Hydropuntia edulis as a Nutritional Therapeutic Agent for Human Melanoma: In Silico Approach and In Vitro Validation for Functional Food Application
DOI:
https://doi.org/10.12873/Palabras clave:
Hydropuntia edulis, melanoma, metabolomics, molecular docking, anticancer, antioxidant, marine bioactivesResumen
Background: Melanoma is one of the deadliest forms of skin cancer, with rising incidence and limited responsiveness to conventional chemotherapy. Marine macroalgae have recentlyemerged as a promising source of novel bioactive compounds with potential anticancer properties. Objective: This study aimed to investigate the anticarcinogenic andantioxidant potential of Hydropuntia edulis extract (HEE) using integrated metabolomicprofiling, in silico predictions, and in vitro validation against melanoma.
Methods: Untargeted LC-HRMS metabolomic profiling was conducted to identify bioactive constituents in HEE. Key compounds were further analyzed through structure–activity relationship (SAR), ADMET, and molecular docking simulations targeting melanoma-related proteins (BRAF, AKT1, EGFR, and TYRO3). Antioxidant and antiproliferative effects were assessed using DPPH and MTT assays on B16-F10 melanoma cells.
Results: Several metabolites including Sangivamycin, Michosterol C, Linamarin, andElaiomycin K were identified. SAR analysis showed high antineoplastic probability for Linamarin (Pa = 0.831), Sangivamycin (Pa = 0.730), and Michosterol C (Pa = 0.759).Michosterol C showed strong binding affinity to BRAF (−9.2 kcal/mol), comparable to Dabrafenib (−9.1 kcal/mol). HEE demonstrated dose-dependent DPPH radical scavenging andinhibited melanoma cell proliferation with IC50 values similar to positive controls.
Conclusion: Hydropuntia edulis holds promise as a natural therapeutic candidate against melanoma due to its multitargeted bioactive profile and significant in vitro efficacy. Further preclinical studies are warranted to explore its translational potential.
Referencias
1. Ahmed, I.; Asgher, M.; Sher, F.; Hussain, S.M.; Nazish, N.; Joshi, N.; Sharma, A.; Parra- Saldívar, R.; Bilal, M.; Iqbal, H.M.N. Exploring Marine as a Rich Source of Bioactive Peptides: Challenges and Opportunities from Marine Pharmacology. Mar. Drugs 2022, 20, 208.
2. Biris-Dorhoi, E.-S.; Michiu, D.; Pop, C.R.; Rotar, A.M.; Tofana, M.; Pop, O.L.; Socaci, S.A.; Farcas, A.C. Macroalgae-A Sustainable Source of Chemical Compounds with Biological Activities. Nutrients 2020, 12, 3085.
3. Prasedya, E.S.; Fitriani, F.; Saraswati, P.B.A.; Haqiqi, N.; Qoriasmadillah, W.; Hikmaturrohmi, H.; Nurhidayati, S.Z.; Ariati, P.E.P. Evaluation of Bioprospecting Potential of Epiphytic Gracilaria Edulis Harvested from Seaweed Farm in Seriwe Bay, Lombok, Indonesia. Biodiversitas 2023, 24, doi:10.13057/biodiv/d241016.
4. Lopes, J.; Rodrigues, C.M.P.; Gaspar, M.M.; Reis, C.P. Melanoma Management: From Epidemiology to Treatment and Latest Advances. Cancers (Basel) 2022, 14, 4652.
5. Fenton, S.E.; Sosman, J.A.; Chandra, S. Resistance Mechanisms in Melanoma to Immuneoncologic Therapy with Checkpoint Inhibitors. Canc. Drug Resist. 2019, 2, 744–761.
6. Helmbach, H.; Rossmann, E.; Kern, M.A.; Schadendorf, D. Drug-Resistance in Human Melanoma. Int. J. Cancer 2001, 93, 617–622.
7. Czarnecka, A.M.; Bartnik, E.; Fiedorowicz, M.; Rutkowski, P. Targeted Therapy in Melanoma and Mechanisms of Resistance. Int. J. Mol. Sci. 2020, 21, 4576.
8. Palmieri, G.; Ombra, M.; Colombino, M.; Casula, M.; Sini, M.; Manca, A.; Paliogiannis, P.; Ascierto, P.A.; Cossu, A. Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets. Front. Oncol. 2015, 5, 183.
9. Imani, S.; Roozitalab, G.; Emadi, M.; Moradi, A.; Behzadi, P.; Jabbarzadeh Kaboli, P. The Evolution of BRAF-Targeted Therapies in Melanoma: Overcoming Hurdles and Unleashing Novel Strategies. Front. Oncol. 2024, 14, 1504142.
