Essential Oils and Their Constituents as Anticancer Agents: A Mechanistic View

Exploring natural plant products as an option to find new chemical entities as anticancer agents is one of the fastest growing areas of research. Recently, in the last decade, essential oils (EOs) have been under study for their use in cancer therapy and the present review is an attempt to collect and document the available studies indicating EOs and their constituents as anticancer agents. This review enlists nearly 130 studies of EOs from various plant species and their constituents that have been studied so far for their anticancer potential and these studies have been classified as in vitro and in vivo studies for EOs and their constituents. This review also highlights in-depth various mechanisms of action of different EOs and their constituents reported in the treatment strategies for different types of cancer. The current review indicates that EOs and their constituents act by multiple pathways and mechanisms involving apoptosis, cell cycle arrest, antimetastatic and antiangiogenic, increased levels of reactive oxygen and nitrogen species (ROS/RNS), DNA repair modulation, and others to demonstrate their antiproliferative activity in the cancer cell. The effect of EOs and their constituents on tumour suppressor proteins (p53 and Akt), transcription factors (NF-κB and AP-1), MAPK-pathway, and detoxification enzymes like SOD, catalase, glutathione peroxidase, and glutathione reductase has also been discussed.


Introduction
Cancer has emerged as one of the most alarming diseases in the last few decades throughout the world. It is a multifactorial disease contributing towards uncontrolled growth and invasion of the abnormal cells leading to the formation of tumour. The steep rise in the number of cancer cases may be attributed to the change in food habits, use of tobacco and alcohol, chronic infections, exposure to harmful radiations and chemicals, or more widely due to change in lifestyle and environmental pollution [1]. International Agency for Research on Cancer (IARC) reported that there are approximately 12 million cancer cases and these have accounted for 7.6 million deaths (around 13% of all deaths) in the year 2008 [2]. The recent estimates reveal that the number of new cancer cases and cancer-related deaths has increased by 11% and 7.9, respectively, in the year 2012 as compared to 2008 [2]. Further, the developing countries have half the number of cancer incidence cases compared to the developed countries [3]. In India, 0.979 million cancer cases were reported in the year 2010 which is expected to increase to 1.148 million by 2020 [4]. The mortality rate among cancer patients is very high. The problem is more serious in economically less developed countries due to the lack of diagnostic techniques, standard methods of treatment, and higher cost of the treatment [5]. People in scientific field are currently overcoming these problems with the use of synthetic drugs. These drugs are designed to specifically target rapidly growing and dividing cells of various tumours. But, these synthetic drugs also affect rapidly dividing normal cells in our body leading to certain other major irreversible side effects. Chemotherapy used in cancer treatment has been reported to induce multidrug resistance 2 BioMed Research International [6,7]. The high cost, increasing drug resistance, and side effects of current therapeutic approaches are forcing the scientists to explore alternative medicines, the traditional medicine, as an option to find new chemical entities for treatment of cancer.
Among the alternative traditional approaches, various plant products classified as alkaloids, saponins, triterpenes, glycosides, and polyphenols among others have shown very promising anticancer properties in both in vitro and in vivo. There are more than one thousand plants which have been reported to possess significant anticancer properties [8]. Vincristine, vinblastine, colchicine, ellipticine, lepachol, taxol, podophyllotoxin, camptothecin, irinotecan, etoposide, and paclitaxel are classical examples of plant-derived compounds which are found to have wide applications in cancer therapeutics [9]. The plant-derived products are expected to induce lesser side effects compared to synthetic drugs. Among plant derived compounds, essential oils (EOs) from aromatic plants have been reported to possess anticancer properties [10,11]. EOs have also been reported to improve the quality of life of the cancer patients by lowering the level of their agony [12]. EOs-mediated therapy cannot be a substitute to the standard chemotherapy and radiotherapy but can be used in combination with cancer therapy to decrease the side effects of the drugs. Hence, EOs can be used for improving the health of the cancer patients and as a source of novel anticancer compounds. In the last two decades, a number of researches are exploring anticancer potential of EOs and their components in vitro and in vivo models. Recently, Bhalla et al. reviewed EOs as anticancer agents limiting to the recent literature and a short mechanism(s) of action [13]. However, the current review is a comprehensive one, enlisting nearly 130 studies of EOs from various plant species and their constituents that have been studied so far for their anticancer potential. The studies have been classified as in vitro and in vivo for EOs and their constituents. The current review also highlights in-depth various mechanisms of action of different EOs reported in the treatment strategies for different cancers.

