Journal of Multidisciplinary Applied Natural Science
Open Access Journal
Scopus CiteScore 2024
4.8
Calculated on 05 May, 2025
SJR 2024
0.31
Powered by scimagojr.com
Open Access Journal
4.8
Calculated on 05 May, 2025
0.31
Powered by scimagojr.com
https://doi.org/10.47352/jmans.2774-3047.165
Yehezkiel Steven Kurniawan
Nela Fatmasari
Jumina Jumina
Harno Dwi Pranowo
Eti Nurwening Sholikhah
Nowadays, cancer is one of the most fatal diseases in developed and developing countries. Therefore, it is an urgent need to find more effective anticancer drugs among the recent commercially available standard drugs. Xanthone derivatives have been researched as anticancer drugs due to their ease of synthesis and structure modification, as well as their excellent anticancer activity. In this work, the in vitro anticancer activity of hydroxyxanthones against the human liver carcinoma cell line (HepG2) was evaluated. Among the twenty-two hydroxyxanthones, 1,3,6,8-tetrahydroxyxanthone was found as the most active anticancer agent with an IC50 value of 9.18 μM, which was better than doxorubicin as the standard drug. From the molecular docking studies against topoisomeraseIIα and two c-KIT protein kinases, 1,3,6,8-tetrahydroxyxanthone yielded strong binding energy in a range of -25.48 to -30.42 kJ/mol. The 1,3,6,8-tetrahydroxyxanthone could bind on the active site of these protein receptors through hydrogen bonds with key amino acid residues (Glu640, Cys673, Gln767, Met769, Asp810, and Asp831), as well as nitrogen bases (Adenine12 and Guanine13), thus leading to the death of HepG2 cancer cells through the apoptosis mechanism.
[1] R. L. Siegel, K. D. Miller, H. E. Fuchs, and A. Jemal. (2022). "Cancer statistics". CA: A Cancer Journal for Clinicians. 72 (1): 7-33. 10.3322/caac.21708.
DOI: https://doi.org/10.3322/caac.21708[2] H. Rumgay, M. Arnold, J. Ferlay, O. Lesi, C. J. Cabasag, J. Vignat, M. Laversanne, K. A. McGlynn, and I. Soerjomataram. (2022). "Global burden of primary liver cancer in 2020 and predictions to 2040". Journal of Hepatology. 77 (6): 1598-1606. 10.1016/j.jhep.2022.08.021.
DOI: https://doi.org/10.1016/j.jhep.2022.08.021[3] C. Christowitz, T. Davis, A. Isaacs, G. van Niekerk, S. Hattingh, and A. M. Engelbrecht. (2019). "Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model". BMC Cancer. 19 (1): 757. 10.1186/s12885-019-5939-z.
DOI: https://doi.org/10.1186/s12885-019-5939-z[4] B. Guiu and E. Assenat. (2020). "Doxorubicin for the treatment of hepatocellular carcinoma: GAME OVER!". Annals of Translational Medicine. 8 (24): 1693. 10.21037/atm-2020-131.
DOI: https://doi.org/10.21037/atm-2020-131[5] J. Cox and S. Weinman. (2016). "Mechanisms of doxorubicin resistance in hepatocellular carcinoma". Hepatic Oncology. 3 (1): 57-59. 10.2217/hep.15.41.
DOI: https://doi.org/10.2217/hep.15.41[6] E. Y. Chen, V. Raghunathan, and V. Prasad. (2019). "An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate". JAMA Internal Medicine. 179 (7): 915-921. 10.1001/jamainternmed.2019.0583.
DOI: https://doi.org/10.1001/jamainternmed.2019.0583[7] C. Moreau Bachelard, E. Coquan, P. du Rusquec, X. Paoletti, and C. Le Tourneau. (2021). "Risks and benefits of anticancer drugs in advanced cancer patients: A systematic review and meta-analysis". eClinicalMedicine. 40101130. 10.1016/j.eclinm.2021.101130.
DOI: https://doi.org/10.1016/j.eclinm.2021.101130[8] Y. S. Kurniawan, K. T. A. Priyangga, Jumina, H. D. Pranowo, E. N. Sholikhah, A. K. Zulkarnain, H. A. Fatimi, and J. Julianus. (2021). "An Update on the Anticancer Activity of Xanthone Derivatives: A Review". Pharmaceuticals. 14 (11): 1144. 10.3390/ph14111144.
