THE POTENTIAL EFFECT OF APORPHINE ALKALOIDS FROM NELUMBO NUCIFERA GAERTN. AS ANTI-BREAST CANCER BASED ON NETWORK PHARMACOLOGY AND MOLECULAR DOCKING

ADRIAN; MUHAMMAD FAUZAN LUBIS; RONY ABDI SYAHPUTRA; RIRIN ASTYKA; SUMAIYAH SUMAIYAH; MUHAMMAD ANDIKA YUDHA HARAHAP; ZAHRATUL AINI

doi:10.22159/ijap.2024v16i1.49171

Authors

ADRIAN Faculty of Medicine, Universitas Methodist Indonesia, Medan, Indonesia
MUHAMMAD FAUZAN LUBIS Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia https://orcid.org/0000-0001-9651-904X
RONY ABDI SYAHPUTRA Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
RIRIN ASTYKA Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
SUMAIYAH SUMAIYAH Department of Pharmaceutical Technology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
MUHAMMAD ANDIKA YUDHA HARAHAP Faculty of Animal Sciences, Universitas Brawijaya, Malang, Indonesia https://orcid.org/0000-0003-0566-2065
ZAHRATUL AINI Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia

DOI:

https://doi.org/10.22159/ijap.2024v16i1.49171

Keywords:

Nuciferine, Nornuciferine, Roemerine, Breast cancer, Network pharmacology, Molecular docking

Abstract

Objective: To demonstrate the efficacy and benefits of aporphine alkaloids from Nelumbo nucifera Gaertn. as anti-breast cancer agents.

Methods: In this study, a combination of network pharmacology and molecular docking was used to investigate the pharmacological actions and underlying mechanisms of action of nuciferine, nor-nuciferine, and roemerine against breast cancer.

Results: Fifty-five potential targets of compounds against breast cancer were identified. The Epidermal Growth Factor Receptor (EGFR), Mitogen-Activated Protein Kinase 8 (MAPK8), Janus Kinase 2 (JAK2), Inhibitor of Nuclear Factor Kappa B Kinase Subunit Beta (IKBKB), and Protein Kinase C Epsilon (PRKCE) were identified as the top five targets of compounds against breast cancer. Molecular docking demonstrated that these compounds could bind spontaneously to the screened top 4 targeted proteins.

Conclusion: The present study demonstrates that these compounds have pharmacological effects against breast cancer via a multi-target and multi-pathway manner.

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References

Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019 Jan 22;321(3):288-300. doi: 10.1001/jama.2018.19323, PMID 30667505.

Lukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanisławek A. Breast cancer-epidemiology, risk factors, classification, prognostic markers, and current treatment strategies-an updated review. Cancers (Basel). 2021 Aug 25;13(17):4287. doi: 10.3390/cancers13174287, PMID 34503097, PMCID PMC8428369.

Sun YS, Zhao Z, Yang ZN, Xu F, Lu HJ, Zhu ZY. Risk factors and preventions of breast cancer. Int J Biol Sci. 2017 Nov 1;13(11):1387-97. doi: 10.7150/ijbs.21635, PMID 29209143, PMCID PMC5715522.

Almansour NM. Triple-negative breast cancer: a brief review about epidemiology, risk factors, signaling pathways, treatment and role of artificial intelligence. Front Mol Biosci. 2022 Jan 25;9:836417. doi: 10.3389/fmolb.2022.836417, PMID 35145999, PMCID PMC8824427.

Anwar SL, Raharjo CA, Herviastuti R, Dwianingsih EK, Setyo-heriyanto D, Avanti WS. Pathological profiles and clinical man-agement challenges of breast cancer emerging in young women in Indonesia: a hospital-based study. BMC Womens Health. 2019 Feb 6;19(1):28. doi: 10.1186/s12905-019-0724-3, PMID 30728000, PMCID PMC6364389.

