Journal of Multidisciplinary Applied Natural Science
##plugins.themes.gdThemes.journalSlogan##
Scopus CiteScore 2025
2.1
Calculated on 05 May, 2025
SJR 2025
0.25
Powered by scimagojr.com
##plugins.themes.gdThemes.journalSlogan##
2.1
Calculated on 05 May, 2025
0.25
Powered by scimagojr.com
https://doi.org/10.47352/jmans.2774-3047.465
Linda Chiuman
Dewi Purnama
Chrismis Novalinda Ginting
Ermi Girsang
Hariyadi Dharmawan Syahputra
Iksen Iksen
Melanoma is an aggressive skin cancer with frequent therapeutic resistance, highlighting the need for multi-target discovery strategies. In this study, an integrative workflow combining LC–HRMS metabolite profiling, network pharmacology, structure-based modeling, and phenotypic evaluation was applied to explore the anti-melanoma potential of Zanthoxylum acanthopodium ethanol extract (ZAE). LC–HRMS analysis followed by ADMET-guided screening prioritized 12 candidate metabolites representing diverse structural classes. Integration of transcriptomic datasets, GeneCards targets, and compound-based predictions identified eight consensus genes, with poly(ADP-ribose) polymerase 1 (PARP1) emerging as the top hub within the protein–protein interaction network. Functional enrichment analysis highlighted pathways associated with DNA damage response and apoptosis-related signaling. Molecular docking against the PARP1 catalytic domain suggested favorable binding profiles for several prioritized metabolites, and molecular dynamics simulation supported stable interaction behavior under dynamic conditions. In vitro anticancer evaluation in A375 melanoma cells demonstrated concentration-dependent reduction in viability (IC₅₀ = 128.03 ± 10.17 μg/mL, 24 h) accompanied by apoptosis-associated nuclear alterations. Overall, this study provides a chemically informed, systems-level framework indicating that ZAE-derived metabolites may influence melanoma cell survival through PARP1-centered stress and apoptosis signaling, offering a foundation for future target validation and structure-guided optimization.
[1] C. Caraviello, G. Nazzaro, G. Tavoletti, F. Boggio, N. Denaro, G. Murgia, E. Passoni, V. B. Mancin, and A. V. Marzano. (2025). "Melanoma Skin Cancer: A Comprehensive Review of Current Knowledge". Cancers. 17 (17). 10.3390/cancers17172920.
DOI: https://doi.org/10.3390/cancers17172920[2] S. J. Hachey and A. D. Boiko. (2016). "Therapeutic Implications of Melanoma Heterogeneity". Experimental Dermatology. 25 (7): 497-500. 10.1111/exd.13002.
DOI: https://doi.org/10.1111/exd.13002[3] L. Maresca, B. Stecca, and L. Carrassa. (2022). "Novel Therapeutic Approaches with DNA Damage Response Inhibitors for Melanoma Treatment". Cells. 11 (9). 10.3390/cells11091466.
DOI: https://doi.org/10.3390/cells11091466[4] Iksen, W. Witayateeraporn, B. Hardianti, and V. Pongrakhananon. (2024). "Comprehensive Review of Bcl-2 Family Proteins in Cancer Apoptosis: Therapeutic Strategies and Promising Updates of Natural Bioactive Compounds and Small Molecules". Phytotherapy Research. 38 (5): 2249-2275. 10.1002/ptr.8157.
DOI: https://doi.org/10.1002/ptr.8157[5] Iksen, N. Singharajkomron, H. M. Nguyen, H. N. T. Hoang, D. V. Ho, and V. Pongrakhananon. (2024). "Adunctin E from Conamomum rubidum Induces Apoptosis in Lung Cancer via HSP90AA1 Modulation: A Network Pharmacology and In Vitro Study". International Journal of Molecular Sciences. 25 (21). 10.3390/ijms252111368.