Chemical Classification, Uses, and Therapeutic Potential of EOs and Their Constituents
EOs are the concentrated hydrophobic liquids with specific aroma produced by aromatic plants [14]. These are also called volatile oils or ethereal oils and are the secondary metabolites present in lower amounts in various plant parts. The composition and other biological properties of the EOs depend on their constituents. The constituents may be terpenes, aromatic compounds and some other compounds of various origins. The constituents of the EOs have been classified on the basis of their chemical structures. EOs are considered more potent than their constituents [15] due to their synergistic and more selective effect. In addition, EOs from plants growing in varied environments differ in their composition and hence have different uses. A general classification based on chemical structures along with examples is enlisted in Table 1.
EOs and their components are used for their specific aromas in perfumery and as flavouring agents in food products since ancient times. EOs have also been used in aromatherapy for improving the health due to sedative and stimulant properties. EOs are used for massage, bath, and inhalation as relaxants and treatment options as aromatherapies for various diseases with active ingredients that are being exploited in medicine [16]. The lipophilic nature of these EOs enables them to easily cross the membranes of the cells and reach inside the cell. EOs are described as strong antioxidants [10,17] and antimicrobial [18] and are in use for the management of severe diseases like cardiovascular [19], diabetes [20], Alzheimer's [21], cancer [22], and others. However, the present review focuses only on the anticancer potential of EOs and their constituents.

EO and Constituents as Anticancer Agents
EO is one among the most valuable plant products used in the medicine and complementary treatment strategies. Exploration of EOs and their constituents toward their beneficial role in different cancers is currently under lens. A search of PubMed (http://www.pubmed.gov/), the National Institute of Health's online research shows 543 results for the search "cancer-essential oils" as of February 2014. Further screening of these research papers, nearly 135 correspond to anticancer properties of EO. Out of these 135 research papers, 117 have been published after the year 2005 indicating the sharp increase in number of publications in this field. EOs from different plants have been reported to have anticancer potential against mouth, breast, lung, prostate, liver cancer, colon cancer, and brain cancer and even in leukemia [23][24][25][26][27][28]. Not only EOs but their constituents like Carvacrol [29], dlimonene [30], Geraniols [31][32][33], Myrcene [34,35], perillyl alcohol (POH) [36], -humulene [37], -caryophyllene [38], Thymol [39,40], Citral [41], and others have also been reported to possess cytotoxic effect on the cancer cell lines and in vivo studies. Some of these like POH have gone through phase I [42] and phase II [43] clinical trials in cancer patients. Terpene analogues like Terpinen-4-ol have also been reported to have anticancer properties and induce apoptosis [44].
The current review has extensively collected and documented the available studies indicating EOs from many plants and their constituents as anticancer agents. The overall literature has been divided into different tables. Tables 2 and  3

Mechanism of Action of EOs
Drugs used in cancer treatment target the cancer cell by inducing apoptosis or cell cycle arrest. Hence, natural products causing apoptosis in the cancer cells are valuable resources in cancer suppression. EOs with therapeutic potential can act by two ways-chemoprevention and cancer suppression. Various mechanisms involved in cancer treatment are