DOI: https://doi.org/10.3390/ph14111144[9] X. Zhang, X. Li, H. Sun, X. Wang, L. Zhao, Y. Gao, X. Liu, S. Zhang, Y. Wang, Y. Yang, S. Zeng, Q. Guo, and Q. You. (2013). "Garcinia xanthones as orally active antitumor agents". Journal of Medicinal Chemistry. 56 (1): 276-92. 10.1021/jm301593r.
DOI: https://doi.org/10.1021/jm301593r[10] V. Kuete, L. P. Sandjo, J. L. Ouete, H. Fouotsa, B. Wiench, and T. Efferth. (2014). "Cytotoxicity and modes of action of three naturally occurring xanthones (8-hydroxycudraxanthone G, morusignin I and cudraxanthone I) against sensitive and multidrug-resistant cancer cell lines". Phytomedicine. 21 (3): 315-22. 10.1016/j.phymed.2013.08.018.
DOI: https://doi.org/10.1016/j.phymed.2013.08.018[11] P. Wang, J. Xu, Z. Hou, F. Wang, Y. Song, J. Wang, H. Zhu, and H. Jin. (2016). "miRNA-34a promotes proliferation of human pulmonary artery smooth muscle cells by targeting PDGFRA". Cell Proliferation 49 (4): 484-93. 10.1111/cpr.12265.
DOI: https://doi.org/10.1111/cpr.12265[12] H. Harliansyah, N. A. Rahmah, and K. Kuslestari. (2021). "α-Mangosteen as An Oxidative Inhibitor in Hepatocellular Carcinoma". Indonesian Journal of Cancer Chemoprevention. 12 (2): 106-113. 10.14499/indonesianjcanchemoprev12iss2pp106-113.
DOI: https://doi.org/10.14499/indonesianjcanchemoprev12iss2pp106-113[13] M. M. M. Pinto, A. Palmeira, C. Fernandes, D. Resende, E. Sousa, H. Cidade, M. E. Tiritan, M. Correia-da-Silva, and S. Cravo. (2021). "From Natural Products to New Synthetic Small Molecules: A Journey through the World of Xanthones". Molecules. 26 (2): 431. 10.3390/molecules26020431.
DOI: https://doi.org/10.3390/molecules26020431[14] I. Miladiyah, I. Tahir, J. Jumina, S. Mubarika, and M. Mustofa. (2016). "Quantitative Structure-Activity Relationship Analysis of Xanthone Derivates as Cytotoxic Agents in Liver Cancer Cell Line HepG2". Molekul. 11(1): 143-157. 10.20884/1.jm.2016.11.1.203.
DOI: https://doi.org/10.20884/1.jm.2016.11.1.203[15] E. Yuanita, H. D. Pranowo, J. Jumina, and M. Mustofa. (2016). "Design of Hydroxyxanthone Derivatives as Anticancer Using Quantitative Structure-Activity Relationship”". Asian Journal of Pharmaceutical and Clinical Research. 9 : 180-185.
[16] E. Yuanita, H. D. Pranowo, D. Siswanta, R. T. Swasono, M. Mustofa, A. K. Zulkarnain, J. Syahri, and J. Jumina. (2016). "One-pot Synthesis, Antioxidant Activity and Toxicity Evaluation of Som e Hydroxyxanthones”". Chemistry & Chemical Technology. 12 : 290-295. 10.23939/chct12.03.290.
[17] I. Miladiyah, J. Jumina, S. M. Haryana, and M. Mustofa. (2018). "Biological activity, quantitative structure-activity relationship analysis, and molecular docking of xanthone derivatives as anticancer drugs". Drug Design, Development and Therapy. 12 : 149-158. 10.2147/DDDT.S149973.
DOI: https://doi.org/10.2147/DDDT.S149973[18] E. Yuanita, H. D. Pranowo, M. Mustofa, R. T. Swasono, J. Syahri, and J. Jumina. (2019). "Synthesis, Characterization and Molecular Docking of Chloro-substituted Hydroxyxanthone Derivatives". Chemistry Journal of Moldova. 14 (1): 68-76. 10.19261/cjm.2018.520.