DOI: https://doi.org/10.3390/ijms252111368[6] Iksen, F. N. Manihuruk, H. D. Syahputra, M. Saragih, I. E. E. Manurung, R. S. U. Peranginangin, D. F. P. Saragih, H. A. Simanjuntak, and K. Gurning. (2026). "Integrative Multi-Omics and Experimental Approaches Identify SRC as a Central Target of Garcinia atroviridis Flavonoids in Lung Cancer". Journal of Multidisciplinary Applied Natural Science. 6 (1): 540-552. 10.47352/jmans.2774-3047.344.
DOI: https://doi.org/10.47352/jmans.2774-3047.344[7] X. Jiang, Z. Xu, H. Wang, H. Wang, J. Zhao, N. Maihemuti, S. Jiang, M. Xiao, K. Zhang, S. Liang, Y. Shi, and K. Wang. (2025). "Metabolomics and Integrated Network Pharmacology Analysis Revealed Multi-Targeted Anti-Cancer Effect of FuZhengXiaoJi Decoction Against Non-Small Cell Lung Cancer". Phytomedicine. 143 : 156855. 10.1016/j.phymed.2025.156855.
DOI: https://doi.org/10.1016/j.phymed.2025.156855[8] P. Zhang, D. Zhang, W. Zhou, L. Wang, B. Wang, T. Zhang, and S. Li. (2023). "Network Pharmacology: Towards the Artificial Intelligence-Based Precision Traditional Chinese Medicine". Briefings in Bioinformatics. 25 (1). 10.1093/bib/bbad518.
DOI: https://doi.org/10.1093/bib/bbad518[9] R. Islamie, Iksen, B. C. Buana, K. Gurning, H. D. Syahputra, and H. S. Winata. (2022). "Construction of Network Pharmacology-Based Approach and Potential Mechanism from Major Components of Coriandrum sativum L. Against COVID-19". Pharmacia. 69 (3): 689-697. 10.3897/pharmacia.69.e84388.
DOI: https://doi.org/10.3897/pharmacia.69.e84388.figure1[10] J. F. Wijaya, L. Chiuman, H. D. Syahputra, V. E. Kaban, R. Razoki, C. N. Ginting, and I. Iksen. (2025). "Investigation of Potential Molecular Targets of Zanthoxylum acanthopodium in Ovarian Cancer Using Network Pharmacology Assessments". Journal of Multidisciplinary Applied Natural Science. 5 (2): 630-643. 10.47352/jmans.2774-3047.268.
DOI: https://doi.org/10.47352/jmans.2774-3047.268[11] Q. Ma, Y. Liu, Q. Zhang, W. Yi, Y. Sun, X. Gao, X. Zhao, H. Wang, K. Lei, and W. Luo. (2024). "Integrating Network Pharmacology, Molecular Docking and Experimental Verification to Reveal the Mechanism of Artesunate in Inhibiting Choroidal Melanoma". Frontiers in Pharmacology. 15 : 1448381. 10.3389/fphar.2024.1448381.
DOI: https://doi.org/10.3389/fphar.2024.1448381[12] I. Syaputri, E. Girsang, and L. Chiuman. (2022). "Test of Antioxidant and Antibacterial Activity of Ethanol Extract of Andaliman Fruit (Zanthoxylum acanthopodium DC.) with DPPH (1,1-Diphenyl-2-Picrylhydrazyl) Trapping Method and Minimum Inhibitory Concentration". International Journal of Health and Pharmaceutical. 2 (2): 215-224. 10.51601/ijhp.v2i2.36.
DOI: https://doi.org/10.51601/ijhp.v2i2.36[13] E. R. Megawati, H. Bangun, I. B. Putra, and M. Rusda. (2025). "Cytotoxicity and Apoptotic Effects of the Ethyl Acetate Fraction of Zanthoxylum acanthopodium DC. Fruit on B16F10 Melanoma Cell Culture". Contemporary Oncology. 29 (4): 354-359. 10.5114/wo.2025.155773.
