Anti-Oncogenic Perspective of Natural Compounds in Breast Cancer

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Cancer is the most prevalent disease not only in the India but worldwide, for more than a decade, in India cervical cancer was the most common cancer in women, and more deaths were attributed to cervical cancer than any other cancer. But now Breast cancer has been rapidly rising, in 2012, breast cancer was the most common cancer in women, a way ahead of cervical cancer.

An estimated data depicts 155,000 new cancer cases and 76,000 cancer deaths in 2015 in India. Breast cancer seems to be more common in the younger age group and 52% of all women suffering from breast cancer. 30 – 40 years [1]. Instead of Conventional therapeutic approaches such as chemotherapy, radiation, combination chemotherapy, and surgical treatments are widely accepted to treat or eradicate tumor, it is often associated with major side effects. In order to overcome with these side effects, effective treatments with an alternative medicine supplements and complimentary medicines. Natural compound and herbs which are commonly used as food ingredients and ancient medicinal treatments to cure several diseases such as inflammation, cardiovascular disease, cold, flu and cancer also, because of their anti-cancerous and anti-inflammatory effects. It has been believed that herbal medicine brings a new hope for preventing cancer cell due to the safety of herbs and lack of discernible toxicity to normal cells. These approaches have been used to treat a wide spectrum of cancers. Several naturally occurring compound have received much attention for their health benefits, including anticarcinogenic properties. In this review we have mentioned four of these compounds including Curcumin, Resveratrol, Eugenol.

 1. Resveratrol

It is a natural polyphenolic compound which has anti-carcinogenic activity, i.e., a phytoestrogen that possesses anti-oxidant, anti-inflammatory, cardioprotective, and anticancer properties. It is present in dietary sources and plant foods, including grapes, peanuts, soybeans, pomegranates, and berries. A plant that contains considerable amounts of resveratrol is Polygonum cuspidatum (Japanese knotweed) which has beneficial effects against inflammation. [2] In Asian countries for 100 years, this plant has been used to prevent and treat several diseases, including cancer. RES induces cell cycle arrest and causes apoptosis of tumor cells. RES also downregulates the expression of tumor derived nitric oxide synthase, functions as an antioxidant, and prevents DNA damage, it also reduces tumor growth.

This compound modifies genetic and epigenetic profiles of cells within tumors. Resveratrol can reverse multidrug resistance in cancer cells, when used in combination with clinically used drugs, it can influence cancer cells to standard chemotherapeutic agents. Several novel studies of resveratrol have been developed with improved anti-cancer activity, pharmacokinetic profile and bioavailability.

Cell Proliferitation

Resveratrol, the compound which is found in grapes, prevents the growth of breast cancer cells by inhibiting the growth effects of estrogen. In recent studies it is found out that, resveratrol is capable in preventing the malignant progression as it curbs down the spreading of hormone which is resistant in breast cancer cells.

By using a number of breast cancer cell lines which express the estrogen receptors in order to evaluate the effects of resveratrol, different cells were treated with resveratrol and their growth were then compared with the cells which were remain untreated, and this will result in the significant amount of decrease in cell growth in comparison with the cells treated with resveratrol, though no changes were observed in cells that were untreated [3].  

Effects Of Resveratrol In Treating Breast Cancer

Resveratrol expresses anti-cancer properties in various breast cancer models of animals. Several naturally occurring polyphenols such as N- nitroso -N-methyl urea (NMU), DMBA, or, estradiol, with the models of spontaneous mammary tumors with Brca1-mutated (K14cre; Brca1F/F; p53F/F) or HER-2/neu-overexpressed mice have been employed to determine resveratrol's anti oncogenic effects. Oral administration of resveratrol is also found successful in reduce tumorigenesis triggered by N- nitroso -N methyl urea (NMU) in rats, in a xenograft animal model, resveratrol also found successful in inhibiting the development of ER-β–positive MDA-MB-231 and estrogen receptor (ER)-α–negative tumor explants, which results lowered angiogenesis and apoptosis in mice. Still, resveratrol did not affect the in vivo development and metastasis of transplanted ER-α–negative 4T1 mammary cancer cells in mice. However further determined that this ineffectiveness may be the result of an inadequate dose of resveratrol. These results manifest both the reduced activity and expression of MMP9, and also state the resveratrol’s effects on breast cancer be conditional on dose and route of administration [5].  

