Anticancer Activity of Essential Oils : Targeting of Protein Networks in Cancer Cells

Data obtained through high throughput technologies is improving our understanding about convergent and divergent pathways that operate in different cancers. Genetic, genomic and proteomic studies have added new layers of knowledge and it is now known that genetic/ epigenetic mutations, overexpression of oncogenes, inactivation of tumor suppressor genes contribute to malignant transformation of cancer progenitor cells. Increasingly it is being realized that there is a dysregulation of spatio-temporally controlled cellular signaling cascades that modulate normal growth and tissue homeostasis. Apoptosis is a programmed cell death and it is now well established that cancer cells escape from cell death. Confluence of information also indicated some other factors which play a role in cancer including genomic instability and oncogenic fusion proteins. BCR-ABL is a fusion oncoprotein that makes leukemic cells difficult to target (Farooqi et al., 2013). TMPRSS2ERG is another fusion transcript identified in prostate cancer cells and recently emerging in-vitro and in-vivo studies are focusing on targeting of the protein product of TMPRSS2-ERG (Farooqi et al., 2014). In addition to overwhelmingly increasing list of potential oncogenic and tumor suppressor proteins which underlie tumour development and progression, tumor microenvironment also plays a significant role and communicates with cancer cells.


Introduction
Data obtained through high throughput technologies is improving our understanding about convergent and divergent pathways that operate in different cancers.Genetic, genomic and proteomic studies have added new layers of knowledge and it is now known that genetic/ epigenetic mutations, overexpression of oncogenes, inactivation of tumor suppressor genes contribute to malignant transformation of cancer progenitor cells.Increasingly it is being realized that there is a dysregulation of spatio-temporally controlled cellular signaling cascades that modulate normal growth and tissue homeostasis.Apoptosis is a programmed cell death and it is now well established that cancer cells escape from cell death.Confluence of information also indicated some other factors which play a role in cancer including genomic instability and oncogenic fusion proteins.BCR-ABL is a fusion oncoprotein that makes leukemic cells difficult to target (Farooqi et al., 2013).TMPRSS2-ERG is another fusion transcript identified in prostate cancer cells and recently emerging in-vitro and in-vivo studies are focusing on targeting of the protein product of TMPRSS2-ERG (Farooqi et al., 2014).In addition to overwhelmingly increasing list of potential oncogenic and tumor suppressor proteins which underlie tumour development and progression, tumor microenvironment also plays a significant role and communicates with cancer cells.

In-vitro Analysis of Different Essential Oils
Essential oil (EO) of Artemisia vulgaris has been reported to induce apoptosis in HL-60 leukemic cell line by promoting release of cytochrome c.Moreover, Caspase were also functionally active upon treatment with essential oils (Saleh et al., 2014).Citral is a bioactive ingredient present in Essential oil obtained from Melissa officinalis.It has recently been shown to induce apoptosis in Glioblastoma Multiforme cells via enhancing ROS generation and activating caspase-3 (Queiroz et al., 2014).There was notably enhanced expression of caspase-3 and Bax in gastric cancer cell line SGC-7901 upon treatment with Essential oils from Toona sinensis.Detailed chemical analysis of Essential oil indicated that there was a higher percentage of sesquiterpenes including β-caryophyllene, β-eudesmene, copaene and caryophyllene as evidenced by GC/MS (Wu et al., 2014).Essential oil from Lavandula angustifolia was effective against MCF-7 and HeLa cell lines.It exerted its biological effects via enhancing Bax expression (Tayarani-Najaran et al., 2014).Essential oil from Curcuma zedoaria roscoe was noted to effectively induced apoptosis in non-small cell lung carcinoma H1299 cells.Results obtained from in-vitro analysis suggested that phosphorylated levels of JNK1/2 and p38 were considerably enhanced.However, there was a slight reduction in pERK1/2 levels and pro-survival pathways including AKT/NF-κB were significantly inhibited in H1299 cells.Downregulation was noted for Bcl-2 and Bcl-xL in H1299 cells.It is also relevant to mention that intraperitoneally administered zedoary essential oil remarkably inhibited tumor growth in mice xenografted with H1299 cells (Chen et al., 2014).Patchouli alcohol is a bioactive components isolated from essential oil of Pogostemon cablin exerted its inhibitory effects on expression levels of cyclin D1 and cyclin-dependent kinase 4 (CDK4) in colorectal cancer cells.Expression and biological activity of HDAC2 (histone deacetylase 2) were also remarkably repressed.NFKB was active in treated cancer cells as evidenced by an increase in nuclear translocation of p65 (Jeong et al., 2013).Cyclin D1 and CDK4 were also substantially reduced in pancreatic cancer cells after treatment with Frankincense essential oil.Akt and Erk1/2 were noted to be activated in treated cancer cells (Ni et al., 2014).Certain hints have emerged emphasizing on the fact that allyl isothiocyanate impressively induced apoptosis in wild type p53 containing bladder cancer cells.Contrarily it did not induce apoptosis in mutant p53 containing bladder cancer cells (Savio et al., 2014).There is an exciting piece of evidence suggesting that partially hydrogenated α-zingiberene isolated from essential oil from Casearia sylvestris was effective against B16F10-Nex2 cell line.However, surprisingly, fully hydrogenated derivative was effective against MCF-7 and B16F10-Nex2 (Bou et al., 2013).
Essential oil from Monarda citriodora has been noted to functionalize extrinsic and intrinsic pathways of apoptosis.There was an upregulated expression of death receptors including Fas and TNF-R1 in treated cancer cells.Methodologies also revealed notably enhanced mitochondrial membrane permeability and increase expression of caspase-9.Intriguingly, PI3K/AKT/mTOR pathway was also inhibited significantly in treated HL-60 cells (Pathania et al., 2013).It is interesting to note that bioactive components in essential oil extracted from Dracocephalum multicaule protected K562 cells from oxidative stress (Esmaeili et al., 2014).Essential oil obtained from Smyrnium olusatrum also induced apoptosis in colon carcinoma cells (Quassinti et al., 2014).