DOI: https://doi.org/10.5114/wo.2025.155773[14] D. Satria, J. Silalahi, G. Haro, S. Ilyas, and P. A. Z. Hasibuan. (2019). "Cell Cycle Inhibition of Ethyl Acetate Fraction of Zanthoxylum acanthopodium DC. Fruit Against T47D Cells". Open Access Macedonian Journal of Medical Sciences. 7 (5): 726-729. 10.3889/oamjms.2019.178.
DOI: https://doi.org/10.3889/oamjms.2019.178[15] D. M. Syari, R. Rosidah, P. A. Z. Hasibuan, G. Haro, and D. Satria. (2019). "Evaluation of Cytotoxic Activity of Alkaloid Fractions of Zanthoxylum acanthopodium DC. Fruits". Open Access Macedonian Journal of Medical Sciences. 7 (22): 3745-3747. 10.3889/oamjms.2019.495.
DOI: https://doi.org/10.3889/oamjms.2019.495[16] S. M. Sinaga, G. Haro, S. Sudarmi, and Iksen. (2019). "Phytochemical Screening and Antihyperglycemic Activity of Ethanolic Extract of Coriandrum sativum L. Leaf". Rasayan Journal of Chemistry. 12 (4): 1992-1996. 10.31788/RJC.2019.1245451.
DOI: https://doi.org/10.31788/RJC.2019.1245451[17] T. Barrett, S. E. Wilhite, P. Ledoux, C. Evangelista, I. F. Kim, M. Tomashevsky, K. A. Marshall, K. H. Phillippy, P. M. Sherman, M. Holko, A. Yefanov, H. Lee, N. Zhang, C. L. Robertson, N. Serova, S. Davis, and A. Soboleva. (2013). "NCBI GEO: Archive for Functional Genomics Data Sets—Update". Nucleic Acids Research. 41 (Database Issue): D991-D995. 10.1093/nar/gks1193.
DOI: https://doi.org/10.1093/nar/gks1193[18] L. Raskin, D. R. Fullen, T. J. Giordano, D. G. Thomas, M. L. Frohm, K. B. Cha, J. Ahn, B. Mukherjee, T. M. Johnson, and S. B. Gruber. (2013). "Transcriptome Profiling Identifies HMGA2 as a Biomarker of Melanoma Progression and Prognosis". Journal of Investigative Dermatology. 133 (11): 2585-2592. 10.1038/jid.2013.197.
DOI: https://doi.org/10.1038/jid.2013.197[19] O. Kabbarah. (2010). "Integrative Genome Comparison of Primary and Metastatic Melanomas". PLoS ONE. 5 (5): e10770. 10.1371/journal.pone.0010770.
DOI: https://doi.org/10.1371/journal.pone.0010770[20] Iksen and B. C. Buana. (2022). "Identification of Potential COVID-19 Targets and Pathways Derivate from Various Phenolic Compounds from Chives (Allium schoenoprasum) by Using Network Pharmacology Approach". Media Pharmaceutica Indonesiana. 4 (2): 157-167. 10.24123/mpi.v4i2.5272.
DOI: https://doi.org/10.24123/mpi.v4i2.5272[21] G. Stelzer, N. Rosen, I. Plaschkes, S. Zimmerman, M. Twik, S. Fishilevich, T. I. Stein, R. Nudel, I. Lieder, Y. Mazor, S. Kaplan, D. Dahary, D. Warshawsky, Y. Guan-Golan, A. Kohn, N. Rappaport, M. Safran, and D. Lancet. (2016). "The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses". Current Protocols in Bioinformatics. 54. 10.1002/cpbi.5.
DOI: https://doi.org/10.1002/cpbi.5[22] A. Daina, O. Michielin, and V. Zoete. (2017). "SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules". Scientific Reports. 7 : 42717. 10.1038/srep42717.
