Studi In Silico Potensi Metabolit Sekunder Eleutherine palmifolia (L.) Merr. sebagai Inhibitor Protein E6 dan E7 dari Human Papilloma Virus
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Abstract
Abstract—Human Papilloma Virus (HPV), especially variants 16 and 18, are the causative agents of cervicals cancer. The E6 and E7 proteins are known to play a role in the cervical cancer regulation. Dayak onion plants have been widely used by local people as traditional medicine, including in treating cancer. Until now, there is no known compound or scientific evidence related to its activity of Dayak onion plants against HPV. The plant contains flavonoids, alkaloids, naphtoquinone and several types of polyphenols. Several flavonoids and naphtoquinones from other plants are known to have the ability to treat cancer, especially cervical cancer. In this study, we performed in silico screening of the secondary metabolites, especially the flavonoid and naphtoquinone groups, of Dayak onions which might be active against E6 and E7 proteins of HPV16 and 18. The result showed that there were six flavonoids’ compounds and four naphtoquinone compounds which were predicted as candidates to treat cervical cancer. The Pa values of all compounds, including the positive control, the resveratrol, were less than 0.5 which meant that all compounds showed no activity as anticancer. Analysis of physicochemical, pharmacokinetics, and toxicity predictions exhibited that all compounds could be absorbed, distributed, metabolized, and excreted in human body and non-toxic. Among the ten compounds, only 1,4-Naphthoquinone had weaker interaction with E6 and E7 proteins than resveratrol. Ephicatecin gallate had the strongest binding affinity with protein E6 HPV16 (-7,7 kkal.mol-1) and E7 HPV18 (-7,1 kkal.mol-1), whilst rutin was the strongest interaction with E6 HPV16 (-7,8 kkal.mol-1) and E7 HPV18 (-6,2 kkal.mol-1). As a conclusion, the ephicatecin gallate and rutin compounds of BDayak onion could be used as potent candidat to inactivate the E6 and E7 proteins of HPV 16 and HPV18. The two compounds were also predicted had similarity as medicine and were suitable in bioavailability to be applied as agents for cervical cancer therapy.
Keywords: E6 and E7 oncogene proteins, cervical cancer, flavonoid, naphtoquinone, onion dayak
Abstrak—Human Papiloma Virus (HPV) varian tipe 16 dan 18 merupakan salah satu penyebab kanker serviks. Protein E6 dan E7 dari HPV merupakan protein utama yang berperan dalam regulasi kanker servix. Tanaman Bawang Dayak telah banyak digunakan secara tradisional untuk mengatasi kanker. Hingga saat ini belum diketahui senyawa atau pembuktian ilmiah terkait khasiatnya pada tanaman Bawang Dayak. Bawang Dayak mengandung senyawa flavonoid, alkaloid, naphtoquinone dan beberapa tipe polifenol. Beberapa senyawa golongan flavonoid dan naphtoquinone dari tumbuhan lain telah dibuktikan berperan dalam mengatasi kanker, terutama kanker servix. Pada penelitian ini dilakukan skrining secara in silico metabolit sekunder, khususnya golongan flavonoid dan naphtoquinone, dari Bawang Dayak yang berpotensi menghambat protein E6 dan E7 dari HPV16 dan HPV18. Hasil analisis menunjukkan bahwa ada enam senyawa golongan flavonoid dan dan empat senyawa naphtoquinone yang diduga berpotensi sebagai anti kanker serviks. Nilai Pa kurang dari 0,5 untuk semua metabolit sekunder dan kontrol positif, resveratrol tidak menunjukkan aktivitas. Analisis sifat fisikokimia, farmakokinetik dan potensi toksisitas bagi tubuh menunjukkan bahwa semua senyawa teridentifikasi mampu diabsorbsi, didistribusi, dimetabolisme dan diekskresi dari tubuh dan tidak toksik. Interaksi sepuluh metabolit sekunder Bawang Dayak dengan protein E618 dan E716 menunjukkan bahwa hanya 1,4-Naphthoquinone yang berinteraksi lebih lemah dibandingkan resveratrol. Ephicatecin gallate berinteraksi paling kuat dengan protein E6 HPV16 (-7,7 kkal.mol-1) dan E7 HPV18 (-7,1 kkal.mol-1). Rutin berinteraksi paling baik dengan E6 HPV16 (-7,8 kkal.mol-1) dan E7 HPV18 (-6,2 kkal.mol-1). Berdasarkan hasil analisa, dapat disimpulkan bahwa senyawa ephicatecin gallate dan rutin Bawang Dayak berpotensi sebagai kandidat penghambat protein E6 dan E7 dari HPV 16 dan HPV18. Kedua senyawa juga diduga memiliki kesamaan dengan obat dan secara bioavailibilitasnya cocok jika diterapkan sebagai agen terapi kanker serviks.
