INTRODUCTION:

According to GLOBACON report, cancer is the reason for nearly19.3 million deathsin 2020 and is considered as leading cause for deaths worldwide. New diagnosis statistics reveal 11.7% female breast cancer, 11.4% lung cancer and 10.0% colorectal cancer cases as the top three cancers¹. WHO report published on 26 March 2021 indicated that, in 2020, worldwide 2.3 million women were diagnosed and 685000 were died due to breast cancer. Closed to 7.8 million women werediagnosed with breast cancer by the end of the year 2020 and this makes it as the most prevalent cancer worldwide.

In view of this, the main aim of GBCI (Global Breast Cancer Initiative) of WHO is to create awareness about breast cancer and thus targeting the reduction in mortality rate globally between 2020 and 2040.Breast cancer involves malignant cell growth with a threat of spreading to other parts in case of no treatment². Traditional herbs have been used for therapy from many years. Natural compounds are still popular and rich source of treatment and have been increasing interest since then. Healthy diets and nutritional supplements are always associated with reduced risk of diseases. The side effects of the existing breast cancer therapy are the motivating factors to research for alternative natural remedies. Antioxidants form phytochemicals and healthy habits like breast feeding and exercise play significant role in preventing breast cancer^3-5. The thrust for anti-tumor agents from plants is an interesting and ongoing area of research right from 1950s with the development of vinca alkoloids^6-7. Increased research on alternative and complementary therapies made them widely accepted⁸. Excess research is focused on development of new chemical agents to treat cancer which is the most fatal disease of 20^th century⁹. The use of nontoxic natural phytochemicals in cancer treatment received huge success due to increased screening of natural products in recent years¹⁰. Among the wide range of available phytochemicals, essential oils (EOs) are always attractive due to their diverse biological activities. This review elaborates the, active ingredients, therapeutic potential and mechanisms along with the additional applications essential oils in breast cancer. The main focus of this review is to elaborate the benefits of common ingredients like edible essential oils in treatment of breast cancer and to create awareness about the same.

ESSENTIAL OILS IN GENERAL:

Essential oils are lipophilic and highly volatile in nature. They are secreted by aromatic plants and stored in different parts like leaves, buds, flowers, stems, fruits, seeds, roots and twigs. They are secondary metabolites of the plant responsible for defense mechanisms against herbivores, insects and microorganisms. They also help in communication with other plants and signaling within a plant for external stimuli. They can be extracted by hydro-distillation, steam distillation as well as infusion, hot pressing and supercritical extraction. Chemically they are complex molecules, general active constituents of are monoterpenes, sesqui-terpenes and di terpenes. They have wide applications in food, pharma, agro and perfume industries.

ESSENTIAL OILS WITH STRONG ACTIVITY AGAINST BREAST CANCER AND THEIR MECHANISMS:

Basil oil

Basil was effective against MCF-7 cells and with a LC50 of 71μg/ml. Seed and leaf essential oils from basil showed potent toxic effects with the IC50 values of 52.45 ± 2.46 and 98.51 ± 6.49 (µg/ml) in MCF-7 cell line¹¹. Ursolic acid (component in basil oil) at a concentration of 100μMresulted a decrease in the cells during anaphase/telophase stages supportingits anti-proliferative activity¹². In another study against MCF-7 cells, Basil was found to have the mechanisms of DNA damage¹³,inhibition of cell viabilityin MCF-7 cells by cell cycle arrest¹⁴ and can activatemTOR pathway in MCF-7 cells with p70S6K¹⁵.

Chamomile oil:

Chamomile, in an investigation after 24Hof treatment on MDA-MB-468 and MCF-7 cells, the IC50levelwasfound to be 992 ± 2.3μg/mL and 1288± 5.6μg/mL respectively. At high concentrations it induced.The MCF-7 cells when tested withroot extract of Matricariachamomilla, there is a reduction in cell viability by 50% after 24H (at 1954± 4.2µg/ml), 48H (1700± 5.1µg/ml) and 72H (1560± 5.3µg/ml) of exposure¹⁶. The reported mechanisms are cellular apoptosis, necrosis and decreased cellular migration¹⁷, and inhibition of cell proliferation with G2/M phase arrest¹⁸.