DOI: https://doi.org/10.1038/srep42717[23] A. Daina, O. Michielin, and V. Zoete. (2019). "SwissTargetPrediction: Updated Data and New Features for Efficient Prediction of Protein Targets of Small Molecules". Nucleic Acids Research. 47 (W1): W357-W364. 10.1093/nar/gkz382.
DOI: https://doi.org/10.1093/nar/gkz382[24] D. Szklarczyk, K. Nastou, M. Koutrouli, R. Kirsch, F. Mehryary, R. Hachilif, D. Hu, M. E. Peluso, Q. Huang, T. Fang, N. T. Doncheva, S. Pyysalo, P. Bork, L. J. Jensen, and C. von Mering. (2025). "The STRING Database in 2025: Protein Networks with Directionality of Regulation". Nucleic Acids Research. 53 (D1): D730-D737. 10.1093/nar/gkae1113.
DOI: https://doi.org/10.1093/nar/gkae1113[25] P. Shannon, A. Markiel, O. Ozier, N. S. Baliga, J. T. Wang, D. Ramage, N. Amin, B. Schwikowski, and T. Ideker. (2003). "Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks". Genome Research. 13 (11): 2498-2504. 10.1101/gr.1239303.
DOI: https://doi.org/10.1101/gr.1239303[26] C. H. Chin, S. H. Chen, H. H. Wu, C. W. Ho, M. T. Ko, and C. Y. Lin. (2014). "CytoHubba: Identifying Hub Objects and Sub-Networks from Complex Interactome". BMC Systems Biology. 8 (Suppl 4): S11. 10.1186/1752-0509-8-S4-S11.
DOI: https://doi.org/10.1186/1752-0509-8-S4-S11[27] P. J. Thul and C. Lindskog. (2018). "The Human Protein Atlas: A Spatial Map of the Human Proteome". Protein Science. 27 (1): 233-244. 10.1002/pro.3307.
DOI: https://doi.org/10.1002/pro.3307[28] K. Chang, C. J. Creighton, C. Davis, L. A. Donehower, J. Drummond, D. R. Wheeler, and A. Ally. (2013). "The Cancer Genome Atlas Pan-Cancer Analysis Project". Nature Genetics. 45 (10): 1113-1120. 10.1038/ng.2764.
DOI: https://doi.org/10.1038/ng.2764[29] Iksen, N. Singharajkomron, A. Wongtayan, O. Wattanathamsan, A. Choonhapan, S. Wademonkolgorn, H. M. Nguyen, T. H. X. Hoang, H. T. Nguyen, and V. Pongrakhananon. (2026). "Unveiling the Antimetastatic Activity and Molecular Mechanism of Montanine in Lung Cancer Cells via the Integration of Network Pharmacology Approaches with In Vitro and In Vivo Investigations". Journal of Integrative Medicine. 10.1016/j.joim.2026.01.001.
DOI: https://doi.org/10.1016/j.joim.2026.01.001[30] H. D. Syahputra, M. Masfria, P. A. Z. Hasibuan, and Iksen. (2022). "In Silico Docking Studies of Phytosterol Compounds Selected from Ficus religiosa as Potential Chemopreventive Agent". Rasayan Journal of Chemistry. 15 (2): 1080-1084. 10.31788/RJC.2022.1526801.
DOI: https://doi.org/10.31788/RJC.2022.1526801[31] Iksen, S. Sinsook, O. Wattanathamsan, K. Buaban, S. Chamni, and V. Pongrakhananon. (2022). "Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis". Molecules. 27 (24): 8948. 10.3390/molecules27248948.
DOI: https://doi.org/10.3390/molecules27248948[32] L. Z. Benet, C. M. Hosey, O. Ursu, and T. I. Oprea. (2016). "BDDCS, the Rule of 5 and Drugability". Advanced Drug Delivery Reviews. 101 : 89-98. 10.1016/j.addr.2016.05.007.