Kata kunci: bawang dayak, flavonoid, kanker servix, naphtoquinone, protein onkogen E6 dan E7
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References
World Health Organization (WHO). The elimination of cancer [Internet]. Cancer Indonesia 2020 country profile. 2020. Available from: https://www.who.int/publications/m/item/cancer-idn-2020
Global Cancer Observatory [Internet]. 2020. Available from: https://gco.iarc.fr/today/data/factsheets/populations/360-indonesia-fact-sheets.pdf
ICO. Human Papillomavirus and Related Diseases Report. 2023;(Maret). Available from: www.hpvcentre.com
Pal A, Kundu R. Human Papillomavirus E6 and E7 : The Cervical Cancer Hallmarks and Targets for Therapy. 2020;10(January). Available from: https://www.frontiersin.org/articles/10.3389/fmicb.2019.03116/full
Kotadiya R, Johnson A, Georrge J j. Natural products as inhibitors of E6 and E7 protein of Human papilomavirus (HPV): an in silico approach. 2020;(January). Available from: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3574478
Vats A, Trejo-cerro O, Thomas M, Banks L. Human papillomavirus E6 and E7 : What remains ? Tumour Virus Res [Internet]. 2021;11:200213. Available from: https://doi.org/10.1016/j.tvr.2021.200213
Wang Y, Lu J, Liang Y. Suppressive Effects of EGCG on Cervical Cancer. 2018;23(9):2334. Available from: https://www.mdpi.com/1420-3049/23/9/2334.
Jiang Z, Albanese J, Kesterson J, Warrick J, Karabakhtsian R, Dadachova E, et al. Monoclonal Antibodies Against Human Papillomavirus E6 and E7 Oncoproteins Inhibit Tumor Growth in Experimental Cervical Cancer. Transl Oncol. 2019;12(10):1289–95. Available from: https://www.sciencedirect.com/science/article/pii/S193652331930018X?via%3Dihub.
Liontos M, Kyriazoglou A, Dimitriadis I, Dimopoulos MA, Bamias A. Systemic therapy in cervical cancer: 30 years in review. Crit Rev Oncol Hematol [Internet]. 2019;137(December 2018):9–17. Available from: https://doi.org/10.1016/j.critrevonc.2019.02.009
Liu L, Wang M, Li X, Yin S, Wang B. An Overview of Novel Agents for Cervical Cancer Treatment by Inducing Apoptosis: Emerging Drugs Ongoing Clinical Trials and Preclinical Studies. Front Med. 2021;8(July):1–11. Available from: https://www.frontiersin.org/articles/10.3389/fmed.2021.682366/full.
Almeida AM, Queiroz JA, Sousa F, Sousa Â. Cervical cancer and HPV infection: ongoing therapeutic research to counteract the action of E6 and E7 oncoproteins. Drug Discov Today. 2019;24(10):2044–57.
