Essential oils are widely used in the pharmaceutical industry for their antimicrobial, antiviral, antifungal, antiparasitic, and insecticidal properties. Their anticancer activity has been increasingly explored as the natural constituents of essential oils play an important role in cancer prevention and treatment. The chemical composition of essential oils includes monoterpenes, sesquiterpenes, oxygenated monoterpenes, phenolic sesquiterpenes, and others. Several mechanisms of action such as antioxidant, antimutagenic, antiproliferative, enhancement of immune functions, modulation of multidrug resistance, and synergistic mechanism of volatile constituents are responsible for their chemotherapeutic properties. This review focuses on the activity of essential oils and their chemical composition in regard to breast cancer.
- essential oils
- antitumor activity
- chemical composition
- antitumor mechanism
- breast cancer
Cancer is a disease in which normal cells change into a type of cell that can continuously proliferate and, by a process named metastasis, migrate to distant parts of the body . Breast cancer (BC) is the most common cancer in women in the world, presenting high morbidity and mortality . It causes a major public health problem, and the incidence is increasing all over the world .
The treatment used for cancer causes many side effects; besides, there are a large number of cases of resistance toward anticancer drugs . These are the main causes that limit the success of treatment in aggressive BC cases. Thus, the need to have novel therapeutic agents is urgent .
Natural products, such as plants, may hold the future of BC treatment as the source for new drugs that can interfere with certain processes and ultimately result in clinical usage as an adjuvant therapy .
Essential oils (EOs) act as protective mechanism for plants against bacteria, viruses, insects, and even herbivores . They are widely used by the population to treat cancer and can change the metabolism of cancer cells in very low doses, besides provide energy for synthetic processes . This way, EOs are being considered as a promising agent opening venues for novel anticancer therapy as a way to defeat side effects and the high cost of chemotherapy approaches in BC . 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.
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 .
Collected from Kerman, Golestan, and East Azerbaijan provinces from Iran, EO from the seed of
Another plant in Iran,
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 ; 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
The inhibition effect of EO from
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 . 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 .
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 . 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 , 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 :
Bisabolene isomers are the main constituents of opoponax (
EO from leaves of
β-Elemene is the major active component of the EO from a traditional plant from China,
Different parts of the same plant can have different chemical constitution and biological activity. For example, the EO of
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.
A ST isolated from the EO of
Multidrug-resistant human BC cells MCF7/ADR were treated with EO of
A primary alcohol named 2-phenylethanol was the main constituent in the EO of
In the Amazon Rain Forest, climate changes seem to influence
STs represent 88.57% of all the compounds detected in
Volatile oil from
Thymoquinone (TQ) is a MT and the main constituent of the EO from the seed of
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 .
In breast tumor xenograft mouse model, TQ was able to reduce the tumor growth and act synergistically with doxorubicin with antiproliferative and proapoptotic effects . 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 , which downregulates steps in protein synthesis and increases solid tumor size in vivo . 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 . 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 .
Eugenol (Eu), an oxygenated MT, is an important volatile constituent of clove EO mainly obtained from
The EO from
The fruit of
The method of preparation affected the composition of EO from
The EO from
EO obtained from the seeds of onion
4. Optimization of the EOs’ use against BC
Nanoemulsions (NEs) can work as an ally to reduce some problems associated with Eos such as sensibility and lability. That is what happened with the use of
Another study made with CS and N,N,N-trimethyl chitosan (TMC) also increased the toxicity of another EO from
Mitomycin C (MTC) was solubilized in NEs of EO from ginger (EOG) and from frankincense, which was shown to increase the toxicity for MCF7 cells when compared with the use of MMC alone. EOG had the strongest apoptotic effect . The same effect was seen when MTC was combined with chamomile NE oil .
Sandal wood EO (SEO), extracted from
5. EOs as an alternative for side effects reduction during BC treatment
Chemotherapy-induced nausea and emesis are one of the most common problems in BC patients and they can be inappropriately managed due to low affordability of new medications . Women suffering from BC received 5-day aroma therapy treatment using either ginger EO or a placebo. Nausea score was significantly lower after ginger EO inhalation but was not sustained for the overall treatment effect. Overall, the EO improved health-related quality of life .
Symptoms of urogenital atrophy (UA) are common in BC survivors . The cause is due to systemic treatments as a side effect of endocrine therapies and topical estrogen is usually used to reduce the symptoms. Other alternatives are being sought and could be valid to improve life quality of the patients with BC. EO of
Reaction on the skin can happen in BC patients under radiotherapy treatment. Twenty four patients received an EO mixture with 32.5% of jojoba (
6. Unsatisfactory EOs results for BC
Some EOs used in research were not able to have satisfactory in vitro anticancer effects on MCF7 as EO from
This information is helpful to elucidate some effects of EOs that are used by the population. Some EOs may not have any effect for BC or can even help stimulate BC cells or have toxic action. Due to this, it is important to determinate if they are safe for common use. Furthermore, it is worth mentioning that the results show unsatisfactory effects in regard to concentrations used, which does not prevent the use of these EOs in other researches with different outcomes.
Sesquiterpenes and monoterpenes are part of the main components of essential oils, some of them already being isolated and with actions described, although it is important to establish the force of the use of multiple compounds together.
A large number of essential oils from different plants have been described in the literature with promising in vitro effect in a variety of breast cancer cells and even with in vivo effects in murine model; it is important to continue this research and take it to the next level with clinical trials.
The articles found in the literature and their results encourage the use of essential oils. The importance of plant research and the production of these oils demonstrated the difference they can make as a supporting anticancer agent or as a reducer of the side effects of breast cancer, which shows its power in the fight against breast cancer.
The authors would like to thank Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Coordination for the Improvement of Higher Education Personnel), Brazil (CAPES) [Finance Code 001] and Instituto Oswaldo Cruz for financial support.
Conflict of interest
The authors declare no conflict of interest.