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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Foeniculum Vulgare and Pelargonium Graveolens Essential Oil Mixture Triggers the Cell Cycle Arrest and Apoptosis in MCF-7 Cells

Author(s): Islam El-Garawani, Sobhy Hassab El Nabi , Ebtesam Nafie and Samar Almeldin *

Volume 19 , Issue 9 , 2019

Page: [1103 - 1113] Pages: 11

DOI: 10.2174/1573399815666190326115116

Price: $65


Background: Fennel (Foeniculum vulgare) and rose geranium (Pelargonium graveolens) oils are known for their various biological effects including anticancer properties.

Objective: This study aimed to evaluate the anticancer mechanism of fennel and geranium oils combined treatment on MCF-7 cells.

Methods: The GC-MS method for essential oil characterization as well as the in vitro cytotoxicity, morphological changes, real-time PCR and immunocytochemical investigation for apoptosis-related markers, in addition, to flow cytometric cell cycle distribution analysis were done.

Results: The major constituents of both essential oils were anethole (55.33 %) and estragole (11.57 %) for fennel essential oil. However, cintronellol (34.40 %) and geraniol (8.67 %) were identified in geranium oil. The results revealed an IC50 of 220±5.7 and 60±2.1µg/ml for fennel and geranium oils, respectively. The mechanistic anticancer properties were investigated throughout the 70, 50, and 25µg/ml of oils mixture. The marked apoptotic morphology and the flow cytometric cell cycle distribution analysis in addition to the levels of apoptosisrelated makers such as p53, caspase-3, mir-21, mir-92a, Bcl-2, and ki-67 confirmed that fennel and geranium oils combination induced cell cycle arrest and apoptosis in MCF-7 cells. Moreover, the oils mixture did not exert any significant (P<0.01) toxicity on normal human peripheral blood lymphocytes in vitro.

Conclusion: The findings showed that the mixture of oils exerted selective cytotoxicity towards MCF-7 cells through induction of cell cycle arrest and apoptosis which may be triggered by the synergistic effect between the active ingredients of fennel and geranium oils.

Keywords: Fennel, geranium, anticancer, MCF-7, apoptosis, GC-MS.