Zhou SG, Wu DF, Yao H, Zhang WY, Tian FJ, Chen G, et al. REBACIN® inhibits E6/E7 oncogenes in clearance of human papillomavirus infection. Front Oncol. 2022;12(December):1–10. Available from: https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1047222/full
Bhandari J, Muhammad B, Thapa P, Shrestha BG. anti-oxidant , and anti-cancer properties of Allium wallichii. 2017;1–9. Available from: https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-017-1622-6
Zhang L, Lv R, Qu X, Chen X, Lu H, Wang Y. Aloesin Suppresses Cell Growth and Metastasis in Ovarian Cancer SKOV3 Cells through the Inhibition of the MAPK Signaling Pathway. 2017;2017. Available from: https://pubmed.ncbi.nlm.nih.gov/28702312/
Gao Y, He C, Ran R, Zhang D, Li D, Xiao PG, et al. The resveratrol oligomers, cis- and trans-gnetin H, from Paeonia suffruticosa seeds inhibit the growth of several human cancer cell lines. J Ethnopharmacol [Internet]. 2015;169:24–33. Available from: http://dx.doi.org/10.1016/j.jep.2015.03.074
Deng LJ, Lei YH, Chiu TF, Qi M, Gan H, Zhang G, et al. The Anticancer Effects of Paeoniflorin and Its Underlying Mechanisms. Nat Prod Commun. 2019;14(9):1–8. Available from: https://journals.sagepub.com/doi/10.1177/1934578X19876409
Bhatia A, Mishra T, Khullar M. Anticancer potential of aqueous ethanol seed extract of Ziziphus mauritiana against cancer cell lines and Ehrlich ascites carcinoma. Evidence-based Complement Altern Med. 2011;2011. Available from: https://www.hindawi.com/journals/ecam/2011/765029/
Beg MA, Teotia UVS, Farooq S. In vitro antibacterial and anticancer activity of Ziziphus. 2016;4(5):230–3. Available from: https://www.semanticscholar.org/paper/In-vitro-antibacterial-and-anticancer-activity-of-Beg-Teotia/6cbcf9f482666e72008e8e75fc7a316f154c4c4b
Muhartono, Sukohar A, Sutyarso, Kanedi M. Anti-proliferative and apoptotic effects of mucoxin (acetogenin) in T47D breast cancer cells. Biomed Pharmacol J. 2016;9(2):491–8. Available from: https://pubmed.ncbi.nlm.nih.gov/27222827/
Muslimah NH, Wijayanti RN, Putriarti D, ... Prediksi Interaksi Senyawa Aktif Bidara (Ziziphus mauritiana) Sebagai Antikanker Terhadap Protein HER2. STIGMA J … [Internet]. 2022;15(April):1–9. Available from: https://jurnal.unipasby.ac.id/index.php/stigma/article/view/4524%0Ahttps://jurnal.unipasby.ac.id/index.php/stigma/article/download/4524/3825
Lee I, Choi BY. Withaferin-A — A Natural Anticancer Agent with Pleitropic Mechanisms of Action. 2016; 17 (3):290. Available from: https://www.mdpi.com/1422-0067/17/3/290
Palliyaguru DL, Singh S V., Kensler TW. Withania somnifera: From prevention to treatment of cancer. Mol Nutr Food Res. 2016;60(6):1342–53. Available from: https://onlinelibrary.wiley.com/doi/10.1002/mnfr.201500756
Munagala R, Kausar H, Munjal C, Gupta RC. Withaferin a induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis. 2011;32(11):1697–705. Available from: https://academic.oup.com/carcin/article/32/11/1697/2463698?login=false
Rastogi N, Duggal S, Singh SK, Porwal K. Proteasome inhibition mediates p53 reactivation and anti- cancer activity of 6-Gingerol in cervical cancer cells. 2015;6(41). Available from: https://www.oncotarget.com/article/6383/text/
Ankola A V, Kumar V, Thakur S, Singhal R, Smitha T, Sankeshwari R. Anticancer and antiproliferative efficacy of a standardized extract of Vaccinium macrocarpon on the highly differentiating oral cancer KB cell line athwart the cytotoxicity evaluation of the same on the normal fibroblast L929 cell line. 2020; 24(2):258–65. Available from: https://journals.lww.com/jpat/Fulltext/2020/24020/Anticancer_and_antiproliferative_efficacy_of_a.16.aspx
Taher ZM, Agouillal F, Lim JR, Marof AQ, Dailin DJ, Razif ENM, et al. Anticancer Molecules from Catharanthus roseus. 2019;30(3):147–56. Available from: https://indonesianjpharm.farmasi.ugm.ac.id/index.php/3/article/view/1467
Ke Y, Saleh M, Aboody A, Alturaiki W, Alsagaby SA, Alfaiz FA, et al. Photosynthesized gold nanoparticles from Catharanthus roseus induces caspase-mediated apoptosis in cervical cancer cells ( HeLa ) caspase-mediated apoptosis in cervical cancer cells ( HeLa ). Artif Cells, Nanomedicine, Biotechnol [Internet]. 2019;41(1):1938–46. Available from: https://doi.org/10.1080/21691401.2019.1614017