Ginger Oil:

In-vitro studies using MCF-7 cell lines produced an IC50 value of 15.53±1.26µM. At a concentration of 15µM, ginger oilnegatively changed anti-apoptotic factors and improved the pro-apoptotic factors¹⁹.In 2021, a recent study on MCF-7 cell lines indicated the proteomic characteristics of ginger oil along with Bisphenol A. Ginger oil combination with Bisphenol A might have caused the death of breast cancer cell lines through oxidative phosphorylation pathway and succinate dehydrogenase signaling pathway as an important mediator²⁰.

Cinnamon Oil:

Cinnamon oil exhibited significant effect in 4T1 adenocarcinoma in mice. At 10g/kg body weight, it reduced tumor occurrence by 15.5% and cumulative tumor volume by 58.5%. Significant reduction in proliferative (Ki67), angiogenic (VEGF and VEGER-2) and improvement in apoptotic (Caspase-3 and BaX) markers was observed. It also significantly reduced methylation of ATM gene promotor. During cell cycle analysisin cell lines,both MCF-7 and MDA-MB-231 indicated clear stimulation of apoptosis²¹.

Clove oil:

The IC50 values of clove oil after 24H and 48H were 36.43μg/mL and 17.6μg/mL respectively against MCF-7 cells²². Treatment with 8μM after 48 h eugenol hindered 76.4% cells in MDA-MB-231²³. Eugenol treatment resulted in 90% decrease in MCF-7 cells at 2.5mM with an EC50 of 0.9mM. 75% decrease in MDA-MB-231 cells at 0.9mM was observed and EC50 was found to be 1.6mM. At increased concentrations of eugenol, MCF-7 cells were more selective than MDA-MB-231 cells. At higher concentration up to 5mM, eugenol can induce destruction of plasma membrane and mitochondria²⁴. Eugenol on MCF-7 cell lines demonstrated mitochondrial impairment. This oil also resulted in DNA fragmentation and cell membrane disruption causing the cell death²³. At a concentration of 350µg/mL, it can cause accretion of cells in S phase after 24H. The anticancer effects of clove oil are due to its antioxidant, pro-apoptotic and anti-angiogenic properties²⁵.

Tea tree oil:

Tea tree oil was also investigated on MDA MB cells and was found to be effective with an IC50 value of 25µg/mL after 48H²⁶. In MCF-7 cell lines, tea tree oil exhibited strong activity with an IC50 value of 0.031%v/v. Cytometric studies indicated its mechanism of action involving G0/G1 phase cell cycle arrest²⁷.

Thyme oil:

Thyme oil was proved to have anti-cancer activity and with an IC50 value of 448µM against MDA-MB-231 cell lines. The same study revealed its dose dependent early apoptotic and late apoptotic activity with a concentration above 400µM²⁸. A recent study reported the IC50 value of thyme oil against MCF-7 cell lines as 11.7µg/mL²⁹. An anti-cancer investigation of thyme oil in 2D and 3D cell cultures was through mitochondrial membrane depolarization, caspase activity and DNA fragmentation³⁰.Another study involving the evaluation of 16 essential oils indicated anticancer activity of Thyme oil against MCF-7 and MDA-MB-231 breast cancer cell lines). Thymus capitatas was more effective against MCF-7 cell linesand its IC50 value was 94.1µg/mL.Thymus vulgaris was effective on both the cell lines cell lines withIC50 values of 39.9µg/mL and 61.5µg/mL on MCF-7 and MDA-MB-231 cells respectively³¹. T. vulgaris L. was found to be more effective against MCF-7 cells at a concentration of 400µg/ml and was found to have anIC50 of 48.01 ± 0.94µg/mL³².

Oregano oil:

Oregano oil was found to have an IC50 value of 10µg/mLagainst breast cancer cells³³. Origanum vulgare and carvacrol were found to have 94.05%±0.11 and 93.43%±0.21 reduced cell proliferation against triple negative breast cancer cell lines. IC50 of carvacrol for all the selected cell lines ranged between 193−166µM after 48H. Comparatively the IC50 value for MDA-MB-231 was highest than other cell lines. 5µM cisplatin plus 100µM carvacrol reduced the cell viability compared to the cell lines treated with Cisplatin alone. This effect might be mediated by apoptosis induction³⁴.

Saffron oil:

Saffron reported to have anti-proliferative activity on MCF-7 cells between 200-2000µg/mL in a dose dependent manner. Saffron acted via induction of apoptosis through caspase dependent pathway. A decrease in Bax protein expression was observed in cells. IC50 value was found to be 400±18.5µg/mL after 48H³⁵. After 24 h incubation, crocetin(an abundant component of saffron) inhibited proliferation of cells and cell invasion at 1 and 10µM against MDA-MB231 cells. At 10µM crocetin reduced pro-MMP-9 activity and levels of pro-MMP-2/MMP-2 protein³⁶.