10. Taslim, N.A.; Hardinsyah, H.; Radu, S.; Mayulu, N.; Tsopmo, A.; Kurniawan, R.; Tallei, T.E.; Herlina, T.; Maksum, I.P.; Nurkolis, F. Functional Food Candidate from Indonesian Green Algae Caulerpa Racemosa (Försskal) J. Agardh by Two Extraction Methods: Metabolite Profile, Antioxidant Activity, and Cytotoxic Properties. J. Agric. Food Res. 2024, 18, 101513.
11. Druzhilovskiy, D.S.; Rudik, A.V.; Filimonov, D.A.; Gloriozova, T.A.; Lagunin, A.A.; Dmitriev, A.V.; Pogodin, P.V.; Dubovskaya, V.I.; Ivanov, S.M.; Tarasova, O.A.; et al. Computational
Platform Way2Drug: From the Prediction of Biological Activity to Drug Repurposing. Russ. Chem. Bull. 2017, 66, 1832–1841.
12. Mahmud, S.; Mita, M.A.; Biswas, S.; Paul, G.K.; Promi, M.M.; Afrose, S.; Hasan, R.; Shimu, S.S.; Zaman, S.; Uddin, S.; et al. Molecular Docking and Dynamics Study to Explore Phytochemical Ligand Molecules against the Main Protease of SARS-CoV-2 from Extensive Phytochemical Datasets. Expert Rev. Clin. Pharmacol. 2021, 14, 1305–1315.
13. Banerjee, P.; Eckert, A.O.; Schrey, A.K.; Preissner, R. ProTox-II: A Webserver for the Prediction of Toxicity of Chemicals. Nucleic Acids Res. 2018, 46, W257–W263.
14. Szklarczyk, D.; Kirsch, R.; Koutrouli, M.; Nastou, K.; Mehryary, F.; Hachilif, R.; Gable, A.L.; Fang, T.; Doncheva, N.T.; Pyysalo, S.; et al. The STRING Database in 2023: Protein–Protein Association Networks and Functional Enrichment Analyses for Any Sequenced Genome of Interest. Nucleic Acids Res. 2023, 51, D638–D646.
15. Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; et al. PubChem in 2021: New Data Content and Improved Web Interfaces. Nucleic Acids Res. 2021, 49, D1388–D1395.
16. Nurkolis, F.; Taslim, N.A.; Qhabibi, F.R.; Kang, S.; Moon, M.; Choi, J.; Choi, M.; Park, M.N.; Mayulu, N.; Kim, B. Ulvophyte Green Algae Caulerpa Lentillifera: Metabolites Profile and Antioxidant, Anticancer, Anti-Obesity, and in Vitro Cytotoxicity Properties. Molecules 2023, 28, doi:10.3390/molecules28031365.
17. Kurniawan, R.; Nurkolis, F.; Taslim, N.A.; Subali, D.; Surya, R.; Gunawan, W.B.; Alisaputra, D.; Mayulu, N.; Salindeho, N.; Kim, B. Carotenoids Composition of Green Algae Caulerpa Racemosa and Their Antidiabetic, Anti-Obesity, Antioxidant, and Anti-Inflammatory Properties. Molecules 2023, 28, doi:10.3390/molecules28073267.
18. Pappalardo, F.; Russo, G.; Candido, S.; Pennisi, M.; Cavalieri, S.; Motta, S.; McCubrey, J.A.; Nicoletti, F.; Libra, M. Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer. PLoS One 2016, 11, e0152104.
19. Pradhan, B.; Nayak, R.; Patra, S.; Jit, B.P.; Ragusa, A.; Jena, M. Bioactive Metabolites from Marine Algae as Potent Pharmacophores against Oxidative Stress-Associated Human Diseases: A Comprehensive Review. Molecules 2020, 26, 37.
20. Yao, W.; Qiu, H.-M.; Cheong, K.-L.; Zhong, S. Advances in Anti-Cancer Effects and Underlying Mechanisms of Marine Algae Polysaccharides. Int. J. Biol. Macromol. 2022, 221, 472–485.
21. Ferdous, U.T.; Yusof, Z.N.B. Medicinal Prospects of Antioxidants from Algal Sources in Cancer Therapy. Front. Pharmacol. 2021, 12, 593116.
22. Chendriadi, V. R., & Sandhika, W. (2024). Exploiting BRAF Mutation for Treatment of Malignant Melanoma: A Literature Review. International Journal of Research and Review, 10(12), 845– 853. https://doi.org/10.52403/ijrr.20231285
23. Gaughan, E. M., & Horton, B. J. (2022). Outcomes From Cytotoxic Chemotherapy Following Progression on Immunotherapy in Metastatic Melanoma: An Institutional Case-Series. Frontiers in Oncology, 12. https://doi.org/10.3389/fonc.2022.855782
24. Rosemary, T., Arulkumar, A., Paramasivam, S., Mondragon-Portocarrero, A., & Miranda, J. (2019). Biochemical, Micronutrient and Physicochemical Properties of the Dried Red Seaweeds Gracilaria edulis and Gracilaria corticata. Molecules, 24(12), 2225.