Abdulridha MK, Al-Marzoqi AH, Al-awsi GRL, Mubarak SMH, Heidarifard M, Ghasemian A. Anticancer Effects of Herbal Medicine Compounds and Novel Formulations: a Literature Review. J Gastrointest Cancer. 2020;51(3):765–73. Available from: https://link.springer.com/article/10.1007/s12029-020-00385-0
Gore GG, Satish S, Ganpule A, Srivastava S. Garlic ( Allium sativum ) exhibits anticancer and anticancer stem cell activity on Breast , Prostate , Colon , Hepatic and Cervical cancer cell lines. 2021;9(1):93–9. Available from: https://www.florajournal.com/search/?q=Garlic+%28Allium+sativum%29+exhibits+anticancer+and+anticancer+stem+cell+activity+on+Breast%2C+Prostate%2C+Colon%2C+Hepatic+and+Cervical+cancer+cell+lines
Padmaharish V, Lakshmi T. Anticancer activities of medicinal plants –An update. J Pharm Sci Res. 2017;9(4):432–40. Available from: https://www.jpsr.pharmainfo.in/issue.php?page=92#
Filippini T, Malavolti M, Borrelli F, Aa I, Sj F, Horneber M, et al. Green tea ( Camellia sinensis ) for the prevention of cancer ( Review ). 2020; 3(3):CD005004. Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005004.pub3/full
Jahani S, Heidari Z. Comparison of Anticancer Effects of Hydroalcoholic Extracts of Camellia sinensis and Lepidium sativum L on HeLa Cell Line. 2020;13(11). :e98913. Available from: https://brieflands.com/articles/ijcm-98913.html
Lanza A, Tava A, Catalano M, Ragona L, Singuaroli I, Robustelli Della Cuna FS, et al. Effects of the Medicago scutellata Trypsin Inhibitor (MsTI) on Cisplatin-induced Cytotoxicity in Human Breast and Cervical Cancer Cells. Anticancer Res. 2004;24(1):227–33. Available from: https://pubmed.ncbi.nlm.nih.gov/15015601/.
Nuraini, Ilyas A, Iin N. Identifikasi dan karakterisasi senyawa bioaktif antikanker dari ekstrak etanol kulit batang kayu bitti (Vitex cofassus). Al Kim. 2015;15–27. Available from: https://journal.uin-alauddin.ac.id/index.php/al-kimia/article/view/1668
Nigam M, Saklani S, Plygun S, Mishra AP. Antineoplastic potential of the vitex species: An overview. Bol Latinoam y del Caribe Plantas Med y Aromat. 2018;17(5):492–502. Available from: https://core.ac.uk/display/162596412?utm_source=pdf&utm_medium=banner&utm_campaign=pdf-decoration-v1
Hussain MN, Alzubaidy MWM. DNA damage assessment of Hela cancer cell line by biosynthetic zinc oxide nanoparticles. Int J Health Sci (Qassim). 2022;6(June):11808–16. Available from: https://sciencescholar.us/journal/index.php/ijhs/article/view/8926
Mahata S, Maru S, Shukla S, Pandey A, Mugesh G, Das BC, et al. Anticancer property of Bryophyllum pinnata (Lam.) Oken. leaf on human cervical cancer cells. BMC Complement Altern Med [Internet]. 2012;12(1):15. Available from: http://www.biomedcentral.com/1472-6882/12/15
Yu HC, Chen LJ, Cheng KC, Li YX, Yeh CH, Cheng JT. Silymarin inhibits cervical cancer cell through an increase of phosphatase and tensin homolog. Phyther Res. 2012;26(5):709–15. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ptr.3618
Koushki M, Farrokhi Yekta R, Amiri-Dashatan N. Critical review of therapeutic potential of silymarin in cancer: A bioactive polyphenolic flavonoid. J Funct Foods [Internet]. 2023;104(January):105502. Available from: https://doi.org/10.1016/j.jff.2023.105502
Sintha Eliestya Purwandari. Ragam Olahan Bawang Dayak [Internet]. 2018 [cited 2023 Jun 21]. Available from: https://repository.pertanian.go.id/items/67065706-08ad-4702-9397-f771a17b9ec5
Yudistira. Jamu Bawang Dayak, Kaya akan Manfaat - MULTIMEDIA CENTER PROVINSI KALIMANTAN TENGAH [Internet]. 2019 [cited 2023 Jun 21]. Available from: https://mmc.kalteng.go.id/berita/read/5257/jamu-bawang-dayak-kaya-akan-manfaat
Ririn Puspadewi, Putranti Adirestuti RM. Khasiat Umbi Bawang Dayak (Eleutherine palmifolia (L.) Merr.) Sebagai Herbal Antimikroba Kulit. J Bioteknol Biosains Indones. 2013;1(1):31–7. Available from: https://www.semanticscholar.org/paper/KHASIAT-UMBI-BAWANG-DAYAK-%28Eleutherine-palmifolia-Puspadewi-Adirestuti/07c1f89c0e7f396e85da653cf6d560dbe4f84e93?p2df
Lestari D, Kartika R, Marliana E. Antioxidant and anticancer activity of Eleutherine bulbosa (Mill.) Urb on leukemia cells L1210. J Phys Conf Ser. 2019;1277(1). Available from: https://iopscience.iop.org/article/10.1088/1742-6596/1277/1/012022.