Graphical Abstract
Gennari, C.; Castoldi, D.; Sharon, O. Natural products with taxol-like anti-tumor activity: Synthetic approaches to eleutherobin and dictyostatin. Pure Appl. Chem., 2007, 79, 173-180.
Wang, L.; Dong, Z.; Huang, B.; Zhao, B.; Wang, H.; Zhao, J.; Kung, H.; Zhang, S.; Miao, J. Distinct patterns of autophagy evoked by two benzoxazine derivatives in vascular endothelial cells. Autophagy, 2010, 6, 1115-1124.
Cancer. Available at: . (Accessed on 22/2/2019)
Amin, A.R.M.R.; Kucuk, O.; Khuri, F.R.; Shin, D.M. Perspectives for cancer prevention with natural compounds. J. Clin. Oncol., 2009, 27, 2712-2725.
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod., 2007, 70, 461-477.
El-Nabi, S.E-S.H.; Dawoud, G.T.M.; El-Garawani, I.M.; El-Shafey, S.S. HPLC Analysis of phenolic acids, antioxidant activity and in vitro effectiveness of green and roasted caffea arabica bean extracts: A comparative study. Anticancer. Agents Med. Chem., 2018, 18(9), 1281-1288.
López-Sáez, J.F.; de la Torre, C.; Pincheira, J.; Giménez-Martín, G. Cell proliferation and cancer. Histol. Histopathol., 1998, 13, 1197-1214.
Villarini, M.; Pagiotti, R.; Dominici, L.; Fatigoni, C.; Vannini, S.; Levorato, S.; Moretti, M. Investigation of the cytotoxic, genotoxic, and apoptosis-inducing effects of estragole isolated from fennel (Foeniculum vulgare). J. Nat. Prod., 2014, 77, 773-778.
Ouariachi, E.M.E.; Lahhit, N.; Bouyanzer, A.; Hammouti, B.; Paolini, J.; Majidi, L.; Desjobert, J.M.; Costa, J. Chemical Composition and antioxidant activity of essential oils and solvent extracts of Foeniculum vulgare mill. from Morocco. J. Chem. Pharm. Res., 2013, 6, 743-748.
Akhbari, M.; Kord, R.; Jafari Nodooshan, S.; Hamedi, S. Analysis and evaluation of the antimicrobial and anticancer activities of the essential oil isolated from Foeniculum vulgare from Hamedan, Iran. Nat. Prod. Res., 2018, 1-4.
Mohamad, R.H.; El-Bastawesy, A.M.; Abdel-Monem, M.G.; Noor, A.M.; Al-Mehdar, H.A.R.; Sharawy, S.M.; El-Merzabani, M.M. Antioxidant and anticarcinogenic effects of methanolic extract and volatile oil of fennel seeds (Foeniculum vulgare). J. Med. Food, 2011, 14(9), 986-1001.
Tognolini, M.; Ballabeni, V.; Bertoni, S.; Bruni, R.; Impicciatore, M.; Barocelli, E. Protective effect of Foeniculum vulgare essential oil and anethole in an experimental model of thrombosis. Pharmacol. Res., 2007, 56, 254-260.
Rather, M.A.; Dar, B.A.; Sofi, S.N.; Bhat, B.A.; Qurishi, M.A. Foeniculum vulgare: A comprehensive review of its traditional use, phytochemistry, pharmacology, and safety. Arab. J. Chem., 2016, 9, S1574-S1583.
Haag, J.D.; Lindstrom, M.J.; Gould, M.N. Limonene-induced regression of mammary carcinomas. Cancer Res., 1992, 52, 4021-4026.
Lai, P.K.; Roy, J. Antimicrobial and chemopreventive properties of herbs and spices. Curr. Med. Chem., 2004, 11, 1451-1460.
Adams, R.P. Identification of essential oil components by gas chromatography/ mass spectrometry, 4th ed; Allured Publishing Corp.: USA, 2007.
Stokes, W.S.; Casati, S.; Strickland, J.; Paris, M. Neutral Red Uptake Cytotoxicity Tests for Estimating Starting Doses for Acute Oral Toxicity Tests. In:Current Protocols in Toxicology; John Wiley & Sons, Inc.: Hoboken, NJ, USA,, 2008, Vol. 20, . p. Unit 20.4.
Moorhead, P.S.; Nowell, P.C.; Mellman, W.J.; Battips, D.M.; Hungerford, D.A. Chromosome preparations of leukocytes cultured from human peripheral blood. Exp. Cell Res., 1960, 20, 613-616.