Widiana IK, Irawan H. Clinical and subtypes of breast cancer in Indonesia. Asian Pac J Cancer Care. 2020;5(4):281-5. doi: 10.31557/apjcc.2020.5.4.281-285.

Tong CWS, Wu M, Cho WCS, To KKW. Recent advances in the treatment of breast cancer. Front Oncol. 2018 Jun 14;8:227. doi: 10.3389/fonc.2018.00227, PMID 29963498, PMCID PMC6010518.

McDonald ES, Clark AS, Tchou J, Zhang P, Freedman GM. Clinical diagnosis and management of breast cancer. J Nucl Med. 2016 Feb;57Suppl 1:9S-16S. doi: 10.2967/jnumed.115.157834, PMID 26834110.

Abrahams HJG, Gielissen MFM, Schmits IC, Verhagen CAHHVM, Rovers MM, Knoop H. Risk factors, prevalence, and course of severe fatigue after breast cancer treatment: a meta-analysis involving 12 327 breast cancer survivors. Ann Oncol. 2016 Jun;27(6):965-74. doi: 10.1093/annonc/mdw099, PMID 26940687.

Akram M, Iqbal M, Daniyal M, Khan AU. Awareness and current knowledge of breast cancer. Biol Res. 2017 Oct 2;50(1):33. doi: 10.1186/s40659-017-0140-9, PMID 28969709, PMCID PMC5625777.

Zuo S, Wang Z, An X, Wang J, Zheng X, Shao D. Self-assembly engineering nano drugs composed of paclitaxel and curcumin for the combined treatment of triple-negative breast cancer. Front Bioeng Biotechnol. 2021 Aug 24;9:747637. doi: 10.3389/fbioe.2021.747637, PMID 34504835, PMCID PMC8421550.

Panth N, Paudel KR, Karki R. Phytochemical profile and bio-logical activity of Juglans regia. J Integr Med. 2016 Sep;14(5):359-73. doi: 10.1016/S2095-4964(16)60274-1, PMID 27641607.

Luo H, Vong CT, Chen H, Gao Y, Lyu P, Qiu L. Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine. Chin Med. 2019 Nov 6;14:48. doi: 10.1186/s13020-019-0270-9, PMID 31719837, PMCID PMC6836491.

Hu P, Ge X, Gao M, Wang X, Zhang Y, Li Y. Nelumbo nucifera Gaertn: an updated review of the antitumor activity and mechanisms of alkaloids. Pharmacological Research-Modern Chinese Medicine. 2022;5. doi: 10.1016/j.prmcm.2022.100167.

Liu CM, Kao CL, Wu HM, Li WJ, Huang CT, Li HT. Antioxidant and anticancer aporphine alkaloids from the leaves of Nelumbo nucifera gaertn. cv. rosa-plena. Molecules. 2014 Nov 3;19(11):17829-38. doi: 10.3390/molecules191117829, PMID 25372397, PMCID PMC6271390.

Zhao X, Feng X, Wang C, Peng D, Zhu K, Song JL. Anticancer activity of Nelumbo nucifera stamen extract in human colon cancer HCT-116 cells in vitro. Oncol Lett. 2017 Mar;13(3):1470-8. doi: 10.3892/ol.2016.5547, PMID 28454279, PMCID PMC5403397.

Yang ZD, Zhang X, Du J, Ma ZJ, Guo F, Li S. An aporphine alkaloid from Nelumbo nucifera as an acetylcholinesterase inhibitor and the primary investigation for structure-activity correlations. Nat Prod Res. 2012;26(5):387-92. doi: 10.1080/14786419.2010.487188, PMID 21732870.

Jin Q, Yang D, Dai Z, Khan A, Wang B, Wei X. Antitumor aporphine alkaloids from Thalictrum wangii. Fitoterapia. 2018 Jul;128:204-12. doi: 10.1016/j.fitote.2018.05.012, PMID 29772303.