Cinnamomum zeylanicum
Normal rat embryonic fibroblasts (F2408) and c-H-ras transformed rat embryonic fibroblasts (5RP7) cell lines Cytotoxicity and apoptosis [138] Citrus reticulate, C. aurantium, C. limon, and C. aurantium Ehrlich ascites carcinoma resistant to Endoxan cells Antitumour activity [139] 6 BioMed Research International     [46]. EOs were also demonstrated to change expression levels of Bcl-2 and Bax genes leading to release of cytochrome C into cytosol in KB human oral epidermoid carcinoma cells [23].
This happens via activation of caspase-9 leading to caspase-3 formation which in turn cleaves target that causes apoptosis and increased phosphorylation of extracellular signalregulated kinase (ERK), c-jun N-terminal kinase, and p38 MAPK [23]. EO-induced apoptosis has been also suggested to be involving mitochondrial and MAPKs pathways [23]. Antiapoptotic Bcl-2 protein is downregulated by the action of EOs on the cancer cells [47]. In mouth cancer KB cells, Artemisia lavandulaefolia EO has been shown to decrease Bcl-2 protein level in dose dependent manner [23], which leads to apoptosis in cancer cells that is an important strategy to control cancer development and progression.
EO constituents lead to poly(ADP-ribose) polymerase-1 (PARP) cleavage [48] which is an indicator of apoptosis [49]. Table 4: List of EO constituents studied for anticancer potential in both in vitro and in vivo models, and major observations reported.

Constituents used
Model systems used Major findings/mechanism(s) reported Reference

Murine mesothelioma (AE17), melanoma cells (B16-F10), and fibroblasts (L929)
Necrotic cell death and apoptosis to lower extent in cancer cells [197] Thymol Human promyelocytic leukemia (HL-60) cells Caspase-dependent and independent apoptosis [40] Thymol Human liver cancer (Bel-7402) cells Antiproliferative activity [198] Thymol K-562, P-815, CEM, MCF-7, and MCF-7 gem Prevention of G 0 /G 1 phase transition [39] Thymoquinone Human colon cancer (LoVo, HCT 116, Caco-2, HT-29 and DLD-1) and human intestinal (FHs74Int) cells ROS generation and mitogen-activated protein kinases (MAPK) JNK and ERK activation in cancer cells leading to apoptosis [199] Trans-caryophyllene Breast cancer (MCF-7), colon cancer (HCT-116) and murine macrophage (RAW264.7) cell lines Cytotoxicity [134] [48]. PARP-1 protein has been shown to be modulated by the EOs and their constituents [23]. Inactivation of PARP results due to the activity of caspases leading to cancer cell death in response to treatment with EOs and their constituents. In a study, Artemisia lavandulaefolia EO and its major compound 1,8-cineole have been shown to adopt the above route for mitochondrial and MAPKs pathways resulting in apoptosis in the mouth cancer, KB cells [23]. EO of Boswellia sacra has also been reported to induce PARP cleavage in MDA-MB-231 cells [50]. Some of the mechanisms leading to apoptosis are summarised below.

Increase in the ROS Levels.
ROS are generated inside the cells in response to external stimuli or stress under normal conditions. Enhanced ROS levels in the abnormal cells instigate the cells to undergo apoptosis. Such response in the cancer cell on treatment with EO has been observed as an effective treatment method. EOs from Aniba rosaeodora (rosewood) were reported to induce apoptosis by increasing ROS production [51]. Similar effect has been observed by the EO of Zanthoxylum schinifolium in liver (HepG2) cancer cells which leads to apoptosis [52]. Decreased levels of cellular antioxidants like glutathione [53] and increased ROS production are the most commonly encountered phenomenon in cancer cells in response to the treatment with EOs that lead to cell death.

Effect on Akt.
Akt is an important protein which also regulates p53, a tumour suppressor protein. Boswellia sacra oil influences the Akt protein expression [50]. Vapor of Litsea cubeba seed oil suppressed mTOR and pPDK1 leading to dephosphorylation of Akt protein at serine (Ser 473 ) and threonine (Thr 308 ), respectively, activating various caspases (caspase 3 and caspase 9) which caused programmed cell death in lung cancer cells [54]. They also reported that the cell cycle gets arrested in the lung cancer cells due to overexpression of p21 resulting from the deactivation of mdm2 due to dephosphorylated Akt protein. Further increased binding of the p21 to cyclins inhibited G 1 -S phase transition [54].

