Ficus deltoidea Ethanol Extract Cytotoxic Activity on MCF-7 Treated Doxorubicin: An In Silico and In vitro Approach
Article Sidebar
Views | PDF/EPUB Downloads:
524
/ 446
/ 19
Main Article Content
Abstract
Female breast cancer is the most frequently diagnosed cancer worldwide, and the number of cases will increase in the next 20 years. Doxorubicin is an effective first-line chemotherapy for breast cancer. Unfortunately, continuous administration of doxorubicin can decrease the sensitivity of cancer cells to the drug. The use of herbal medicines as a valuable and efficient approach to cancer treatment is increasing. Several studies have confirmed the anti-breast cancer activity of extract Ficus deltoidea (FD), but no study has revealed the cytotoxicity of extract FD in MCF-7 breast cancer cell lines that have been exposed to doxorubicin repeatedly. This study aims to evaluate the cytotoxic potential of ethanolic extracts from the F.deltoidea leaves against MCF-7/Dox. In addition to assessing the total flavonoid contents in the extract. We performed a molecular docking analysis. The 3-(4, 5-dimethyl thiazolyl-2)-2, 5-diphenyltetrazolium bromide) (MTT) assay is conducted using doxorubicin treated-MCF-7 cell lines (MCF-7/Dox). The total flavonoid content is 130.77 mg QE/g extract of FD. Based on molecular docking, kaempferol-3-O-β-D-glucuronopyranosyl methyl ester interacted best with Bax and Bcl-2 proteins compared to 11 compounds. The IC50 value of the FD extract on MCF-7/Dox was 2.85 ppm ± 0.47. Our results provide valuable insight into FD as an herb to be developed as an alternative or additional therapy to reduce sensitivity in patients with breast cancer.
Downloads
Article Details
Section
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
How to Cite
References
Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Laversanne M., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74 (3):229–263.
Satherley L, Lloyd Davies E. Breast cancer. J Med. 2023;51(1):42–47.
Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020; 17(7):395–417.
Tian X, Srinivasan PR, Tajiknia V, Sanchez Sevilla Uruchurtu AF, Seyhan AA, Carneiro BA, DLC Arielle, PS Maximilian, G Andrew, Z Shuai, S Jillian, DC Francesca, Z Shuai, S Jillian, DR Alexander, N Arunasalam, Z Yiqun, V Nataliia, G Maryam, R Dinara, ED Wafik. Targeting apoptotic pathways for cancer therapy. J Clin Invest. 2024; 134(14): e179570.
Carrington EM, Zhan Y, Brady JL, Zhang JG, Sutherland RM, Anstee NS, LS Robyn, BV Ingela, BD Rebecca, S David, DH Nicholas, B Philippe, MT David, CSH David, S Andreas, C Suzanne, JH Marco, ML Andrew. Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo. Cell Death Differ. 2017; 24(5):878–888.
Wanner E, Thoppil H, Riabowol K. Senescence and apoptosis: Architects of mammalian development. Fro in Cell and Dev Bio. 2021; 8:1-16.
Akhlaghi E, Lehto RH, Torabikhah M, Sharif Nia H, Taheri A, Zaboli E, NS Hamid, T Ahmad, Z Ehsan, Y Ameneh. Chemotherapy use and quality of life in cancer patients at the end of life: an integrative review. Health Qual Life Outcomes. 2020; 18(1):332-341.
Shao W, Wang X, Liu Z, Song X, Wang F, Liu X, W Fukai, L Xiaoyu, Y Zhiyong. Cyperotundone combined with Adriamycin induces apoptosis in MCF-7 and MCF-7/ADR cancer cells by ROS generation and NRF2/ARE signalling pathway. Sci Rep. 2023; 13(1):1384-1396.
Yang R, Guo Z, Zhao Y, Ma L, Li B, Yang C. Compound 968 reverses adriamycin resistance in breast cancer MCF-7ADR cells via inhibiting P-glycoprotein function independently of glutaminase. Cell Death Discov. 2021; 7(1):204-213.
Cox J, Weinman S. Mechanisms of doxorubicin resistance in hepatocellular carcinoma. Hep Onc. 2016; 57–59.
Mirzaei S, Gholami MH, Hashemi F, Zabolian A, Farahani MV, Hushmandi K, Zarrabi A, Goldman Aaron, Ashfrafizadeh M, O Gorka. Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects. Drug Discov Today. 2022; 27(2):436–455.
Christowitz C, Davis T, Isaacs A, van Niekerk G, Hattingh S, Engelbrecht AM. Mechanisms of doxorubicin-induced drug resistance and drug-resistant tumour growth in a murine breast tumour model. BMC Cancer. 2019; 19(1):757-767.
