led to a decrease in the XIAP, survivin, Bcl-xL, and Bcl-2 antiapoptotic proteins [78].

Eugenol (Eu), an oxygenated MT, is an important volatile constituent of clove EO mainly obtained from *Syzygium*, which has promising results in vitro for the prevention of the progression of BC, with alteration in cellular energy metabolism of MCF10A-ras [82]. For MCF-7 cell, there were cytotoxicity of cinnamon, thyme, chamomile, and jasmine EOs. MT eugenol seems to play an important role in cinnamon action [83].

EO rich in MT eucalyptol from *Cinnamomum glanduliferum* from Egypt and *Nepeta menthoides* from Iran inhibited respectively, MCF7 [84] and MCF7, T47D and MDA-MB-231 [85].

The EO from *Hedychium spicatum* from different regions of western Himalaya where collected and the samples from Almora, Binsar and Uttarakhand were rich in MT and ST and showed cytotoxicity action in MCF7 [86]. Similar effect was observed with EOs obtained from mint (*Mentha spicata*), ginger (*Zingiber officinale*), lemon (*Citrus limonum*), grapefruit (*Citrus paradisi*), jasmine (*Jasminum grandiflora*), lavender (*Lavandula stoechas*), chamomile (*Anthemis nobilis*), thyme (*Thymus vulgaris*), rose (*Rosa centifolia*) and cinnamon (*C. zeylanicum*) from a commercial source in China, composed by elements such as MTs limonene and menthol [83].

*Protium heptaphyllum* (Aubl.) EO was collected during 3 years and did not exhibit significant cytotoxicity against MCF7 cancer cells, with no change in caspase-3 and TNF-α levels. The major compounds were MT such as terpinolene and p-cymene-8-ol, and p-cymene. However, the EO had antimutagenic activity, which might provide a chemo-preventive effect [87].

The fruit of *Angelica archangelica* L. growing in Iceland provides MT-rich α-pinene EOs differing mainly in the absence or presence of the MT β-phellandrene. However the cytotoxic activity in Crl mouse-BC-cells was independent of the quantity of their main components [88].

The method of preparation affected the composition of EO from *Pituranthos tortuosus* (Desf.) Benth and Hook (Apiaceae). The EO was rich in MT and the major components of the sample prepared by hydrodistillation (HD) were MT β-myrcene, MT sabinene, phenylpropanoids trans-iso-elemicin and MT alcohol terpinen-4-ol. The mayor components from the sample prepared by simultaneous hydrodistillation solvent (n-pentane) (DE) were MTs terpinen-4-ol, sabinene, gamma-terpinene and beta-myrcene. And the mayor components from the sample prepared by conventionalvolatile-solvent extraction (SE) were MT terpinen-4-ol, phenylpropanoid dillapiole, and MT allo-ocimene. The DE sample was the most potent against MCF7 [89].

*Solanum erianthum* leaf volatile oil demonstrated potent inhibitory activity against Hs 578T characterized by the abundance of MT α-terpinolene (17.8%), MT α-phellandrene (17.5%), MT ρ-cymene (15.7%), and MT β-pinene (11.7%) in the leaves [90].

The EO from *Myristica fragrans* (nutmeg) was composed of MT, oxygenated MT, SQ, phenolic ether, and phenylpropanoids, while *Morinda citrifolia* (mengkudu) had mostly carboxylic acids, esters, and isothiocyanate. Both Eos decreased MCF7 cells

[91]. Similar effect was obtained with EO from leaves of *Solanium spirale* Roxb containing 48.10% of diterpene alcohol (E)-Phytol [92], with EO from leaf, stem, stem bark, and root of *Uvariodendron angustifolium* with the presence of citral (a mixture of terpenoids) [93] and with EO from *Syzygium aromaticum*, a source of TT [4].

*Litsea cubeba*, composed by 68.9% of MT citral, and *Cinnamomum zeylanicum*, mainly composed by (E)-cinnamaldehyde, also had inhibitory action on BC cells MCF7, T47D and MDA-MB-231 [94].

EO from *Erigeron acris* root showed higher antiproliferative activity for MCF7 and MDA-MBA-231 than *E. annuus*, which may be due to polyacetylenic compounds, matricaria and lachnophyllum ester [95], while *Waldheimia glabra* from the Himalayan Mountains, composed mainly of ST spathulenol and thujopsene, fatty alcohol 9-tetradecenol, MT α-thujone, santolina alcohol, and MT tertiary alcohols terpinen-4-ol only had mild action [96].

EO obtained from the seeds of onion *Afro styrax lepidophyllus* and garlic tree *Scorodophloeus zenkeri* are usually used as spices in Africa. It exhibited a strong inhibitory effect on MDA-MB 231. The predominant compound in both oils was the terpenoid 2,4,5,7-tetrathiaoctane [97]. EO of aerial parts, branches and leaves, of *Glandora rosmarinifolia* (Ten.) D.C. Thomas is composed mostly of aliphatic alkanes and diterpene hydrocarbons; it induces cell growth inhibition at triple negative-breast cancercell lines SUM 149 and MDA-MB-231 in part due to a pro-oxidant mechanism [5].