Effect on NF-B.
Nuclear factor, NF-B, is a transcription factor (TF) that gets activated in the tumour cells [55]. Thus, it serves as a potential target for developing anticancer drugs and blocking of this TF advocates towards anticancer activity of the natural compounds. -terpineol have been reported to target NF-B and downregulates its related genes such as IL-1 , IL1R1, IFNG, ITK, and EGFR [56]. Linalyl acetate and -terpineol monoterpenes act synergistically and inhibit the expression of NF-B leading to cell death of colon cancer cells [57]. Human leukaemia cell line (HL-60) treated with EO of Cymbopogon flexuosus and its major constituent isointermedeol has been reported to lower NF-B which is one of the contributing multiple pathways resulting in apoptosis [58]. EO of Artemisia capillaries leads to NF-B-DNA binding activation at the concentration above 0.5 L/mL, leading to apoptosis in the mouth cancer KB cells [47].

Effect on AP-1.
Activator protein-1 (AP-1) is another TF which plays vital role in different processes like differentiation, proliferation, transformation, and apoptosis of the cells. Its activity is regulated by MAPK proteins which are also affected by EO treatment in cancer cells [47]. Dietary intake of POH results in decreasing the tumours induced by Azoxymethane-(AOM-) induced colon cancer [59]. It prevents the skin cancer induced by UV-B radiations [60] by activation of AP-1. DNA binding activity of AP-1 increases up on effective treatment of Artemisia capillaries EO resulting in apoptosis in mouth cancer cells [47]. AP-1 thus is affected by the EO treat ment and its activation mediate apoptosis in the cancer cells.

MAPK-Pathway.
MAP kinases get activated in response to oxidative stress in the cells [61,62]. Various MAPKs like JNK, ERK, and p38 kinase are the signaling molecules of MAPK pathway involved in the apoptosis in cancer cell. EOs mediated apoptosis involves phosphorylated MAPK forms in the cells [62]. These forms increase with time of exposure to the EO of Artemisia capillaris in mouth cancer cells [47].

Cell Cycle Arrest.
Mammalian cells have different cell cycle phases (G 1 , S, G 2 , and metaphase) to complete their life cycle. Fidelity of the cell cycle is lost due to the lack of response to the negative regulators of cell cycle progression in the cancer cells leading to uncontrolled cell division [63]. Regulation of the genes involved in this process is also hampered. Thus, halting any cell cycle event in the cancer cell leads to prevention of their growth and division, a widely employed therapeutic strategy [64]. Various cell cycle checkpoints act as potential targets for cancer treatment [64]. Patchouli alcohol which is an important component of Pogostemon cablin EO has been reported to upregulate p21 expression and suppress cyclin D1 and cyclin-dependent kinase 4 (CDK4) expression in colorectal cancer cells with increase in dose [65]. As p21 is negative regulator of G 1 phase transition, increased expression of this protein by the action of patchouli alcohol is indicative of cell cycle inhibition [65]. Similar arresting of the G 1 transition has also been reported in different types of cancer in response to various other EOs [66,67]. EOs of Curcuma wenyujin inhibit S/G 2 phase transition leading to cancer cell death [68]. G 2 /M phase transition has been reported on the treatment of liver tumour (J-5) cells with diallyl trisulfide, garlic EO constituents [69]. Various constituents like geraniol, thymol, and carvacrol of EOs inhibit different phases of cell cycle [39,[70][71][72]. Monoterpenes act by altering the expression of cell cycle. Genes like DDIT3, IL8, and CDKNIA causing cell cycle arrest have been reported to be upregulated by frankincense oil [46]. Therefore, EOs and their constituents serve as effective anticancer substances by targeting cell cycle progression in cancer cells.