Fennel oil:

Fennel oil increased the levels of a pro-apoptotic factor Bax and simultaneously decreased anti-apoptotic factor Bcl2 gene expression leading to the death of MCF7 cells³⁷. In another report, the seed oil is with strong anticancer activity with IC50 of less than 10μg/mLagainst MDA-MB cells³⁸. Thymoquinone from fennel seeds demonstrated anti-cancer effect against MCF-7/Dox which isdrug resistant cancer cell lines. It caused cell cycle arrest at G2/M phase and was found to elevate the levels of P53 and P21 proteins³⁹.

CONCLUSION:

Essential oils have been studied widely for their effectiveness against breast cancer. Lethal concentrations of several essential oils have been established depicting a strong correlation to anticancer activity that is under exploited in the treatment of breast cancer. Cumin oil in combination with retinoic acid and melatonin has demonstrated a reduction in mammary carcinoma in mammals as well as ginger oil. Similarly, ginger oil has improved cancer treatment outcomes as an adjuvant product in women. Other routes of administration apart from taking orally have produced positive therapeutic outcomes. Inhalation of essential oils has an established effect on the mind, reducing anxiety that is associated with cancer treatment outcomes. Overall, edible essential oils require further studies to determine effects on combination during treatment and future studies will need larger groups, other routes of administration including intradermal as well as the effects of longer durations when evaluating the role of edible essential oils in breast cancer treatment.

CONFLICT OF INTEREST:

The authors have no conflict of interest in regard to this review.

ACKNOWLEDGEMENT:

Authors express their deep gratitude to school of pharmacy and Mount Kenya University for the support in completing this review successfully.

REFERENCES:

1. Hyuna S, Jacques F, Rebecca LS, Mathieu L, Isabelle S, Ahmedin J, et al. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2021; 71: 209-249. https://doi.org/10.3322/caac.21660

2. Borkar S, Shende V, Chatap V, Sawant V, Suresh R, Dama G. Tamoxifen citrate loaded solid lipid nanoparticles- a novel approach in the treatment of ER+ breast cancer. Research Journal of Pharmaceutical Dosage Forms and Technology. 2009; 1(2): 143-149.

3. Arjun P, Shivhare SC, Umesh A, Sonu C. A comprehensive review on breast cancer. Indian Journal of Public Health Research and Development. 2013; 4(3): 291- 297.

4. Sampoornam W. Nurse navigator and quality of life research. Asian Journal of Nursing Education and Research. 2012; 2(4): 224-227.

5. Lavanya, Nalini JS, Gowri S. A study to assess the effectiveness of exercise on cancer related fatigue among women with breast cancer admitted in erode cancer center, erode. International Journal of Advances in Nursing Management. 2014; 2(3): 134-138.

6. Dibyajyoti S, Tarashankar M, Mayukh J, Supradip M. Cancer treatment strategy- an overview. Asian Journal of Pharmacy Technology. 2011; 1(2): 28-33.

7. Poonam G, Mohd YK, Vikas KV, Ashish P. Beating cancer with natural plant sources. Asian Journal of Pharmacy and Technology. 2013; 3(2): 39-44.

8. Padmavathi P, Raja S, Kokilavani N. A study to assess the effectiveness of ginger powder on dysmenorrhea among adolescents in a selected school at erodes. Asian Journal of Nursing Education and Research. 2012; 2(2): 79-82.

9. Ravindra BS, Nachiket SD, Deepak SM, Vinayak MG, Jain DA. Serm’s in treatment of breast cancer. Asian Journal of Pharmaceutical Research. 2011; 1(4): 81-86.

10. Nachiket SD, Shashikant RP, Deepak SM, Abhijeet NM, Manisha SK, Deepak KT, et al. Recent synthesis of marine natural products with anticancer activity: an overview. Research Journal of Science and Technology. 2009; 1(2): 63-70.

