Exploring the Anticancer and Anti-inflammatory Activities of Ferruginol in MCF-7 Breast Cancer Cells
Breast cancer is one of the most prevalent cancers in women, and it has the highest mortality and morbidity worldwide. Breast cancer can be treated by hormone therapies, radiotherapy, surgery, and chemotherapy, but it is often associated with multiple deleterious effects. In this present work, we explored the anti-inflammatory and anticancer effects of ferruginol in MCF-7 cells. The effects of ferruginol on the cell growth and viability of MCF-7 cells were determined by the MTT assay and apoptotic markers. In addition, mitochondrial membrane potential (MMP) status as well as the levels of intracellular reactive oxygen species (ROS), superoxide dismutase, catalase, glutathione, thiobarbituric acid reactive substances (TBARS), caspase-3 and caspase-9 in the ferruginol-treated MCF-7 cells were examined. In addition, expression of inflammation-related proteins such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), nuclear factor kappa B (NF-κB) p65, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) was determined using Western blotting. Our findings showed that ferruginol activated the apoptosis in MCF-7 through a reduction of cell viability. Furthermore, ferruginol-treated MCF-7 cells also showed a decrease of MMP, an increase of ROS, TBARS, caspase-3 and caspase-9, as well as a reduction of antioxidant proteins. Ferruginol treatment is also downregulated the expression of inflammatory modulators such as TNF-α, iNOS, COX-2, NF-κB p65, and IL-6 in MCF-7 cells. In conclusion, ferruginol inhibits the inflammation and activated apoptosis by modulating the expression of inflammatory and apoptotic markers. Therefore, ferruginol may serve as a potential curative agent for breast cancer
Siegel R, Naishadham D, Jemal A, 2012, Cancer Statistics. CA Cancer J Clin, 62:10–29.
Masoud V, Pages G, 2017, Trageted Therapies in Breast Cancer: New Challenges to Fight against Resistance. World J Clin Oncol, 8(2):120–243. DOI: 10.5306/wjco.v8.i2.120.
Palit S, Kar S, Sharma G, et al., 2015, Hesperetin Induces Apoptosis in Breast Carcinoma by Triggering Accumulation of ROS and Activation of ASK1/JNK Pathway. J Cell Physiol, 230:1729–39. DOI: 10.1002/jcp.24818.
Chamberlin SR, Blucher A, Wu G, et al., 2019, Natural Product Target Network Reveals Potential for Cancer Combination Therapies. Front Pharmacol,10:557. DOI: 10.3389/fphar.2019.00557.
Newton K, Dixit VM, 2012, Signaling in Innate Immunity and Inflammation. Cold Spring Harb Perspect Biol, 4(3):a006049. DOI: 10.1101/cshperspect.a006049.
Chen L, Deng H, Cui H, et al., 2018, Inflammatory Responses and Inflammation-associated Diseases in Organs. Oncotarget, 9(6):7204–18.
Venkatesan T, Park EJ, Choi YW, et al., 2017, Anti-inflammatory Activity of Ternstroemia gymnanthera Stem Bark Extracts in Bacterial Lipopolysaccharide-stimulated RAW264.7 Murine Macrophage Cells. Pharm Biol, 55:837–46. DOI: 10.1080/13880209.2017.1278778.
Lu B, Li M, 2014, Helicobacter pylori Eradication for Preventing Gastric Cancer. World J Gastroenterol, 20:5660–5.
Singh N, Baby D, Rajguru JP, et al., 2019, Inflammation and Cancer. Ann Afr Med, 18(3):121–6.
Condello M, Pellegrini E, Caraglia M, et al., Targeting Autophagy to Overcome Human Diseases. Int J Mol Sci, 20(3):725. DOI: 10.3390/ijms20030725.
Kang TH, Bang JY, Kim MH, et al., 2011, Atractylenolide III, a Sesquiterpenoid, Induces Apoptosis in Human Lung Carcinoma A549 Cells Via Mitochondria-mediated Death Pathway. Food Chem Toxicol, 49:514–9. DOI: 10.1016/j. fct.2010.11.038.
Thamizhiniyan V, Young-Woong C, Young-Kyoon K, 2015, The Cytotoxic Nature of Acanthopanax sessiliflorus Stem Bark Extracts in Human Breast Cancer Cells. Saudi J Biol Sci, 22:752–9. DOI: 10.1016/j.sjbs.2015.04.004.
Varghese E, Samuel SM, Sadiq Z, et al., 2019, Anti-cancer Agents in Proliferation and Cell Death: The Calcium Connection. Int J Mol Sci, 20(12):3017.
Chan KS, Koh CG, Li HY, 2012, Mitosis-targeted Anti-cancer Therapies: Where they Stand. Cell Death Dis, 3:e411. DOI: 10.1038/cddis.2012.148.