Antimetastatic and Antiangiogenic.
Angiogenesis is a process that occurs in the tumours, which helps them to survive and proliferate. Inhibition of this process stops the supply of required nutrients to the cancer cell and is an efficient way to control cancer. Certain anticancer drugs target cancer cell by this way. EO of Curcuma zedoaria has been tested in vitro and in vivo for antiangiogenic effect and it was reported to exhibit antiproliferative activity against various cancer cell lines and also suppressed melanoma growth and lung metastasis in mice [73]. This action was reported to be attributed towards downregulation of matrix metalloproteinases (MMP) [73]. POH which is one of the components of many EOs has been reported as the angiogenesis inhibitor molecule [74]. EO from Citrus sinensis has been reported to inhibit angiogenesis and metastasis in colon cancer cells [75]. Inhibition of vascular endothelial growth factor (VEGF) which plays an important role in angiogenesis is the key indicator of antiangiogenic behaviour displayed by the EOs [75]. In addition, downregulation of matrix metalloproteases (MMP-6) by the Citrus sinensis EO in a dose dependent manner and blockage of vascular endothelial growth factor receptor 1 (VEGFR1) also confirmed the role of EO in inhibition of metastasis in colon cancer [75]. Limonene and perillic acid are the antimetastatic molecules which are well studied in mice [76]. -Pinene isolated from the EO of Schinus terebinthifolius also had antimetastatic activity in the C57Bl/6 mice with melanomas [77]. As both these processes are the most harmful and unique properties of the cancer cells, targeting these can prevent spreading of cancer to the other parts and inhibit proliferation of the localised tumours. Efficacy of the EOs in inhibiting these processes will enable potential treatment strategies for cancer therapy.

Effect on Detoxification Enzymes.
Genotoxins lead to alteration of the internal antioxidants and antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) along with alteration of various important body functions resulting in damage to tissues and membranes. Phase I and phase II detoxification enzymes are responsible for the degradation of the harmful compounds. Certain compounds of the EOs act as inducer of these detoxification enzymes and thus prevent the induced-toxicity and even cancer in the cell line models. Citral is the example of one such compound which increases the activity of a key phase II detoxification enzyme-glutathione-S-transferase [78]. Dietary intake of (POH) also plays a role in the prevention of carcinogenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [79]. EOs have been reported to have preventive effect on cancer treatment [80]. Varying concentrations of Allium sativum (garlic) EO were administered to mouse having diethylnitrosamine induced gastric cancer with basic diet and this EO affected phase I enzymes, SOD, CAT, and GPx activities. EO of Allium sativum has also been reported to be efficient in gastric cancer in mouse model [81]. EOs induce phase I and phase II enzymes which prevent the interaction of carcinogens with DNA. This results in chemopreventive effect of the EOs [15,81].
EO of holy basil prevents fibrosarcoma tumours induced by 20-methylcholanthrene in Swiss albino mice thighs by increasing the level of endogenous antioxidants [82]. Ocimum sanctum EO affects enzymes, namely SOD, CAT, and GST, and increases the levels of reduced glutathione, a nonenzymatic antioxidant which is responsible for decrease in the size of tumour and its incidence in the mice with the induced toxicity [82]. Salvia libanotica EO has potential to prevent the proliferation of skin papillomas induced by 7,12 dimethylbenz[a]anthracene (DMBA)-and 12-0-tetradecanoylphorbol-13-acetate (TPA) in mice [83]. Pomegranate seed oil has ability to inhibit TPA induced skin cancer in the mice [84].
Antioxidant activity of EOs has been reported to be helpful in the scavenging of free radicals generated in the diseased state, leading to the cancer prevention. Wedelia chinensis EO has high antioxidant potential which was evaluated in lung cancer cell line implanted in C57BL/6 mice [85]. Increase in the activity of antioxidant enzymes like CAT, SOD, and GPx along with increased level of glutathione was observed in the mice model, showing the preventive effect of these EOs even in the in vivo models [85]. A proposed overall mechanism by which EOs display anticancer activity is presented in Figure 2.

