**2. Induction of apoptosis in breast cancer cells by essential oils**

Apoptosis is a cellular process involved in physiological and pathological conditions. The mechanism of apoptosis plays an important role in the pathogenesis of many diseases, such as cancer, in which it can be reduced by the cells as a mechanism of survival so they can continue to proliferate, leading to metastasis and resistance to drugs. Caspases can act as initiators and executers of this process and can be activated in an intrinsic or extrinsic way. The intrinsic, or mitochondrial, pathway is controlled by proteins from the Bcl-2 family, which can be proapoptotic proteins such as Bax, Bak, Bad, Bcl-Xs, Bid, Bik, Bim, and Hrk, or antiapoptotic such as Bcl-2, Bcl-XL, Bcl-W, Bfl-1, and Mcl-1 [8].

Collected from Kerman, Golestan, and East Azerbaijan provinces from Iran, EO from the seed of *Foeniculum vulgar* Mill, known as fennel (FN), increased the expression of a proapoptotic factor Bax and decreased antiapoptotic factor Bcl2 gene expression, which leads to cytotoxic effects on MCF7 [7]. FN also had action against MDA-MB [9]. But the FN from Tajikistan presented low cytotoxicity when compared to doxorubicin [10].

Another plant in Iran, *Oliveria decumbens,* is used as a vegetable and medicinal plant by the population to treat cancer-related symptoms. Its EO (OEO) inhibited viability of murine mammary carcinoma 4T1, promoting apoptosis in vitro and led to a TH1 anticancer response in 4T1 tumor-challenging mice [11]. OEO and its main component, thymol, also showed anticancer properties in MDA-MB-231 BC monolayers by activation of intrinsic and maybe extrinsic apoptosis [12]. Also, in Iran, all EOs obtained from the aerial parts of *Zhumeria majdae* collected from five different localities were active and did not show cytotoxicity variability for MCF7 [13].

EO of *Decatropis bicolor* (Zucc.) Radlk, empirically used in Mexico for BC treatment, showed a selective cytotoxic effect toward MDA-MB-231 by activation of Bax and caspases 9 and 3 through intrinsic apoptosis pathway [14]. The apoptosis of MCF7 was stimulated by *Ocimum sanctum* EO with the regulation of apoptotic genes p53 and Bid and elevation of Bax/Bcl-2 [15]. Similar results were found with MCF7 apoptosis induction by *Tetraclinis articulata* [16] and *Myrtus communis* L., commonly used in Morocco for culinary purposes [17]. Carvacrol is the major ingredient of *Zataria Multiflora* EO and induced apoptosis in 2D and 3D cell cultures of MDA-MB-231, MCF7, and T47D with selectivity and increased reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential (ΔΨm), caspase 3 activation, and DNA damage [18]. *Thymus vulgaris* L. EO was also proapoptotic to MCF7 and MDA-MB-231 cells [6].

Nuclear factor-κB (NF-κB) is involved in tumor development by regulation of cell proliferation, apoptosis, and cell migration, and its activation is associated with both inflammation and development of cancer, processes that seem to be linked [19]; therefore, its influence by components can be used as a target. Justified by the use already made by the local population, research has shown that *Cyphostemma juttae* (Dinter & Gilg) Desc. EO decreased NF-κB activation with suppressive action on triple negative breast cancer cell lines (TNBCs) [20].

The inhibition effect of EO from *Erythrina corallodendron* L. (ECEO) seems to be mediated by the suppression of the epithelial-mesenchymal transition (EMT) process, implicated with metastasis in cancer progression. Another aspect that

**57**

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

as the positive drugs, it may qualify as an adjuvant drug [21].

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

carbon atoms [25]. The biosynthesis of terpenoids is shown in **Figure 1**.

associated with decreasing progression of cancer.

the growth of transplanted 4T1 mammary tumors [38].

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

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,

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

points to it being a possible good target for a new chemotherapeutic agent is that ECEO had greater cytotoxicity to breast cancer cells MDA-MB-231 and MCF7 than to normal human mammary epithelial cells (HMLEs). Although it was not as good

MCF7 cells treated with frankincense EO (FCO), pine needle, and geranium activated the 5′-adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathway, which controls cell growth, proliferation, and autophagy and is deregulated in cancer [22]. As a consequence, there was suppression of cell viability, proliferation, migration, and invasion activity. FCO was also effective in inhibiting tumor growth and inducing

*Aquilaria* spp. can provide agarwood, and its EO has proven to reduce the cell number of MCF7, suggesting an effect on cell death and attachment inhibition. Although there have not been any reports of its traditional use for cancer treatment, many reports show its use for inflammatory-associated diseases [23]. On the other hand, *Boswellia* sp. gum has proved to have anti-neoplastic effects and is very commonly used for aroma therapy. EO of *B. sacra* induced cell death in T47D, MCF7, and MDA-MB-231, and the EO hydrodistilled at 100°C was more potent than the one prepared at 78°C, which demonstrates the importance of the form of prepara-

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

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

apoptosis in human BC mouse model [2].

tion in the effect of the EO [24].

β-pinene, and ρ-cymene) [29].