Tennant, J.R. Evaluation of the trypan blue technique for determination of cell viability. Transplantation, 1964, 2, 685-694.
Singh, N.P.; McCoy, M.T.; Tice, R.R.; Schneider, E.L. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp. Cell Res., 1988, 175, 184-191.
Thippeswamy, G.; Salimath, B.P. Curcuma aromatica extract induces apoptosis and inhibits angiogenesis in ehrlich ascites tumor cells in vivo. My Sci., 2006, 1, 79-92.
Kirsch-Volders, M.; Sofuni, T.; Aardema, M.; Albertini, S.; Eastmond, D.; Fenech, M.; Ishidate, M.; Kirchner, S.; Lorge, E.; Morita, T.; Norppa, H.; Surrallés, J.; Vanhauwaert, A.; Wakata, A. Report from the in vitro micronucleus assay working group. Mutat. Res., 2003, 540, 153-163.
Tolbert, P.E.; Shy, C.M.; Allen, J.W. Micronuclei and other nuclear anomalies in buccal smears: Methods development. Mutat. Res., 1992, 271, 69-77.
Evans, E.P. Karyotyping and Sexing of gametes, embryos and fetuses and in situ hybridization to chromosomes. Mamm. Dev. Pract.Approach / Ed. by M. Monk; , 1987, pp. 93-114.
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 1979, 95, 351-358.
Green, L.C.; Wagner, D.A.; Glogowski, J.; Skipper, P.L.; Wishnok, J.S.; Tannenbaum, S.R. Analysis of nitrate, nitrite, and [15N]Nitrate in biological fluids. Anal. Biochem., 1982, 126, 131-138.
Ellman, G.L. Tissue sulfhydryl groups. Arch. Biochem. Biophys., 1959, 82, 70-77.
Dobashi, Y.; Takehana, T.; Ooi, A. Perspectives on cancer therapy: Cell cycle blockers and perturbators. Curr. Med. Chem., 2003, 10, 2549-2558.
Maraqa, L.; Cummings, M.; Peter, M.B.; Shaaban, A.M.; Horgan, K.; Hanby, A.M.; Speirs, V. Carcinoembryonic antigen cell adhesion molecule 6 predicts breast cancer recurrence following adjuvant tamoxifen. Clin. Cancer Res., 2008, 14, 405-411.
Reichling, J.; Schnitzler, P.; Suschke, U.; Saller, R. Essential oils of aromatic plants with antibacterial, antifungal, antiviral, and cytotoxic properties - an overview. Complement. Med. Res., 2009, 16, 79-90.
Burt, S. Essential oils: Their antibacterial properties and potential applications in foods - a review. Int. J. Food Microbiol., 2004, 94, 223-253.
Panchal, R.G. Novel therapeutic strategies to selectively kill cancer cells. Biochem. Pharmacol., 1998, 55, 247-252.
Pistritto, G.; Trisciuoglio, D.; Ceci, C.; Garufi, A.; D’Orazi, G. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY), 2016, 8, 603-619.
Schwartz, G.K.; Shah, M.A. Targeting the cell cycle: A new approach to cancer therapy. J. Clin. Oncol., 2005, 23, 9408-9421.
Green, D.R.; Reed, J.C. Mitochondria and apoptosis. Science, 1998, 281, 1309-1312.
Vasudevan, S.; Tong, Y.; Steitz, J.A. Switching from repression to activation: MicroRNAs can up-regulate translation. Science, 2007, 318, 1931-1934.
Si, M-L.; Zhu, S.; Wu, H.; Lu, Z.; Wu, F.; Mo, Y-Y. MiR-21-mediated tumor growth. Oncogene, 2007, 26, 2799-2803.
Otsuki, N.; Dang, N.H.; Kumagai, E.; Kondo, A.; Iwata, S.; Morimoto, C. Aqueous extract of carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects. J. Ethnopharmacol., 2010, 127, 760-767.
Isola, J.; Helin, H.; Kallioniemi, O-P. Immunoelectron-microscopic localization of a proliferation-associated antigen Ki-67 in MCF-7 cells. Histochem. J., 1990, 22, 498-506.
Stathopoulos, G.P.; Malamos, N.A.; Markopoulos, C.; Polychronis, A.; Armakolas, A.; Rigatos, S.; Yannopoulou, A.; Kaparelou, M.; Antoniou, P. The role of Ki-67 in the proliferation and prognosis of breast cancer molecular classification subtypes. Anticancer Drugs, 2014, 25, 950-957.