Wang Y, Zhang Y, Wang Y, Shu X, Lu C, Shao S. Using network pharmacology and molecular docking to explore the mecha-nism of Shan Ci Gu (Cremastra appendiculata) against non-small cell lung cancer. Front Chem. 2021 Jun 9;9:682862. doi: 10.3389/fchem.2021.682862, PMID 34178945, PMCID PMC8220148.

Wang K, Wang Y, Yan J, Hou C, Zhong X, Zhao Y. Network phar-macology and molecular docking integrated strategy to the screening of active components and mechanisms of stephaniae tetrandrae radix on breast cancer. Processes. 2022;10(11):2340. doi: 10.3390/pr10112340.

Zhang X, Shen T, Zhou X, Tang X, Gao R, Xu L. Network phar-macology based virtual screening of active constituents of Prunella vulgaris L. and the molecular mechanism against breast cancer. Sci Rep. 2020;10(1):15730. doi: 10.1038/s41598-020-72797-8, PMID 32978480.

Li ZH, Yu D, Huang NN, Wu JK, Du XW, Wang XJ. Immunoregu-latory mechanism studies of ginseng leaves on lung cancer based on network pharmacology and molecular docking. Sci Rep. 2021;11(1):18201. doi: 10.1038/s41598-021-97115-8, PMID 34521875.

Syahputra HD, Masfria M, Hasibuan PAZ, Iksen I. In silico dock-ing studies of phytosterol compounds selected from Ficus re-ligiosa as potential chemopreventive agent. Rasayan J Chem. 2022;15(2):1080-4. doi: 10.31788/RJC.2022.1526801.

Daina A, Michielin O, Zoete V. Swiss target prediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019 Jul 2;47(W1):W357-64. doi: 10.1093/nar/gkz382, PMID 31106366, PMCID PMC6602486.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003 Nov;13(11):2498-504. doi: 10.1101/gr.1239303, PMID 14597658, PMCID PMC403769.

Iksen I, Witayateeraporn W, Wirojwongchai T, Suraphan C, Pornputtapong N, Singharajkomron N. Identifying molecular targets of aspiletrein-derived steroidal saponins in lung cancer using network pharmacology and molecular docking-based assessments. Sci Rep. 2023;13(1):1545. doi: 10.1038/s41598-023-28821-8, PMID 36707691.

Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta Cepas J. STRING v11: protein-protein association networks with in-creased coverage, supporting functional discovery in ge-nome-wide experimental datasets. Nucleic Acids Res. 2019 Jan 8;47(D1):D607-13. doi: 10.1093/nar/gky1131, PMID 30476243, PMCID PMC6323986.

Von Mering C, Jensen LJ, Snel B, Hooper SD, Krupp M, Foglierini M. STRING: known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic Acids Res. 2005 Jan 1;33:D433-7. doi: 10.1093/nar/gki005, PMID 15608232, PMCID PMC539959.

Yi Y, Fang Y, Wu K, Liu Y, Zhang W. Comprehensive gene and pathway analysis of cervical cancer progression. Oncol Lett. 2020 Apr;19(4):3316-32. doi: 10.3892/ol.2020.11439, PMID 32256826, PMCID PMC7074609.

Chen J, Zhang D, Shen B, Zhang X, Xu B, Xu X. Enantioseparation of D, L-α-amine acid on crown ester chiral stationary phases. Fenxi Huaxue Chin J Anal Chem. 2006;34(11):1535-40.

Seeliger D, de Groot BL. Ligand docking and binding site analy-sis with PyMOL and Autodock/Vina. J Comput Aided Mol Des. 2010 May;24(5):417-22. doi: 10.1007/s10822-010-9352-6, PMID 20401516, PMCID PMC2881210.

Dallakyan S, Olson A. Participation in global governance: coor-dinating’ the voices of those most affected by food insecurity. Glob Food Secur Gov. 2015;1263:1-11. doi: 10.1007/ 978-1-4939-2269-7.

Then R. Dihydropteroate synthase. X Pharm Compr. Pharmacol Ref. 2007:1-7. doi: 10.1016/B978-008055232-3.60524-0.