Muti’ah R, Listiyana A, Nafisa BB, Suryadinata A. Kajian Efek Ekstrak Umbi Bawang Dayak (Eleutherine palmifolia (L.) Merr) sebagai Antikanker. J Islam Pharm. 2020;5(2):14–25. Available from: http://ejournal.uin-malang.ac.id/index.php/jip/article/view/9778#
Anam S, Khumaidi A, Yuyun Y. Original article Standardization of Eleutherine bulbosa Urb . Bulbs Extract from Lampo , Donggala , Central Sulawesi. 2023;12(1):29–34. Available from: https://bestjournal.untad.ac.id/index.php/ejurnalfmipa/article/view/16146.
Annisa R, Hendradi E, Yuwono M. Analysis of 1,4 naphthoquinone in the Indonesian medical plant from extract Eleutherine palmifolia (L.) Merr by UHPLC. IOP Conf Ser Earth Environ Sci. 2020;456(1). Available from: https://iopscience.iop.org/article/10.1088/1755-1315/456/1/012020.
Kamarudin AA, Sayuti NH, Saad N, Razak NAA, Esa NM. Eleutherine bulbosa (Mill.) urb. bulb: Review of the pharmacological activities and its prospects for application. Int J Mol Sci. 2021;22(13). Available from: https://www.mdpi.com/1422-0067/22/13/6747
Listyani TA, Herowati R. Analisis Docking Molekuler Senyawa Derivat Phthalimide sebagai Inhibitor Non-Nukleosida HIV-1 Reverse Transcriptase. J Farm Indones. 2018;15(2):123–34. Available from: https://link.springer.com/protocol/10.1007/978-1-4939-2269-7_19
Zhou XY, Hu XX, Wang CC, Lu XR, Chen Z, Liu Q, et al. Enzymatic activities of CYP3A4 allelic variants on quinine 3-hydroxylation in vitro. Front Pharmacol. 2019;10(MAY). Available from: https://onlinelibrary.wiley.com/doi/10.1002/jcc.20084
BPOM RI. Peraturan Badan Pengawas Obat Dan Makanan Tentang Pedoman Uji Toksisitas Praklinik Secara in vivo. J Chem Inf Model [Internet]. 2020;53(9):21–5. Available from: http://www.elsevier.com/locate/scp
Fitri Y, Suwarso E. Effects of inhibition cell cycle and apoptosis of sabrang onion extract (Eleutherine bulbosa (Mill.) Urb.) on breast cancer cells. Int J PharmTech Res CODEN IJPRIF ISSN. 2014;6(4):1392–6. Available from: https://discover.3ds.com/discovery-studio-visualizer-download.
Kori M, Arga KY. Potential biomarkers and therapeutic targets in cervical cancer: Insights from the meta-analysis of transcriptomics data within network biomedicine perspective. PLoS One. 2018;13(7):1–27. Available from: http://www.adrianomartinelli.it/Fondamenti/Tutorial_0.pdf
Tan S, G.E. de Vries E, G.J. van der Zee A, de Jong S. Anticancer Drugs Aimed at E6 and E7 Activity in HPV-Positive Cervical Cancer. Curr Cancer Drug Targets. 2012;12(2):170–84. Available from: https://digitallibrary.ump.ac.id/520/
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