*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*

such as Bcl-2, Bcl-XL, Bcl-W, Bfl-1, and Mcl-1 [8].

proapoptotic to MCF7 and MDA-MB-231 cells [6].

on triple negative breast cancer cell lines (TNBCs) [20].

compared to doxorubicin [10].

effects and the high cost of chemotherapy approaches in BC [7]. This review focuses on apoptosis as an action mechanism by EOs in breast cancer cells, antitumoral activity of EOs and their bioactive compounds, and optimization of EOs' use and their potential as an alternative for side effects reduction during breast cancer treatment.

Apoptosis is a cellular process involved in physiological and pathological conditions. The mechanism of apoptosis plays an important role in the pathogenesis of many diseases, such as cancer, in which it can be reduced by the cells as a mechanism of survival so they can continue to proliferate, leading to metastasis and resistance to drugs. Caspases can act as initiators and executers of this process and can be activated in an intrinsic or extrinsic way. The intrinsic, or mitochondrial, pathway is controlled by proteins from the Bcl-2 family, which can be proapoptotic proteins such as Bax, Bak, Bad, Bcl-Xs, Bid, Bik, Bim, and Hrk, or antiapoptotic

Collected from Kerman, Golestan, and East Azerbaijan provinces from Iran, EO from the seed of *Foeniculum vulgar* Mill, known as fennel (FN), increased the expression of a proapoptotic factor Bax and decreased antiapoptotic factor Bcl2 gene expression, which leads to cytotoxic effects on MCF7 [7]. FN also had action against MDA-MB [9]. But the FN from Tajikistan presented low cytotoxicity when

Another plant in Iran, *Oliveria decumbens,* is used as a vegetable and medicinal plant by the population to treat cancer-related symptoms. Its EO (OEO) inhibited viability of murine mammary carcinoma 4T1, promoting apoptosis in vitro and led to a TH1 anticancer response in 4T1 tumor-challenging mice [11]. OEO and its main component, thymol, also showed anticancer properties in MDA-MB-231 BC monolayers by activation of intrinsic and maybe extrinsic apoptosis [12]. Also, in Iran, all EOs obtained from the aerial parts of *Zhumeria majdae* collected from five different localities were active and did not show cytotoxicity variability for MCF7 [13]. EO of *Decatropis bicolor* (Zucc.) Radlk, empirically used in Mexico for BC treatment, showed a selective cytotoxic effect toward MDA-MB-231 by activation of Bax and caspases 9 and 3 through intrinsic apoptosis pathway [14]. The apoptosis of MCF7 was stimulated by *Ocimum sanctum* EO with the regulation of apoptotic genes p53 and Bid and elevation of Bax/Bcl-2 [15]. Similar results were found with MCF7 apoptosis induction by *Tetraclinis articulata* [16] and *Myrtus communis* L., commonly used in Morocco for culinary purposes [17]. Carvacrol is the major ingredient of *Zataria Multiflora* EO and induced apoptosis in 2D and 3D cell cultures of MDA-MB-231, MCF7, and T47D with selectivity and increased reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential (ΔΨm), caspase 3 activation, and DNA damage [18]. *Thymus vulgaris* L. EO was also

Nuclear factor-κB (NF-κB) is involved in tumor development by regulation of cell proliferation, apoptosis, and cell migration, and its activation is associated with both inflammation and development of cancer, processes that seem to be linked [19]; therefore, its influence by components can be used as a target. Justified by the use already made by the local population, research has shown that *Cyphostemma juttae* (Dinter & Gilg) Desc. EO decreased NF-κB activation with suppressive action

The inhibition effect of EO from *Erythrina corallodendron* L. (ECEO) seems to be mediated by the suppression of the epithelial-mesenchymal transition (EMT) process, implicated with metastasis in cancer progression. Another aspect that

**2. Induction of apoptosis in breast cancer cells by essential oils**

**56**

points to it being a possible good target for a new chemotherapeutic agent is that ECEO had greater cytotoxicity to breast cancer cells MDA-MB-231 and MCF7 than to normal human mammary epithelial cells (HMLEs). Although it was not as good as the positive drugs, it may qualify as an adjuvant drug [21].

MCF7 cells treated with frankincense EO (FCO), pine needle, and geranium activated the 5′-adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathway, which controls cell growth, proliferation, and autophagy and is deregulated in cancer [22]. As a consequence, there was suppression of cell viability, proliferation, migration, and invasion activity. FCO was also effective in inhibiting tumor growth and inducing apoptosis in human BC mouse model [2].

*Aquilaria* spp. can provide agarwood, and its EO has proven to reduce the cell number of MCF7, suggesting an effect on cell death and attachment inhibition. Although there have not been any reports of its traditional use for cancer treatment, many reports show its use for inflammatory-associated diseases [23]. On the other hand, *Boswellia* sp. gum has proved to have anti-neoplastic effects and is very commonly used for aroma therapy. EO of *B. sacra* induced cell death in T47D, MCF7, and MDA-MB-231, and the EO hydrodistilled at 100°C was more potent than the one prepared at 78°C, which demonstrates the importance of the form of preparation in the effect of the EO [24].