 2. Curcumin:

Curcumin loonga i.e., Turmeric is most popular used Indian Medicinal plant belongs to family Zingiberaceae [6]. The components of the curcumin are; DMC (dimethoxy curcumin) and BDMC (Bisdemethoxycurcumin) these both components collectively known as curcuminoids [7]. Curcuminoids which are yellow colored isolated from rhizomes of Curcuma loonga L. (turmeric) [8]. Curcumin which is a low molecular weight polyphenolic and lipophilic compound, it is insoluble in water, ether but soluble in organic solvents like ethanol, dimethyl sulphoxide . Curcumin (1,7- bis (4- hydroxy-3methoxyphenyl)-1,6-heptadiene-3,5-dione) i.e., diferuloylmethane [9] shows various anti-bacterial, anti-viral, anti-fungal, anti-arthritis, anticancer etc. biological activities. From Vedic culture this plant is known i.e., 4000 years ago and it had some religious significance too.

 Curcumin Role In Breast Cancer

Today Breast cancer is the most common malignant cancer type due to which many women die. But many experiments done on breast cells and it shows that curcumin play a very important role by inhibiting the growth of breast cancer cells. Curcumin also inhibits the expression of ki67, proliferating cell nuclear antigen (PCNA), p53 mRNA, Bax mRNA expression, p21 mRNA in the epithelial cell line of Mammary gland (11). Wnt / beta-catenin signaling pathway gets abnormally activated when there is a development of breast cancer and experiments shows that curcumin inhibit beta-catenin, cyclin D1 expression in MCF-7 & MD-MBA-231 cells (11).

Maspin which is an inhibitor of serine protease, it inhibits growth of tumor and metastasis both in vitro and in vivo. Prasad et al. [11] experiments shows that curcumin increased maspin gene expression in MCF-7 cells by upregulation of p53 protein and Bcl-2 gets downregulated (11). Another study shows that curcumin inhibit the Bcl-2 expression and there is an upregulation of miR-15a & miR-16 in MCF cells (11). Chiu & Su data showed that MDA-MB-231 cells proliferation inhibited by curcumin, either by an upregulation of p21 expression or by up regulation of Bax to Bcl-2 ratio. In curcumin treated malignant breast cancer cells AIP-1 / Alix protein gets inhibited (11) Also, curcumin inhibited breast cancer cells motility and invasion by inhibition of alpha 6 beta 4 integrins 

 Effect Of Curcumin On Nuclear Factor-k B

It is found that most anti-cancer also activates the nuclear factor-kB (NFkB). This factor mediates cell survival, proliferation and metastasis. Studies shows that curcumin also inhibits the breast cancer cells by inhibiting expression of NF-kB p65 [12]. In 15% to 25% breast cancers (HER2) human epidermal factor 2 gets overexpressed, curcumin also inhibited HER2 oncoprotein, by AKT, MAPK phosphorylation, also expression of NF-kB in BT-474 & SK-BR cells. Curcumin also block Receptor d`origine Nantais (RON) by inhibiting p65 protein expression and transcriptional activity via NF-kB. Also, VEGF (vascular endothelial growth factor) gets inhibited. 

Treatment Of Breast Cancer Cells  

Mitomycin C (MMC) which is a DNA cross linker and antineoplastic agent which fight with various other cancers. But, if MMC is used for long time then it can cause permanent kidney failures as well as damage to bone marrow. If MMC and curcumin both are used in combination then GRP58 gets inhibited by ERK / p38 MAPK pathway. Also, study shows that in MCF-7 cells anti-proliferative effect gets enhanced by curcumin along with MMC via p38 MAPK pathway. Lastly, cell cycle gets arrested by inhibition of Cyclin E, Cyclin A, CDK-2, CDK-4 etc. but p21 and p27 which is cell inhibitors gets induced in MCF-7 and MCF-7 xenografts.