Wang KL, Hsia SM, Yeh JY, et al., 2013, Anti-proliferative Effects of Evodiamine on Human Breast Cancer Cells. PLoS One, 8:e67297. DOI: 10.1371/journal.pone.0067297.
de Jesus MB, Zambuzzi WF, de Sousa RR, et al., 2008, Ferruginol Suppresses Survival Signaling Pathways in Androgen-independent Human Prostate Cancer Cells. Biochimie, 90:843–54. DOI: 10.1016/j.biochi.2008.01.011.
Rodríguez JA, Theoduloz C, Yáñez T, et al., 2006, Gastroprotective and Ulcer Healing Effect of Ferruginol in Mice and Rats: Assessment of its Mechanism of Action Using in vitro Models. Life Sci, 78:2503–9. DOI: 10.1016/j. lfs.2005.10.018.
Wei Y, He J, Qin H, et al., 2009, Determination of Ferruginol in Rat Plasma Via High-performance Liquid Chromatography and its Application in Pharmacokinetics Study. Biomed Chromatogr, 23:1116–20. DOI: 10.1002/bmc.1232.
Son KH, Oh HM, Choi SK, et al., Anti-tumor Abietane Diterpenes from the Cones of Sequoia sempervirens. Bioorg Med Chem Lett, 15:2019–21.
Espinoza M, Santos LS, Theoduloz C, et al., 2008, New Gastroprotective Ferruginol Derivatives with Selective Cytotoxicity against Gastric Cancer Cells. Planta Med, 74:802–8. DOI: 10.1055/s-2008-1074532.
Ulubelen A, Birman H, Öksüz S, et al., 2002, Cardioactive Diterpenes from the Roots of Salvia eriophora. Planta Med, 68:818–21. DOI: 10.1055/s-2002-34408.
Ho ST, Tung YT, Kuo YH, et al., 2015, Ferruginol Inhibits Non-small Cell Lung Cancer Growth by Inducing Caspase-associated Apoptosis. Integr Cancer Ther, 14:86–97. DOI: 10.1177/1534735414555806.
Khazaei M, Pazhouhi M, Khazaei S, 2018, Evaluation of Hydro-alcoholic Extract of Trifolium pratens L for its anti-cancer potential on U87MG cell line. Cell J, 20(3):412–21. DOI: 10.4103/0973-1482.187241.
Demsie DG, Yimer EM, Berhe AH, et al., 2019, Anti-nociceptive and Anti-inflammatory Activities of Crude Root Extract and Solvent Fractions of Cucumis ficifolius in Mice Model. J Pain Res, 12:1399–409. DOI: 10.2147/jpr.s193029.
Johnson LV, Walsh ML, Chen LB, 1980, Localization of Mitochondria in Living Cells with Rhodamine 123. Proc Natl Acad Sci U S A, 77:990–4.
Ohkawa H, Ohishi N, Yagi K, 1979, Assay for Lipid Peroxides in Animal Tissues by Thiobarbituric Acid Reaction. Anal Biochem, 95:351–8. DOI: 10.1016/0003- 2697(79)90738-3.
Kakkar P, Das B, Viswanathan PN, 1984, A Modified Spectrophotometric Assay of Superoxide Dismutase. Indian J Biochem Biophys, 21:130–2.
Sinha AK, 1972, Colorimetric Assay of Catalase. Anal Biochem, 47:389–94.
Ellman GL, 1959, Tissue Sulfhydryl Groups. Arch Biochem Biophys, 82:70–7.
Lowry OH, Rosebrough MJ, Farr AL, et al., 1951, Protein Measurement with Folin-phenol Reagent. J Biol Chem, 193:265–75.
Wang Y, Yu H, Zhang J, et al., 2015, Anti-tumor Effect of Emodin on Gynecological Cancer Cells. Cell Oncol (Dordr), 38(5): 353–63. DOI: 10.1007/s13402-015-0234-8.
George BP, Abrahamse H, 2019, Increased Oxidative Stress Induced by Rubus Bioactive Compounds Induce Apoptotic Cell Death in Human Breast Cancer Cells. Oxid Med Cell Longev, 2019:6797921. DOI: 10.1155/2019/6797921.
Lopes CM, Dourado A, Oliveira R, 2017, Phytotherapy and Nutritional Supplements on Breast Cancer. Biomed Res Int, 2017:7207983.
Herrantz-Lopez M, Losada-Echeberria M, Barrajin- Catalan E, 2018, The Multidrug Activity of Natural Extracts on Cancer: Synergy and Xenohormesis. Medicines, 6:6. DOI: 10.3390/medicines6010006.
Wali AF, Majid S, Rasool S, et al., 2019, Natural Products Against Cancer: Review on Phytochemicals from Marine Sources in Preventing Cancer. Saudi Pharm J, 27(6):767– 77. DOI: 10.1016/j.jsps.2019.04.013.
Calavaruso, M, Pucci G, Musso R, et al., 2019, Nutraceutical Compounds as Sensitizers for Cancer Treatment in Radiation Therapy. Int J Mol Sci, 20(21):5267. DOI: 10.3390/ijms20215267.