https://doi.org/10.3390/molecules24122225
25. Teixido, C., Castillo, P., Martinez-Vila, C., Arance, A., & Alos, L. (2021). Molecular markers and targets in melanoma. In Cells (Vol. 10, Issue 9). MDPI. https://doi.org/10.3390/cells10092320
26. Arnold, M., Singh, D., Laversanne, M., Vignat, J., Vaccarella, S., Meheus, F., Cust, A. E., de Vries, E., Whiteman, D. C., & Bray, F. (2022). Global Burden of Cutaneous Melanoma in 2020 and Projections to 2040. JAMA Dermatology, 158(5), 495.
https://doi.org/10.1001/jamadermatol.2022.0160
27. Hsu, P.-L., Jou, J., & Tsai, S.-J. (2019). TYRO3: A potential therapeutic target in cancer. Experimental Biology and Medicine, 244(2), 83–99. https://doi.org/10.1177/1535370219828195
28. Baliyan, S., Mukherjee, R., Priyadarshini, A., Vibhuti, A., Gupta, A., Pandey, R. P., & Chang, C.
M. (2022). Determination of Antioxidants by DPPH Radical Scavenging Activity and Quantitative Phytochemical Analysis of Ficus religiosa. Molecules, 27(4). https://doi.org/10.3390/molecules27041326
29. Ghasemi, M., Turnbull, T., Sebastian, S., & Kempson, I. (2021). The MTT Assay: Utility, Limitations, Pitfalls, and Interpretation in Bulk and Single-Cell Analysis. International Journal of Molecular Sciences, 22(23), 12827. https://doi.org/10.3390/ijms222312827
30. Agu, P.C., Afiukwa, C.A., Orji, O.U. et al. Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Sci Rep 13, 13398 (2023). https://doi.org/10.1038/s41598-023-40160-2
31. Gurning K, Suratno S, Astuti E, Haryadi W. Untargeted LC/HRMS Metabolomics Analysis and Anticancer Activity Assay on MCF-7 and A549 Cells from Coleus amboinicus Lour Leaf
Extract. Iran J Pharm Res. 2024 Apr 20;23(1):e143494. doi: 10.5812/ijpr-143494. PMID: 39108647; PMCID: PMC11302430.
32. Niu, W. H., Wu, F., Cao, W. Y., Wu, Z. G., Chao, Y. C., Liang, C., et al. (2021). Network pharmacology for the identification of phytochemicals in traditional Chinese medicine for COVID-19 that may regulate interleukin-6. Biosci. Rep. 41, BSR20202583. doi:10.1042/BSR20202583
33. Gao, X., Li, S., Cong, C., Wang, Y., and Xu, L. (2021). A network pharmacology approach to estimate potential targets of the active ingredients of epimedium for alleviating mild cognitive impairment and treating alzheimer's disease. Evid. Based. Complement. Altern. Med. 2021, 2302680. doi:10.1155/2021/2302680.
34. Schreiber R.D., Old L.J., Smyth M.J. Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion. Science. 2011;331:1565–1570. doi: 10.1126/science.1203486.
35. Gurzu S., Beleaua M.A., Jung I. The Role of Tumor Microenvironment in Development and Progression of Malignant Melanomas—A Systematic Review. Rom. J. Morphol. Embryol. 2018;59:23–28.
36. .Khair D.O., Bax H.J., Mele S., Crescioli S., Pellizzari G., Khiabany A., Nakamura M., Harris R.J., French E., Hoffmann R.M., et al. Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma. Front. Immunol. 2019;10:453. doi: 10.3389/fimmu.2019.00453.
37. .Larkin J., Chiarion-Sileni V., Gonzalez R., Grob J.-J., Rutkowski P., Lao C.D., Cowey C.L., Schadendorf D., Wagstaff J., Dummer R., et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 2019;381:1535–1546. doi: 10.1056/NEJMoa1910836.
38. Agrawal, K.K., Yadav, A., Kumar, S. et al. In silico assessment of antioxidant activity and toxicity profiling of bioactive molecules from Murraya koenigii. Discov Appl Sci 6, 523 (2024). https://doi.org/10.1007/s42452-024-06232-2
39. Udensi, U.K.; Tchounwou, P.B. Dual effect of oxidative stress on leukemia cancer induction and treatment. J. Exp. Clin. Cancer Res. 2014, 33, 106.
40. Arany, I.; Hall, S.; Reed, D.K.; Dixit, M. The pro-oxidant gene p66shc increases nicotine exposure-induced lipotoxic oxidative stress in renal proximal tubule cells. Mol. Med. Rep. 2016, 14, 2771–2777. Available online: https://www.spandidos-
publications.com/mmr/14/3/2771 (accessed on 30 April 2025)
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