DOI: https://doi.org/10.19261/cjm.2018.520[19] N. Fatmasari, Y. S. Kurniawan, J. Jumina, C. Anwar, Y. Priastomo, H. D. Pranowo, A. K. Zulkarnain, and E. N. Sholikhah. (2022). "Synthesis and in vitro assay of hydroxyxanthones as antioxidant and anticancer agents". Scientific Reports. 12 (1): 1535. 10.1038/s41598-022-05573-5.
DOI: https://doi.org/10.1038/s41598-022-05573-5[20] M. R. Iresha, J. Jumina, H. D. Pranowo, E. N. Sholikhah, and F. Hermawan. (2022). "Synthesis, Cytotoxicity Evaluation and Molecular Docking Studies of Xanthyl-Cinnamate Derivatives as Potential Anticancer Agents". Indonesian Journal of Chemistry. 22 (5): 1407-1417. 10.22146/ijc.76164.
DOI: https://doi.org/10.22146/ijc.76164[21] Q. G. Su, Y. Liu, Y. C. Cai, Y. L. Sun, B. Wang, and L. J. Xian. (2011). "Anti-tumour effects of xanthone derivatives and the possible mechanisms of action". Investigational New Drugs. 29 (6): 1230-40. 10.1007/s10637-010-9468-5.
DOI: https://doi.org/10.1007/s10637-010-9468-5[22] J. Liu, J. Zhang, H. Wang, Z. Liu, C. Zhang, Z. Jiang, and H. Chen. (2017). "Synthesis of xanthone derivatives and studies on the inhibition against cancer cells growth and synergistic combinations of them". European Journal of Medicinal Chemistry. 133 50-61. 10.1016/j.ejmech.2017.03.068.
DOI: https://doi.org/10.1016/j.ejmech.2017.03.068[23] B. D. Zhou, Z. M. Weng, Y. G. Tong, Z. T. Ma, R. R. Wei, J. L. Li, Z. H. Yu, G. F. Xu, Y. Y. Fang, and Z. P. Ruan. (2021). "Syntheses of xanthone derivatives and their bioactivity investigation". Journal of Asian Natural Products Research. 23 (3): 271-283. 10.1080/10286020.2020.1739024.
DOI: https://doi.org/10.1080/10286020.2020.1739024[24] P. Chaniad, A. Chukaew, A. Payaka, A. Phuwajaroanpong, T. Techarang, W. Plirat, and C. Punsawad. (2022). "Antimalarial potential of compounds isolated from Mammea siamensis T. Anders. flowers: in vitro and molecular docking studies". BMC Complementary Medicine and Therapies. 22 (1): 266. 10.1186/s12906-022-03742-7.
DOI: https://doi.org/10.1186/s12906-022-03742-7[25] O. Trott and A. J. Olson. (2010). "AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading". Journal of Computational Chemistry. 31 (2): 455-61. 10.1002/jcc.21334.
DOI: https://doi.org/10.1002/jcc.21334[26] T. D. Wahyuningsih, A. A. T. Suma, and E. Astuti. (2019). "Synthesis, Anticancer Activity, and Docking Study of N-acetyl Pyrazoli nes from Veratraldehyde”". Journal of Applied Pharmaceutical Science. 9 (3): 14-20. 10.7324/JAPS.2019/90303.
DOI: https://doi.org/10.7324/JAPS.2019.90303[27] M. Ghasemi, T. Turnbull, S. Sebastian, and I. Kempson. (2021). "The MTT Assay: Utility, Limitations, Pitfalls, and Interpretation in Bulk and Single-Cell Analysis". International Journal of Molecular Sciences. 22 (23): 12827. 10.3390/ijms222312827.
DOI: https://doi.org/10.3390/ijms222312827[28] J. L. Nitiss. (2009). "Targeting DNA topoisomerase II in cancer chemotherapy". Nature Reviews Cancer. 9 (5): 338-50. 10.1038/nrc2607.
DOI: https://doi.org/10.1038/nrc2607[29] J. Stamos, M. X. Sliwkowski, and C. Eigenbrot. (2002). "Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor". Journal of Biological Chemistry. 277 (48): 46265-72. 10.1074/jbc.M207135200.
DOI: https://doi.org/10.1074/jbc.M207135200[30] K. Komposch and M. Sibilia. (2015). "EGFR Signaling in Liver Diseases". International Journal of Molecular Sciences. 17 (1): 30. 10.3390/ijms17010030.