Sun Y, Xun K, Wang Y, et al., 2009, A Systematic Review of the Anticancer Properties of Berberine, a Natural Product from Chinese Herbs. Anticancer Drugs, 20:757–69. DOI: 10.1097/cad.0b013e328330d95b.
Luo G, Zhou J, Li G, et al., 2019, Ferruginol Diterpenoid Selectively Inhibits Human Thyroid Cancer Growth by Inducing Mitochondrial Dependent Apoptosis, Endogenous Reactive Oxygen Species (ROS) Production, Mitochondrial Membrane Potential Loss and Suppression of Mitogen- Activated Protein Kinase (MAPK) and PI3K/AKT Signaling Pathways. Med Sci Monit, 25:2935–42. DOI: 10.12659/msm.914348.
Weinberg F, Ramnath N, Nagrath D, 2019, Reactive Oxygen Species in the Tumor Microenvironment: An Overview. Cancers (Basel), 11(8):1191. DOI: 10.3390/ cancers11081191.
Safaei M, Maleki H, Soleimanpour H, et al., 2019, Development of a Novel Method for the Purification of C-phycocyanin Pigment from a Local Cyanobacterial Strain Limnothrix sp. NS01 and Evaluation of its Anticancer Properties. Sci Rep, 9:9474. DOI: 10.1038/s41598-019-45905-6.
Anderson AJ, Jackson TD, Stroud DA, et al., 2019, Mitochondria-hubs for Regulating Cellular Biochemistry: Emerging Concepts and Networks. Open Biol, 9(8):190126. DOI: 10.1098/rsob.190126.
Zhao Y, Ye L, Liu H, et al., 2010, Vanadium Compounds Induced Mitochondria Permeability Transition Pore (PTP) Opening Related to Oxidative Stress. J Inorg Biochem, 104:371–8. DOI: 10.1016/j.jinorgbio.2009.11.007.
Kelly PN, Strasser A, 2011, The Role of Bcl-2 and its Pro-survival Relatives in Tumourigenesis and Cancer Therapy. Cell Death Differ, 18:1414–24. DOI: 10.1038/cdd.2011.17.
Kitazumi I, Tsukahara M, 2011, Regulation of DNA Fragmentation: The Role of Caspases and Phosphorylation. FEBS J, 278:427–41. DOI: 10.1111/j.1742-4658.2010.07975.x.
Jamalzadeh L, Ghafoori H, Aghamaali M, et al., 2017, Induction of Apoptosis in Human Breast Cancer MCF-7 Cells by a Semi-Synthetic Derivative of Artemisinin: A Caspase-Related Mechanism. Iran J Biotechnol, 15:157. DOI: 10.15171/ijb.1567.
Xiong WD, Gong J, Xing C, 2017, Ferruginol Exhibits Anticancer Effects in OVCAR3 Human Ovary Cancer Cells by Inducing Apoptosis, Inhibition of Cancer Cell Migration and G2/M Phase Cell Cycle Arrest. Mol Med Rep, 16:7013–17. DOI: 10.3892/mmr.2017.7484.
Tayarani-Najaran Z, Mousavi SH, Tajfard F, et al., 2013, Cytotoxic and Apoptogenic Properties of Three Isolated Diterpenoids from Salvia chorassanica through bioassay-guided fractionation. Food Chem Toxicol, 57:346–51. DOI: 10.1016/j.fct.2013.03.037.
Dolan RD, McSorley ST, Horgan PG, et al., 2017, The Role of the Systemic Inflammatory Response in Predicting Outcomes in Patients with Advanced Inoperable Cancer: Systematic Review and Meta-analysis. Crit Rev Oncol Hematol, 116:134–46. DOI: 10.1016/j. critrevonc.2017.06.002.
Zhang X, Li J, Peng Q, et al., 2019, Association of Markers of Systemic and Local Inflammation with Prognosis of Patients with Rectal Cancer who Received Neoadjuvant Radiotherapy. Cancer Manag Res, 11:191–9. DOI: 10.2147/cmar.s187559.
Wang P, Qiao Q, Li J, et al., 2016, Inhibitory Effects of Geraniin on LPS-induced Inflammation via Regulating NF-κB and Nrf2 Pathways in RAW 264.7 Cells. Chem Biol Interact, 253:134–42. DOI: 10.1016/j.cbi.2016.05.014.
Byun EH, Fujimura Y, Yamada K, et al., 2010, TLR4 Signaling Inhibitory Pathway Induced by Green Tea Polyphenol Epigallocatechin-3-gallate through 67-kDa Laminin Receptor. J Immunol, 185:33–45. DOI: 10.4049/ jimmunol.0903742.
Bertani B, Ruiz N, 2018, Function and Biogenesis of Lipopolysaccharides. EcoSal Plus, 8(10):30066669. DOI: 10.1128/ecosalplus.esp-0001-2018.
Jia Y, Wu C, Zhang B, et al., 2019, Ferruginol Induced Apoptosis on SK-Mel-28 Human Malignant Melanoma Cells Mediated through P-p38 and NF-κB. Hum Exp Toxicol, 38:227–38. DOI: 10.1177/0960327118792050.