Chen D, Oezguen N, Urvil P, Ferguson C, Dann SM, Savidge TC. Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci Adv. 2016 Mar 25;2(3):e1501240. doi: 10.1126/sciadv.1501240, PMID 27051863, PMCID PMC4820369.

Jin J, Chen B, Zhan X, Zhou Z, Liu H, Dong Y. Network pharmacology and molecular docking study on the mechanism of colorectal cancer treatment using Xiao-Chai-Hu-Tang. Plos One. 2021 Jun 14;16(6):e0252508. doi: 10.1371/journal.pone.0252508, PMID 34125845, PMCID PMC8202922.

Bai H, Wang R, Li Y, Liang X, Zhang J, Sun N. Network pharma-cology analysis, molecular docking, and in vitro verification reveal the action mechanism of Prunella vulgaris L. in treating breast cancer. Evid Based Complement Alternat Med. 2022 Aug 10;2022:5481563. doi: 10.1155/2022/5481563, PMID 35990843, PMCID PMC9385303.

Song Y, Sakharkar MK, Yang J. Probing the mechanism of action (MOA) of Solanum nigrum linn against breast cancer using network pharmacology and molecular docking. SN Appl Sci. 2023;5(5). doi: 10.1007/s42452-023-05356-1.

Kang EJ, Lee SK, Park KK, Son SH, Kim KR, Chung WY. Liensinine and nuciferine, bioactive components of Nelumbo nucifera, inhibit the growth of breast cancer cells and breast can-cer-associated bone loss. Evid Based Complement Alternat Med. 2017;2017:1583185. doi: 10.1155/2017/1583185, PMID 29333179, PMCID PMC5733186.

Tang X, Jin L, Cao P, Cao K, Huang C, Luo Y. MicroRNA-16 sensi-tizes breast cancer cells to paclitaxel through suppression of IKBKB expression. Oncotarget. 2016 Apr 26;7(17):23668-83. doi: 10.18632/oncotarget.8056, PMID 26993770, PMCID PMC5029655.

Balko JM, Schwarz LJ, Luo N, Estrada MV, Giltnane JM, Davila Gonzalez D. Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific depend-ence. Sci Transl Med. 2016 Apr 13;8(334):334ra53. doi: 10.1126/scitranslmed.aad3001. Erratum in: Sci Transl Med. 2019 Jan 23;11(476). PMID 27075627, PMCID PMC5256931.

Gong L, Tang H, Luo Z, Sun X, Tan X, Xie L. Tamoxifen induces fatty liver disease in breast cancer through the MAPK8/FoxO pathway. Clin Transl Med. 2020 Jan;10(1):137-50. doi: 10.1002/ctm2.5, PMID 32508033, PMCID PMC7240857.

Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat. 2012 Nov;136(2):331-45. doi: 10.1007/s10549-012-2289-9. PMID 23073759, PMCID PMC3832208.

Maennling AE, Tur MK, Niebert M, Klockenbring T, Zeppernick F, Gattenlöhner S. Molecular targeting therapy against EGFR family in breast cancer: progress and future potentials. Cancers (Basel). 2019 Nov 20;11(12):1826. doi: 10.3390/cancers11121826, PMID 31756933, PMCID PMC6966464.

Ali R, Wendt MK. The paradoxical functions of EGFR during breast cancer progression. Signal Transduct Target Ther. 2017;2:16042. doi: 10.1038/sigtrans.2016.42, PMID 28435746.

Ma JH, Qin L, Li X. Role of STAT3 signaling pathway in breast cancer. Cell Commun Signal. 2020 Feb 28;18(1):33. doi: 10.1186/s12964-020-0527-z, PMID 32111215, PMCID PMC7048131.

Rocca A, Braga L, Volpe MC, Maiocchi S, Generali D. The predic-tive and prognostic role of RAS-RAF-MEK-ERK pathway alterations in breast cancer: revision of the literature and comparison with the analysis of cancer genomic datasets. Cancers (Basel). 2022 Oct 28;14(21):5306. doi: 10.3390/cancers14215306, PMID 36358725, PMCID PMC9653766.