In vitro analysis of Efficacy of Elemene
It has been shown that Elemene effectively improved cisplatin sensitivity in MCAS and A2780/CP70 human ovarian carcinoma cells by exerting its inhibitory effects on expression of an anti-apoptotic gene, XIAP.Moreover, cisplatin induced ERCC-1 was also significantly inhibited in Elemene treated carcinoma cells (Li et al., 2013).Elemene has been shown to stimulate the expression of Caspase-3 and Cytochrome C in lung cancer A549 cells, thus overcoming drug resistance and improving cisplatin mediated apoptosis in A549 cancer cells (Yao et al., 2014).Chemically improved β-elemene derivative has been designed with a cis-2, 6-dimethylpiperazine substitution and noted to be efficient in substantially reducing phosphorylated levels of 4EBP1 and p70S6K1 in MCF-7 and MDA-MB-468 cells (Ding et al., 2013).It has recently been convincingly revealed that gene silencing of mTOR in lung adenocarcinoma A549 cells notably enhanced Elemene induced apoptosis (Zou et al., 2014).There is exciting piece of evidence suggesting that ERK1/2-Bcl-2/survivin pathway was remarkably inhibited in Elemene treated U87 glioblastoma cells.Elemene mediated inhibitory effects were enhanced upon treating cells with ERK1/2 inhibitors.Furthermore, efficacy of temozolomide was also improved in Elemene treated glioblastoma cells (Zhu et al., 2014).

In vitro and in vivo analysis of Efficacy of Perillyl Alcohol (POH)
Conjugate of temozolomide to POH (NEO212) has recently been tested for its efficacy in immune incompetent mice xenografted with Temozolomide-Resistant Gliomas.Results revealed that there was considerably reduced intracranial tumor growth in xenografted mice treated with NEO212 (Cho et al., 2014).NEO212 has also produced encouraging results in an intracranial mouse tumor model with triple-negative breast cancer as median survival of cancer model was increased.NEO212 mediated DNA damage was more notable as compared to temozolomide (Chen et al., 2014).POH has also been noted to suppress protein levels of telomerase catalytic subunit reverse transcriptase (hTERT).Mechanistically it was shown that different proteins including hTERT-mTOR-RAPTOR assembled to form multi-protein complex which was dissociated in POH treated prostate cancer cells (Sundin et al., 2013).

In vitro analysis of Efficacy of Limonene
Limonene has been shown to activate ERK pathway in lymphoma cell line to induce apoptosis (Manuele et al., 2010).Limonene effectively induced apoptosis in LS174T colon cancer cells by inhibiting phosphorylation of Akt and GSK-3β.Moreover, intrinsic pathway was noted to be activated in Limonene treated LS174T colon cancer cells (Jia et al., 2013).Limonene and docetaxel synergistically induced greater ROS production and considerably enhanced apoptosis in prostate cancer cells (Rabi Bishayee, 2009).mitochondrial apoptosis pathway.Oncol Rep, 31, 2131-8. Zhu TZ, Li XM, Luo LH, et al (2014).β-Elemene inhibits proliferation through crosstalk between glia maturation factor β and extracellular signal-regulated kinase 1/2 and impairs drug resistance to temozolomide in glioblastoma cells.Mol Med Rep, 10, 1122-8. Zou K, Tong E, Xu Y, et al (2014).Down regulation of mammalian target of rapamycin decreases HIF-1α and survivin expression in anoxic lung adenocarcinoma A549 to elemene and/or irradiation.Tumour Biol, 2014 Jun 28.