Modulation of DNA Damage and Repair Signaling by
EOs. Increased ROS production (as discussed above) results in DNA damage and can lead to the cell death. EOs have potential to induce damages at the DNA level that drives the cancer cells towards cell death. This activity is especially harmful in cancer cells, while no such damage is encountered in the normal cells; this provides added advantage of using these EOs. Targeting DNA repair pathways is an effective treatment method currently in use in the cancer to encounter the high proliferation rate in the cancer cells [86,87].
One of the peculiar properties of the EOs is that though being cytotoxic to cancer cells, these induce proliferation of the normal cells [88]. DNA repair potential is present in various EOs and their constituents. Cells pretreated with the compounds like linalool, myrcene, and eucalyptol were studied for repair activity by their recovery on the normal media and it was found that these can reduce the damage caused by hydrogen peroxide (H 2 O 2 ), a potential genotoxin, but their coadministration is not that beneficial [34]. Effect of the monoterpenes was dependent on the concentrations used and these had themselves induced breaks in DNA at higher concentrations [34]. Therefore, their dose response studies are important from therapeutic point of view. Camphor and thujone [89] are other monoterpenes reported to mediate via DNA repair process in the cells with induced toxicity and also known as antimutagenic in mammalian cells [89]. Thymus species EO was comparatively nontoxic to the normal fibroblast cells than MCF-7 and LNCaP human cancer cell lines [90]. IC 50 values of Tetraclinis articulate EO on blood lymphocytes were reported almost double than for different cancer cells [91].
On the other hand, targeting the DNA repair pathways is helpful in cancer therapy as cells become reluctant to chemotherapy. Downregulation of the repair genes by the EOs can prove to be effective treatment strategy towards targeting DNA repair processes. Genes like H2AFX and HDAC4 are responsible for DNA repair and cell cycle progression and were found to be suppressed by frankincense oil in human bladder cancer (J82) cells using microarray analysis [46]. Therefore, EOs inhibit the cancer cell progression and thereby showing anticancer properties.
More specifically, the DNA polymerases are the enzymes involved in DNA repair and replication (DNA polymerases , , and ). These have been reported to be very effective targets in the development of drugs for cancer treatment. EOs inhibit the activity of the DNA polymerases [11] and therefore can be used as chemotherapeutic agents in cancer treatment. Chamomile EO was found to be very strong mammalian polymerase ( and ) inhibitor among many other EOs tested which account for their increased therapeutic potential against cancer [11]. As polymerase is a DNA replicative polymerase and polymerase is a DNA repair/recombination polymerase, hence inhibition of both these polymerases will be helpful in cancer therapeutics [11].
The important DNA damage signaling protein, namely, PARP-1, is most abundantly found nuclear protein almost in all eukaryotes other than yeast. It is the first protein to act on the damaged DNA (single strand DNA and double strand DNA breaks) and initiates the DNA repair by the process of PARsylation and recruiting other DNA repair proteins associated with Base Excision Repair (BER) [86,92] and nonhomologous end joining (NHEJ) [93]. Many EOs and their constituents lead to PARP cleavage [68]. Proteolytic cleavage of PARP-1 by the action of EOs might be indicative of modification of the DNA repair process in the cancer cells. . Alteration in expression of NF-B by EOs and further binding of NF-B to DNA result in apoptosis in cancer cells. Dephosphorylation of Akt by the action of EOs results in overexpression of p21, which either induces apoptosis by increasing caspases level or results in cell cycle arrest by binding to cyclins. In addition, EOs-induced mitochondrial stress leads to activation of Bcl-2 and membrane depolarisation resulting in enhanced release of cytochrome-C to the cytoplasm which induces apoptotic cell death in cancer cells. EOs also modulate DNA repair mechanisms by acting as DNA polymerase inhibitors and lead to PARP cleavage which also results in apoptosis in cancer cells.
More elaborative studies are still required in the determination of the role of EOs in modulation of different repair pathways like BER and NHEJ in cancer prevention.