11. Mohammadi M, Majid A, Nejadsattari T, Hashemi M. Antioxidant and anticancer activities of ocimumbasilicum l. cv. dark opal (lamiaceae). Pharmacognosy Communications. 2014; 4(4): 48–58. https://doi.org/10.5530/pc.2014.4.5

12. Arshad QK, Dar AS, Siddiqui SB, Kabir N, Aslam H, Ahmed S, et al. Anticancer activity of ocimumbasilicum and the effect of ursolic acid on the cytoskeleton of mcf 7 human breast cancer cells. Letters in Drug Design and Discovery. 2010; 7(10): 726-736. http://dx.doi.org/10.2174/1570180811007010726

13. Al AK. El BHA, El BAA, Alkhalaf M. Cytotoxic activity of methanolic extract of menthe longifolia and ocimumbasilicum against breast cancer. Pakistan Journal of Biological Sciences. 2013; 16(23): 1744-1750. https://doi.org/10.3923/pjbs.2013.1744.1750

14. Hosam OE, Eman AM.Invitro antioxidant and antiproliferative activities of six international basil cultivars.Natural Product Research. 2015; 29(22): 2149-2154.https://doi.org/10.1080/14786419.2014.995653

15. Renan GT, Livia C, Julia C, Mariah CM, Sonia SC, Mauro SP, et al. OcimumBasilicum but not Ocimumgratissimum present cytotoxic effects on human breast cancer cell line Mcf-7, inducing apoptosis and triggering Mtor/Akt/P70s6k pathway. Journal of Bioenergetics and Biomembranes. 2018; 50: 93–105. https://doi.org/10.1007/s10863-018-9750-3

16. Ali MK, Mohsen N, Hamdollah D, Mehrzad JB, Mahsa S, Maryam TA, et al. In vitro cytotoxic activity of matricariachamomilla root extract in human breast cancer cell line mcf-7. Life Science Journal. 2014; 11(5): 403-406.

17. Mohsen N, Ali MK, Hamid RR, Hamdollah D, Mehdi AT, Iraj RK, Reza M. The hydroalcoholic extract of matricariachamomilla suppresses migration and invasion of human breast cancer mda-mb-468 and mcf-7 cell lines. Pharmacognosy Research. 2017; 9(1): 87–95. https://doi.org/10.4103%2F0974-8490.199778

18. Hirsa MK, Misha S, Vahid K, Noushin R, Amir A, Mona S. Mitochondrial apoptosis induced by chamaemelumnobile extract in breast cancer cells. Iranian Journal of Pharmaceutical Research. 2016; 15: 197-204.

19. Hongyun G, Yaqing Z, Qingyn Z, Lierui Z, Xiaofeng X, Vishnu PV, et al. Zingerone induced caspase-dependent apoptosis in mcf-7 cells and prevents 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in experimental rats. Journal of Biochemical and Molecular Toxicology. 2019; 33(10): e22387. https://doi.org/10.1002/jbt.22387

20. Dan L, Tao H, Longxue L, Lai C, Xiaoquan L, Qinghua W, et al. Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol a-induced breast cancer cell proliferation. Oncology Letters. 2020; 21(2): 101-113. https://doi.org/10.3892/ol.2020.12362

21. Peter K, Martin K, Karol K, Marek S, Karin J, Desanka V. Chemopreventive and therapeutic efficacy of cinnamomumzeylanicum l. bark in experimental breast carcinoma: mechanistic in vivo and in vitro analyses. Molecules. 2020; 25(6):1399- 1431. https://doi.org/10.3390/molecules25061399

22. Parvinnesh SK, Raden MF, Ferry FS, Dimas EL, Rizky A. Anticancer potential of syzygiumaromaticum l in mcf-7 human breast cancer cell lines. Pharmacognosy Research. 2014; 6(4): 350-354. https://doi.org/10.4103%2F0974-8490.138291

23. Rana AW, Warde ER, Meghri K, Remi S, Marwan ES, Omar ER, et al. Chemosensitivity of mcf-7 cells to eugenol: release of cytochrome –c and lactate dehydrogenase. Scientific Reports. 2017; 7(43730): 1- 13. https://doi.org/10.1038/srep43730

24. Mashan LA, Mohamed MH, Ali AH, Othman AS. Anti-metastatic and anti-proliferative activity of eugenol against triple negative and her2 positive breast cancer cells. BMC Complementary and Alternative Medicine. 2018; 18(321): 1-11. https://doi.org/10.1186/s12906-018-2392-5

25. Peter K, Sona U, Martin K, Karol K, Peter K, Jan M et al. Antineoplastic effects of clove buds (syzygiumaromaticum L) in the model of breast carcinoma. Journal of Cellular and Molecular Medicine. 2017; 21(11): 2837-2851.https://doi.org/10.1111/jcmm.13197