Xu P, Zhang G, Hou S, Sha LG. MAPK8 mediates resistance to temozolomide and apoptosis of glioblastoma cells through MAPK signaling pathway. Biomed Pharmacother. 2018 Oct;106:1419-27. doi: 10.1016/j.biopha.2018.06.084, PMID 30119215.

Semba T, Wang X, Xie X, Cohen EN, Reuben JM, Dalby KN. Iden-tification of the JNK-active triple-negative breast cancer cluster associated with an immunosuppressive tumor microenvironment. J Natl Cancer Inst. 2022 Jan 11;114(1):97-108. doi: 10.1093/jnci/djab128, PMID 34250544, PMCID PMC8755499.

Zhai CL, Tang GM, Qian G, Han BJ, Hu HL, Wang SJ. miR-190 protects cardiomyocytes from apoptosis induced by H2O2 through targeting MAPK8 and regulating MAPK8/ERK signal pathway. Int J Clin Exp Pathol. 2018 Apr 1;11(4):2183-92. PMID 31938330, PMCID PMC6958226.

Liu Q, Ai B, Kong X, Wang X, Qi Y, Wang Z. JAK2 expression is correlated with the molecular and clinical features of breast cancer as a favorable prognostic factor. Int Immunopharmacol. 2021 Jan;90:107186. doi: 10.1016/j.intimp.2020.107186, PMID 33290964.

Zhu N, Zhang J, Du Y, Qin X, Miao R, Nan J. Loss of ZIP facilitates JAK2-STAT3 activation in tamoxifen-resistant breast cancer. Proc Natl Acad Sci USA. 2020 Jun 30;117(26):15047-54. doi: 10.1073/pnas.1910278117, PMID 32532922, PMCID PMC7334450.

Kim MS, Jeong J, Seo J, Kim HS, Kim SJ, Jin W. Author correction: dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer. Sci RepSci Rep. 2020;10(1):11103. doi: 10.1038/s41598-020-68128-6, PMID 32632170.

Schneider J, Jeon YW, Suh YJ, Lim ST. Effects of ruxolitinib and calcitriol combination treatment on various molecular subtypes of breast cancer. Int J Mol Sci. 2022 Feb 25;23(5):2535. doi: 10.3390/ijms23052535, PMID 35269680, PMCID PMC8910493.

Gong Y, Zhao W, Jia Q, Dai J, Chen N, Chen Y. IKBKB rs2272736 is associated with gastric cancer survival. Pharmgenomics Pers Med. 2020 Aug 19;13:345-52. doi: 10.2147/PGPM.S258761, PMID 32884329, PMCID PMC7443400.

Pan F, Zhang J, Tang B, Jing L, Qiu B, Zha Z. The novel circ_0028171/miR-218-5p/IKBKB axis promotes osteosar-coma cancer progression. Cancer Cell Int. 2020 Oct 6;20:484. doi: 10.1186/s12935-020-01562-8, PMID 33041665, PMCID PMC7542388.

Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L. Breast cancer development and progression: risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis. 2018 May 12;5(2):77-106. doi: 10.1016/j.gendis.2018.05.001, PMID 30258937, PMCID PMC6147049.

Song D, Cui M, Zhao G, Fan Z, Nolan K, Yang Y. Pathway-based analysis of breast cancer. Am J Transl Res. 2014 May 15;6(3):302-11, PMID 24936222, PMCID PMC4058311.

Yousefnia S, Seyed Forootan F, Seyed Forootan S, Nasr Esfahani MH, Gure AO, Ghaedi K. Mechanistic pathways of malignancy in breast cancer stem cells. Front Oncol. 2020 Apr 30;10:452. doi: 10.3389/fonc.2020.00452, PMID 32426267, PMCID PMC7212408.