    3. Eugenol:

  A phenolic compound which exhibits weak acidity, is an allyl chain substituted guaiacol and a member of allyl benzene is Eugenol [13]. It is a purely natural compound.

Eugenol shows an appearance of being colorless to pale yellow. Obtained from essential oils such as nutmeg, cinnamon, bay leaf, basil and especially from Clove oil. Eugenol is a phenol-like compound, which exhibits aromaticity due to high levels of conjugation present in it. The smell of Eugenol is clove-like yet pleasing. Eugenol has a molecular formula C10H12O2 and is designated as 4 Allyl-2-methoxyphenol by IUPAC [14]. It possesses a pKa of 10.19 at 25 degrees. Eugenol comes under the range of essential oils and is extracted from clove trees. The clove tree is scientifically known as Syzygium aromaticum, comes under the family Myrtaceae, whereas it has several vernacular names like Laung, etc. that is famous in different regions. The clove buds consists of essential oil, the chief component of which is the aromatic oil eugenol.

Eugenol contains 70-90% of essential oils derived from cloves, and is primarily responsible for clove’s fragrance. The homeland of Syzygium aromaticum is Southeast Asia, however it is nowadays widely cultivated in several other locations. World’s largest producer of cloves was Indonesia, in the 21st century and was followed by Madagascar, Tanzania, and Sri Lanka [15].

Structure Of Eugenol:

 Eugenol has been approved to encompass number of beneficial aspects against a vast spectrum of life-threatening indispositions including oxidative stress, inflammation, hyperglycemia, elevated cholesterol level, neural disorders and cancer [16]. Eugenol id considered as non-mutagenic and non-carcinogenic and is considered safe by FDA. Eugenol’s potential to regulate an array of cellular biochemical processes, the reported in vivo and in vitro studies suggest eugenol to be effective chemo preventor and chemotherapeutic for cancer. Eugenol is found to show dual nature, anti-oxidant and pro-oxidant, presenting beneficial effects in cancer formation and cancer manifestation.

 Role Of Eugenol In Breast Cancer

Antioncogenic effect of eugenol on inhibition of cell proliferation and induction of apoptosis in human MCF-7 breast cancer cells has been investigated in some recent studies.

The cell death caused by eugenol was examined followed by MTT assay & monitoring lactate dehydrogenase that was released into the culture medium for checking cell viability and cell cytotoxicity, then giemsa staining for morphological alterations, cells analyzed using fluorescence microscopy using ethidium bromide & acridine orange and quantitative analysis of DNA fragments for triggering the apoptosis is done. By determining the proportion of Glutathione, also known as GSH or agifutol S, and lipid peroxidation products, the outcome of eugenol on intracellular redox status of the breast cancer cells in humans was examined. The thing that eugenol did to the human MCF7 breast cancer cells is that it inhibited its growth and proliferation via persuading the death of cells which was dose as well as time dependent. Cells treated with eugenol was examined microscopically, these cells showed shrinkage, membrane bleb formation and also apoptotic body formations. Further, the level of intracellular glutathione was decreased and the level of lipid peroxidation was increased with eugenol treatment. The increase in the percentage of apoptotic cells and DNA fragments which depends on dose proposed that apoptosis was involved in eugenol induced cell death and also apoptosis might engage in the chemo preventive activity of eugenol [17].

Hence, Eugenol which is a natural compound derived from clove oil inhibits the growth and proliferation of human breast cancer cells and shows potential toxicity against breast cancer cells and can be used as a natural therapy in the treatment of breast cancer cells.

 References:

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  2. Ferraz Da Costa, D.C.; Campos, N.P.C.; Santos, R.A.; Guedes-DaSilva, F.H.; Martins-Dinis, M.M.D.C.; Zanphorlin, L.; Ramos, C.; Rangel, L.P.; Silva, J.L. Resveratrol prevents p53 aggregation in vitro and in breast cancer cells. Oncotarget 2018, 9, 29112–29122.
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