Choi, H.J.; Lim, D.Y.; Park, J.H.Y. Induction of G1 and G2/M cell cycle arrests by the dietary compound 3,3′-Diindolylmethane in HT-29 human colon cancer cells. BMC Gastroenterol., 2009, 9, 39.
Martínez, V.; Barberá, O.; Sánchez-Parareda, J.; Alberto Marco, J. Phenolic and acetylenic metabolites from artemisia assoana. Phytochemistry, 1987, 26, 2619-2624.
Nakanishi, M.; Shimada, M.; Niida, H. Genetic instability in cancer cells by impaired cell cycle checkpoints. Cancer Sci., 2006, 97, 984-989.
Krek, W.; Xu, G.; Livingston, D.M. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint. Cell, 1995, 83, 1149-1158.
Katayose, Y.; Kim, M.; Rakkar, A.N.; Li, Z.; Cowan, K.H.; Seth, P.; Martelli, F.; Shapiro, G.I. Promoting apoptosis: A novel activity associated with the cyclin-dependent kinase inhibitor P27. Cancer Res., 1997, 57, 5441-5445.
Shah, M.A.; Schwartz, G.K. Cell cycle-mediated drug resistance: An emerging concept in cancer therapy. Clin. Cancer Res., 2001, 7, 2168-2181.
Wang, Y.; Ji, P.; Liu, J.; Broaddus, R.R.; Xue, F.; Zhang, W. Centrosome-associated regulators of the G2/M checkpoint as targets for cancer therapy. Mol. Cancer, 2009, 8, 8.
Viuda-Martos, M.; Mohamady, M.A.; Fernández-López, J.
Abd ElRazik, K.A.; Omer, E.A.; Pérez-Alvarez, J.A.; Sendra, E. In vitro antioxidant and antibacterial activities of essentials oils obtained from egyptian aromatic plants. Food Control, 2011, 22, 1715-1722.
Díaz-Maroto, M.C.; Díaz-Maroto Hidalgo, I.J.; Sánchez-Palomo, E.; Pérez-Coello, M.S. Volatile components and key odorants of fennel (Foeniculum vulgare Mill.) and thyme (Thymus vulgaris L.) oil extracts obtained by simultaneous distillation-extraction and supercritical fluid extraction. J. Agric. Food Chem., 2005, 53, 5385-5389.
Džamić, A.M.; Soković, M.D.; Ristić, M.S.; Grujić, S.M.; Mileski, K.S.; Marin, P.D. Chemical composition, antifungal and antioxidant activity of Pelargonium graveolens essential oil. J. Appl. Pharm. Sci., 2014, 4, 1-5.
Dantas, M.; Maria Barbosa-Filho, J. Natural products reported as potential inhibitors of uterine cervical neoplasia. Acta Farm. Bonaer, 2002, 21, 67-74.
Zhuang, S-R.; Chen, S-L.; Tsai, J-H.; Huang, C-C.; Wu, T-C.; Liu, W-S.; Tseng, H-C.; Lee, H-S.; Huang, M-C.; Shane, G-T.; Yang, C-H.; Shen, Y-C.; Yan, Y-Y.; Wang, C-K. Effect of citronellol and the chinese medical herb complex on cellular immunity of cancer patients receiving chemotherapy/radiotherapy. Phytother. Res., 2009, 23, 785-790.
Udensi, U.K.; Tchounwou, P.B. Dual effect of oxidative stress on leukemia cancer induction and treatment. J. Exp. Clin. Cancer Res., 2014, 33, 106.
Elkhateeb, W.A.; Zaghlol, G.M.; El-Garawani, I.M.; Ahmed, E.F.; Rateb, M.E.; Abdel Moneim, A.E. Ganoderma applanatum secondary metabolites induced apoptosis through different pathways: In vivo and in vitro anticancer studies. Biomed. Pharmacother., 2018, 101, 264-277.
Barrera, G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncol., 2012, 2012137289
Mates, J.M.; Perez-Gomez, C.; Nunez de Castro, I. Antioxidant enzymes and human diseases. Clin. Biochem., 1999, 32, 595-603.
Barrera, G.; Pizzimenti, S.; Dianzani, M.U. Lipid peroxidation: Control of cell proliferation, cell differentiation and cell death. Mol. Aspects Med., 2008, 29(1), 1-8.

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