DOI: https://doi.org/10.1016/j.addr.2016.05.007[33] A. Reichel and P. Lienau. (2016). "Pharmacokinetics in Drug Discovery: An Exposure-Centred Approach to Optimising and Predicting Drug Efficacy and Safety". Handbook of Experimental Pharmacology. 232 : 235-260. 10.1007/164_2015_26.
DOI: https://doi.org/10.1007/164_2015_26[34] E. M. Novoa-Del-Toro and M. Witting. (2024). "Navigating Common Pitfalls in Metabolite Identification and Metabolomics Bioinformatics". Metabolomics. 20 (5): 103. 10.1007/s11306-024-02167-2.
DOI: https://doi.org/10.1007/s11306-024-02167-2[35] P. Donizy, C. Wu, J. Mull, M. Fujimoto, A. Chłopik, Y. Peng, S. C. Shalin, M. A. Selim, S. Puig, M. Fernandez-Figueras, C. R. Shea, W. Biernat, J. Ryś, A. Marszalek, and M. P. Hoang. (2020). "Up-Regulation of PARP1 Expression Significantly Correlated with Poor Survival in Mucosal Melanomas". Cells. 9 (5): 1135. 10.3390/cells9051135.
DOI: https://doi.org/10.3390/cells9051135[36] P. Kupczyk. (2021). "PARP1 as a Marker of an Aggressive Clinical Phenotype in Cutaneous Melanoma: A Clinical and an In Vitro Study". Cells. 10 (2): 286. 10.3390/cells10020286.
DOI: https://doi.org/10.3390/cells10020286[37] P. Kupczyk, A. Simiczyjew, J. Marczuk, E. Dratkiewicz, A. Beberok, J. Rok, M. Pieniazek, P. Biecek, D. Nevozhay, B. Slowikowski, G. Chodaczek, D. Wrzesniok, D. Nowak, and P. Donizy. (2019). "PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells". Frontiers in Physiology. 10 : 538. 10.3389/fphys.2019.00538.
DOI: https://doi.org/10.3389/fphys.2019.00538[38] F. Fratangelo, R. Camerlingo, M. V. Carriero, G. Pirozzi, G. Palmieri, G. Gentilcore, C. Ragone, M. Minopoli, P. A. Ascierto, and M. L. Motti. (2018). "Effect of ABT-888 on the Apoptosis, Motility and Invasiveness of BRAFi-Resistant Melanoma Cells". International Journal of Oncology. 53 (3): 1149-1159. 10.3892/ijo.2018.4457.
DOI: https://doi.org/10.3892/ijo.2018.4457[39] M. J. Schiewer, J. F. Goodwin, S. Han, J. C. Brenner, M. A. Augello, J. L. Dean, F. Liu, J. L. Planck, P. Ravindranathan, A. M. Chinnaiyan, P. McCue, L. G. Gomella, G. V. Raj, A. P. Dicker, J. R. Brody, J. M. Pascal, M. M. Centenera, L. M. Butler, W. D. Tilley, and K. E. Knudsen. (2012). "Dual Roles of PARP-1 Promote Cancer Growth and Progression". Cancer Discovery. 2 (12): 1134-1149. 10.1158/2159-8290.CD-12-0120.
DOI: https://doi.org/10.1158/2159-8290.CD-12-0120[40] Y. Wang, W. Luo, and Y. Wang. (2019). "PARP-1 and Its Associated Nucleases in DNA Damage Response". DNA Repair. 81 : 102651. 10.1016/j.dnarep.2019.102651.
DOI: https://doi.org/10.1016/j.dnarep.2019.102651[41] J. O. Spiegel, B. Van Houten, and J. D. Durrant. (2021). "PARP1: Structural Insights and Pharmacological Targets for Inhibition". DNA Repair. 103 : 103125. 10.1016/j.dnarep.2021.103125.
DOI: https://doi.org/10.1016/j.dnarep.2021.103125