Bonam S, Wu Y, Tunki L, Chellian R, Halmuthur M, Muller S, P Vijayapandi. What has come out from phytomedicines and herbal edibles for the treatment of cancer? ChemMedChem. 2018; 13(18):1854–1872.
Jeon YJ, Kim JH, Shin JI, Jeong M, Cho J, Lee K. Salubrinal-mediated upregulation of eIF2α phosphorylation increases doxorubicin sensitivity in MCF-7/ADR cells. Mol Cells. 2016; 39(2):129–135.
Peniwidiyanti P, Irsyam ASD, Dewi AP, Hariri MR, Irwanto RR, Anshori Z Al. Newly recorded alien species of Ficus L. (Moraceae) in Java, Indonesia. J Trop Biodivers Biotechnol. 2021; 6(2):1-11.
Omar MH, Mullen W, Crozier A. Identification of proanthocyanidin dimers and trimers, flavone C-glycosides, and antioxidants in Ficus deltoidea, a malaysian Herbal Tea. J Agric Food Chem. 2011; 59(4):1363–1369.
Ramamurthy S. Phytochemical, pharmacological and toxicological properties of Ficus deltoidea: A review of a recent research. Annu Res Rev Biol. 2014; 4(14):2357–2371.
Eden WT, Wahyuono S, Cahyono E, Astuti P. Phytochemical, antioxidant, and cytotoxic activity of water hyacinth (Eichhornia crassipes) ethanol extract. Trop J Nat Prod Res. 2023; 7(8):3606–3612.
Nowak J, Wambebe C, Mukonzo J, Katuura E. Cytotoxic activity of combining molecular iodine and dihydroartemisinin with methanol extracts of Carica papaya linn and Vernonia amygdalina delile leaves against MCF-7 and MDA-MB-231 breast cancer cell lines. Trop J Nat Prod Res. 2021; 5(3):485–493.
Ladeska V, Elya B, Hanafi M, Kusmardi k. Antioxidants, total phenolic and flavonoid content and toxicity assay of ampelas (Tetracera macrophylla Wall.Ex Hook.F.& Thoms) from Kalimantan-Indonesia.Phcog J. 2022;14(5):642–648.
Kusmardi, Tedjo A, Nurlaili A. Antiinflammation effect of tabat barito (Ficus deltoidea) leaf extract on small intestine of mice induced by dextran sodium sulfate. Int. J. Pharm. Res. 2020; 12(01): 636–645.
Harborne J. Phytochemical methods: A guide to modern techniques of plant analysis. 2nd ed. London: Chapman and Hall; 1984.
Qiao L, Lewis R, Hooper A, Morphet J, Tan X, Yu K. Application note using natural products application solution with UNIFI for the identification of chemical ingredients of green tea extract; 2014.
Hakim RW, Putri RC, Fachri W, Fadilah F, Krisnamurti DGB, Fitriani R, GBK Desak, F Rizki, HH Euis, W Dewi. Exploring the anti-breast cancer potential of chalcomoracin, guangsangon e, and morushalunin: A computational analysis of compounds from Morus sp. Int. J. Technol. 2023; 14(7):1586-1595.
Dulsat J, López-Nieto B, Estrada-Tejedor R, Borrell JI. Evaluation of free online ADMET tools for academic or small biotech environments. Molecules. 2023; 28(2):776-793.
Ponnulakshmi R. Molecular docking data of piperine with bax, caspase 3, cox 2 and caspase 9. Bioinformation. 2020; 16(6):458–461.
Gowtham HG, Ahmed F, Anandan S, Shivakumara CS, Bilagi A, Pradeep S, S Chandan, AS Ali, YA Mohammad, EIE Serag, RA Raghu, S Ekaterina, S Victor, M Mahadevamurthy, PK Shiva. In silico computational studies of bioactive secondary metabolites from Wedelia trilobata against anti-apoptotic b-cell lymphoma-2 (bcl-2) protein associated with cancer cell survival and resistance. Molecules. 2023; 28(4):1588-1604.
Permana MY, Soediro TM, Louisa M. Silymarin increases the sensitivity of breast cancer cells to doxorubicin in doxorubicin-induced MCF-7 cells by inhibiting breast cancer resistance protein expression. J Phys Conf Ser. 2018; 1073:1-8.
Chong KH, Chang YJ, Hsu WH, Tu YT, Chen YR, Lee MC, HH Wei, WT Kuo. Breast cancer with increased drug resistance, invasion ability, and cancer stem cell properties through metabolism reprogramming. Int J Mol Sci. 2022;23(21):1-12.