26. Sujata B, Chetana B, Kishore B, Girish D. Evaluation of anticancer activity of melaleuka alternifolia. (i.e. tea tree oil) on breast cancer cell line (mda-mb)- an invitro study. International Journal of Medical Microbiology and Tropical Disease. 2018;4(3):176-180. https://doi.org/10.18231/2581-4761.2018.0038

27. Xia L, Yuangang Z, Yujie F, Liping Y, Chengbo G, Wei W, et al. Antimicrobial activity and cytotoxicity towards cancer cells of melaleuca alternifolia (tea tree) oil. European Food Research and Technology. 2009; 229: 247-253. https://doi.org/10.1007/s00217-009-1057-5

28. Elbe H, Yigitturk G, Cavusoglu T, Uyanikgil Y, Ozturk F. Apoptotic effects of thymol, a novel monoterpene phenol, on different types of cancer. BratislavskeLekrskeListy. 2020; 121(2): 122-128. https://doi.org/10.4149/bll-2020-016

29. Ameur E, Eman E, Ridha EM, Haifa D, Virginia B, Simona N, et al. Chemical composition, antifungal and antiproliferative activities of essential oils from thymus numidicus l. Natural Product Research. 2021; 35(24): 5888-5893. https://doi.org/10.1080/14786419.2020.1800697

30. Tahereh J, Gholamreza K, Maliheh S, Susan KA. Invitrovelautaion of apoptic effect of OEO and thymol in 2d and 3d cell cultures and the study of their interaction mode with DNA. Scientific Reports. 2018; 8: 15787. https://doi.org/10.1038/s41598-018-34055-w

31. Basma N, Jorge ES, Luisa P, Joseph B. Chemical composition and invitro cytotoxic screening of sixteen commercial essential oils on five cancer cell lines. Chemistry and Biodiversity. 2019; 17(1): e1900478. https://doi.org/10.1002/cbdv.201900478

32. Seyed MT, Fatemeh K, Mahdi N, Nasibeh T, Maryam A, Mahshid G. Invitro inhibition of mcf-7 human breast cancer cells by essential oils of rosmarinus officinalis, thymus vulgaris l., and lavender x intermedia. Archives of Breast Cancer. 2018; 5(2): 81-89. https://doi.org/10.19187/abc.20185281-89

33. Katerina S, Eleni F, Eleni B, Angeliki TK, Manolis V, Antigoni O, et al. Extraction, chemical composition and anticancer potential of origanumonites l. essential oil. Molecules. 2019; 24(14): 2612. https://doi.org/10.3390/molecules24142612

34. Leilei L, Liang H, Yalei W, Yanwu Z. Carvacrol affects breast cancer cells through trpm7 mediated cell cycle regulation. Life Sciences. 2021; 266: 118894. https://doi.org/10.1016/j.lfs.2020.118894

35. Seyed HM, Jalil TA, Azam B, Iraj JA. Role of caspases and bax protein in saffron-induced apoptosis in mcf-7 cells. Food and Chemical Toxicology. 2009; 47(8): 1909-1913. https://doi.org/10.1016/j.fct.2009.05.017

36. Dimitra GC, Petros GD, Nikos KK, Paul C, Fotini NL. Crocetin inhibits invasiveness of mda-mb-231 breast cancer cells via downregulation of matrix metalloproteinases. Planta Medica. 2011; 77(2): 146-151. https://doi.org/10.1055/s-0030-1250178

37. Abdolmajid G, Ali HAM, Seyyed KSM, Yasemin KA, Maryam T. Chemical composition and antimicrobial and cytotoxic activities of foeniculum vulgare mill essential oils. Journal of Gastrointestinal Cancer. 2020; 51: 260-266. https://doi.org/10.1007/s12029-019-00241-w

38. Maryam A, Reza K, Saeedeh JN, Sepideh H. Analysis and evaluation of the antimicrobial and anticancer activities of the essential oil isolated from foeniculum vulgare from Hamedan, Iran. Natural Product Research. 2019; 33(11): 1629-1632. https://doi.org/10.1080/14786419.2017.1423310

39. El SAA, Qianzheng Z, Zubair IS, Gulza W, Bassant MB, Ira R, et al. Thymoquinone up-regulates pten expression and induces apoptosis in doxorubicin-resistant human breast cancer cells. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2011; 706(1-2): 28–35. https://doi.org/10.1016/j.mrfmmm.2010.10.007

Received on 27.09.2021 Modified on 24.03.2022

Research J. Pharm. and Tech 2023; 16(1):477-480.

DOI: 10.52711/0974-360X.2023.00081