Multidrug Resistance (MDR) in Cancer: A Potential Set Back
Multidrug resistance (MDR) is the most frequently encountered problem in the cancer patients, which makes most of the routinely used anticancer drugs ineffective [7,94]. Lots of research are oriented on circumventing this problem. This arises due to different mechanisms like induction of repair of the damaged DNA in response to drug, change in drug uptake capability, and change in the level and response of the targeted enzymes. Adenosine triphosphate cassette (ABC)-transporter family proteins confer MDR due to their increased activity [95]. EOs can circumvent the reluctance of tumours to respond to the cytotoxic drugs [96]. EOs of thyme are effective against widely used drugs like Adriamycin, Vincristine, and Cisplatin resistant ovarian cancer cell lines and, in addition, tumour size reduction was also observed in vivo which indicates the efficacy of the EO in mammalian system [96,97]. Juniperus excels EO was effective against MDR P-glycoprotein-expressing CEM/ADR5000 leukemia cells and reversed their resistance indicating the use of EO in MDR treatment in cancer [98]. Melaleuca alternifolia, tea tree oil, can ameliorate Adriamycin resistance in human melanoma cells and terpinen-1-ol is responsible for this activity [99]. Various EO constituents are reported as the anti-MDR molecules and are summarized below. Linalool, monoterpene alcohol, is a constituent of many EOs and is reported to increase the therapeutic potential of Doxorubicin in breast cancer cells MCF-7 (adriamycin resistant) by increasing its accumulation in these cells for effective response [100]. It has also been reported to cause membrane damage in the Epirubicin-resistant lung cancer, H1299 cells [101]. Emergence of Dox resistance is the other most widely encountered chemotherapeutic hurdle [102] in the treatment of cancer patients. Thymoquinone (TQ) is the constituent of Nigella sativa and various other EOs have been found to prevent Dox induced resistance in breast cancer (MCF-7/ Dox) cells. It inhibits their growth, induces apoptosis by upregulation of phosphatase and tensin homolog (PTEN), leading to downregulation of Akt cell survival protein, and causes cell cycle arrest at G 2 /M phase [103]. Use of the EOs as dietary supplements and coadministration with drugs can enhance the response to the treatment. However, limited studies are available in this aspect but EOs and their active constituents are the promising avenues for combating MDR in cancer patients. Hence, some EOs can be used as combinational therapy in cancer patients due to their beneficial effects after indepth research on the capability to overcome MDR.

Prevention of Side Effects of Cancer Treatment
Cancer patients suffer from different side effects which can be preferentially reduced by alternative methods. EOs are used in the aromatherapy for reducing the agony of brain cancer patients [104]. EO is efficient in depression and reduction of anxiety in cancer patients [105]. Cancer patients undergoing chemotherapy, one of the most frequently used treatment method in cancer, are prone to various side effects [106]. These are nausea and vomiting. Mentha spicata and M. piperita have been found to be effective in overcoming these emetic conditions (chemotherapy-induced nausea and vomiting, CINV) along with the reduction of expenditure on treatment in the cancer patients undergoing chemotherapy [107]. EOs of Leptospermum scoparium and Kunzea ericoides were reported to prevent mucositis in the head and neck cancer patients undergoing radiotherapy when used in the preparation of mouthwash [108]. Some cancer patients having metastatic tumorigenic ulcers of skin develop necrosis and malodour [109]. Patients suffering from such malodour were reported to have improvement in their state on treatment of these ulcers with the mixture of EOs having eucalyptus, melaleuca, lemongrass, lemon, clove leaf, and thyme on a 40% ethanol base [110]. Lavender EO is widely used in aromatherapy and is found to be beneficial in reducing the distress in cancer patients [111]. Hence, EOs serve as the valuable preparations in amelioration of the side effects and sufferings of the cancer patients.

Conclusions and Future Perspectives
EOs have been used in medicine from the ancient times and the present review is an attempt to highlight their therapeutic and chemopreventive value with major emphasis on the mechanistic approaches. Main aim of summarizing the research in this area is to provide better understanding of various pathways and mode of action of different EOs. EO constituents are potent in cancer prevention and treatment. Novel potent anticancer molecules can be found in EOs which can further be exploited in therapeutics. EOs can efficiently be exploited in pharmaceutical preparations with more research and some of them are already in the different phases of clinical trials. EOs are more effective in the preliminary studies than the individual constituents. Further, EOs and their constituents can be evaluated as therapeutic agents and can be used in complementation to standard therapies. Research on EOs as anticancer therapeutic agents is still in growing stage and immense potential of the EOs needs to be explored due to the lack of target specific release. Further, studies including clinical trials are required along with the use of advanced techniques for the targeted organ-specific release of the EOs for making the treatment more effective. Phosphatase and tensin homolog TQ: Thymoquinone.