DOI: https://doi.org/10.3390/ijms17010030[31] M. L. Uribe, I. Marrocco, and Y. Yarden. (2021). "EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance". Cancers. 13 (11): 2748. 10.3390/cancers13112748.
DOI: https://doi.org/10.3390/cancers13112748[32] A. Kikuchi and S. P. Monga. (2015). "PDGFRalpha in liver pathophysiology: emerging roles in development, regeneration, fibrosis, and cancer". Gene Expression The Journal of Liver Research. 16 (3): 109-27. 10.3727/105221615X14181438356210.
DOI: https://doi.org/10.3727/105221615X14181438356210[33] P. H. Chen, X. Chen, and X. He. (2013). "Platelet-Derived Growth Factors and Their Receptors: Structural and Fu nctional Perspectives”. Biochimica et Biophysica Acta – Proteins and P roteomics. 10.1016/j.bbapap.2012.10.015.
DOI: https://doi.org/10.1016/j.bbapap.2012.10.015[34] X. Zou, X. Y. Tang, Z. Y. Qu, Z. W. Sun, C. F. Ji, Y. J. Li, and S. D. Guo. (2022). "Targeting the PDGF/PDGFR signaling pathway for cancer therapy: A review". International Journal of Biological Macromolecules. 202 539-557. 10.1016/j.ijbiomac.2022.01.113.
DOI: https://doi.org/10.1016/j.ijbiomac.2022.01.113[35] S. Akkoc, S. C. Yavuz, M. Akkurt, and C. C. Ersanli. (2018). "Density Functional Theory Study of A Silver N-heterocyclic Carbene Com plex”". Journal of the Chinese Advanced Materials Society. 6 (2): 112-122. 10.1080/22243682.2018.142906.
DOI: https://doi.org/10.1080/22243682.2018.1425906[36] K. Lemke, M. Wojciechowski, W. Laine, C. Bailly, P. Colson, M. Baginski, A. K. Larsen, and A. Skladanowski. (2005). "Induction of unique structural changes in guanine-rich DNA regions by the triazoloacridone C-1305, a topoisomerase II inhibitor with antitumor activities". Nucleic Acids Research. 33 (18): 6034-47. 10.1093/nar/gki904.
DOI: https://doi.org/10.1093/nar/gki904[37] B. Tylinska, A. Dobosz, J. Spychala, L. Cwynar-Zajac, Z. Czyznikowska, A. Kuzniarski, and T. Gebarowski. (2021). "Evaluation of Interactions of Selected Olivacine Derivatives with DNA and Topoisomerase II". International Journal of Molecular Sciences. 22 (16): 8492. 10.3390/ijms22168492.
DOI: https://doi.org/10.3390/ijms22168492[38] K. Bukowski, M. Kciuk, and R. Kontek. (2020). "Mechanisms of Multidrug Resistance in Cancer Chemotherapy". International Journal of Molecular Sciences. 21 (9): 3233. 10.3390/ijms21093233.
DOI: https://doi.org/10.3390/ijms21093233[39] S. Dallavalle, V. Dobricic, L. Lazzarato, E. Gazzano, M. Machuqueiro, I. Pajeva, I. Tsakovska, N. Zidar, and R. Fruttero. (2020). "Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors". Drug Resistance Updates. 50 100682. 10.1016/j.drup.2020.100682.
DOI: https://doi.org/10.1016/j.drup.2020.100682[40] C. P. Wu, S. H. Hsiao, M. Murakami, Y. J. Lu, Y. Q. Li, Y. H. Huang, T. H. Hung, S. V. Ambudkar, and Y. S. Wu. (2017). "Alpha-Mangostin Reverses Multidrug Resistance by Attenuating the Function of the Multidrug Resistance-Linked ABCG2 Transporter". Molecular Pharmaceutics. 14 (8): 2805-2814. 10.1021/acs.molpharmaceut.7b00334.
DOI: https://doi.org/10.1021/acs.molpharmaceut.7b00334[41] A. D. F. Adli, R. Jahanban-Esfahlan, K. Seidi, S. Samandari-Rad, and N. Zarghami. (2018). "An overview on Vadimezan (DMXAA): The vascular disrupting agent". Chemical Biology & Drug Design. 91 (5): 996-1006. 10.1111/cbdd.13166.
DOI: https://doi.org/10.1111/cbdd.13166