Al-Ameertaha AR, Al-Asadi RH. Synthesis, characterisation, and anti-cancer evaluation of thiourea benzamide derivatives and their Cu (II) and Pt (IV) complexes against PC3 and HepG2 cancer cell lines. Trop J Nat Prod Res. 2024; 8(11):9050-9060.
Ashraf K, Halim H, Lim SM, Ramasamy K, Sultan S. In vitro antioxidant, antimicrobial and antiproliferative studies of four different extracts of Orthosiphon stamineus, Gynura procumbens and Ficus deltoidea. Saudi J Biol Sci. 2020; 27(1):417–432.
Abolmaesoomi M, Abdul Aziz A, Mat Junit S, Mohd Ali J. Ficus deltoidea: Effects of solvent polarity on antioxidant and anti-proliferative activities in breast and colon cancer cells. Eur J Integr Med. 2019;28:57–67.
Nazarni Che Isa M, Ajit A, Naila A, Sulaiman AZ. Effect of microwave assisted hydrodistillation extraction on extracts of Ficus deltoidea. Mater Today Proc. 2018; 5(10):21772–21779.
Jamal NA. Chemical constituents from Ficus deltoidea var. kunstleri corner and its antidiabetic property. Universiti Pendidikan Sultan Idris; 2017.
Abdulrahman MD. Crude extract of Ficus deltoidea Jack (FD) as a natural biological therapy. Explor target anti-tumor ther. 2023; 4(1):57–88.
Farsi E, Shafaei A, Hor SY, Khadeer Ahamed MB, Yam MF, Asmawi MZ, Ismail Z. Genotoxicity and acute and subchronic toxicity studies of a standardised methanolic extract of Ficus deltoidea leaves. Clinics. 2013; 68(6):865–875.
Abrahim NN, Abdul-Rahman PS, Aminudin N. The antioxidant activities, cytotoxic properties, and identification of water-soluble compounds of Ficus deltoidea leaves. PeerJ. 2018; 6:1-20.
Park MY, Kim Y, Ha SE, Kim HH, Bhosale PB, Abusaliya A, Jeong SH, Kim GS. Function and application of flavonoids in the breast cancer. Int J Mol Sci. 2022; 23(14):7732-7748.
Putri RC. The Effect of Ethanol Extract of Ficus deltoidea Leaves on the Expression of Bax, Bcl-2, and Cyclin D-1 Genes and the Viability of MCF-7 Cells Exposed to Repeated Doxorubicin. [Central Jakarta]: University of Indonesia; 2024.
Bolleddula J, Brady K, Bruin G, Lee A, Martin JA, Walles M, X Keyang, Y Tong, Z Xiaochun, Y Hongbin. Absorption, distribution, metabolism, and excretion of therapeutic proteins: Current industry practices and future perspectives. Drug Metab Dispos. 2022; 50(6):837–845.
Asano D, Takakusa H, Nakai D. Oral absorption of middle-to-large molecules and its improvement, with a focus on new modality drugs. Pharmaceutics. 2023; 16(1):47-74.
Scheiner S. The hydrogen bond: a hundred years and counting. J. Indian Inst. Sci. 2020; 100(1): 61-76.
Bergström CAS, Yazdanian M. Lipophilicity in drug development: Too Much or Not Enough? AAPS Journal. 2016; 18(5):1095–1100.
Bilginer R, Arslan Yildiz A. Biomimetic model membranes as drug screening platform. In: Biomimetic lipid membranes: fundamentals, applications, and commercialisation. Springer International Publishing; 2019. p. 225–247.
Shahidi F, Dissanayaka CS. Phenolic-protein interactions: insight from in-silico analyses – a review. Food Production, Processing and Nutrition. 2023; 5(1):2.
Apriasari M, Nadia H, Hanifa N, Utami J, Firdaus I. In vitro and In vivo Nephrotoxicity Evaluation of the Methanol Extract of Ficus deltoidea Jack Leaf. Trop J Nat Prod Res. 2024 Jun 29; 8(6).
Kusmardi K, Aryo T, Eka WP, Fadilah F, Pontjo PB, Wilzar F. In silico, in vitro and in vivo Tests of Ficus deltoidea Jack Leaves Extract as Inhibitor for Beta-Catenin Expression in Colon Carcinogenesis Model. Pharmacognosy Journal. 2018; 10:808–813.
Hanafi MMM, Afzan A, Yaakob H, Aziz R, Sarmidi MR, Wolfender JL, Jose MP. In vitro Pro-apoptotic and Anti-migratory Effects of Ficus deltoidea L. Plant extracts on the Human Prostate Cancer Cell Lines PC3. Front Pharmacol. 2017; 8.