Anticancer Activity, Radiolabelling, Cellular Uptake, and Computational Analysis of [131I]-4-methoxyresorcinol and [131I]-kaempferol 7-O-rutinoside
Keywords:
Melia azedarach L., anticancer, radioiodination, cellular uptake, computational analysis
Abstract
We evaluated the anticancer activity of two flavonoids isolated from Melia azedarach L. leaves, namely 4-methoxyresorcinol and kaempferol 7-O-rutinoside. 4-methoxyresorcinol and kaempferol 7-O-rutinoside displayed moderate anticancer activity against MCF-7, MDA-MB-231, and LNCaP cell lines with IC50 values ranging from 92 to 275 µg/mL. Kaempferol 7-O-rutinoside showed the highest anticancer activity against LNCaP cells with IC50 value of 92 µg/mL, which has also been in line with the computational studies. To assess the feasibility of these compounds as natural product-based radiopharmaceuticals for diagnosing and treating cancers, we then performed radioiodination with iodine-131. The radiolabelling was accomplished using chloramine-T as oxidising agent under acidic conditions in DMSO/H2O at room temperature for 30 min to produced new [131I]-4-methoxyresorcinol and [131I]-kaempferol 7-O-rutinoside. Radio-thin layer chromatography analysis revealed the radiochemical purity of above 95% was obtained for both compounds. Furthermore, the radioiodinated compounds were subjected into a cellular uptake study. The results demonstrated that the highest cellular accumulation of [131I]-4-methoxyresorcinol was observed in MCF-7 (3.17 ± 0.11%) after 24 h of incubation, approximately 20-folds greater than the uptake of control group (iodine-131). On the other hand, [131I]-kaempferol 7-O-rutinoside showed the highest uptake in MCF-7 (3.05 ± 0.9%) after 1 h of incubation, around 23-folds higher than iodine-131 uptake. Taken together, the present study suggests the potential use of both 4-methoxyresorcinol and kaempferol 7-O-rutinoside as anticancer drugs, which can be further developed as new radiopharmaceutical candidates.
References
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Nugrahaa, A. S., & Keller, P. A. (2011). Revealing Indigenous Indonesian Traditional Medicine: Anti-infective Agents. Natural Product Communications, 6, 1956-1966.
Panche, A. N., Diwan, A. D., & Chandra, S. R. (2016). Flavonoids: an overview. Journal of Nutritional Science, 5, e47. doi:10.1017/jns.2016.41
Petrov, S. A., Yusubov, M. S., Beloglazkina, E. K., & Nenajdenko, V. G. (2022). Synthesis of Radioiodinated Compounds. Classical Approaches and Achievements of Recent Years. International Journal of Molecular Sciences, 23(13789), 1-41. doi:10.3390/genes1030413
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Tungmunnithum, D., Thongboonyou, A., Pholboon, A., & Yangsabai, A. (2018). Flavonoids and Other Phenolic Compounds from Medicinal Plants for Pharmaceutical and Medical Aspects: An Overview. Medicines (Basel), 5(3). doi:10.3390/medicines5030093
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Wang, X., Yang, Y., An, Y., & Fang, G. (2019). The mechanism of anticancer action and potential clinical use of kaempferol in the treatment of breast cancer. Biomedicine & Pharmacotherapy, 117, 109086. doi:10.1016/j.biopha.2019.109086
Wang, X., Zhu, J., Yan, H., Shi, M., Zheng, Q., Wang, Y., Zhu, Y., Miao, L., & Gao, X. (2021). Kaempferol inhibits benign prostatic hyperplasia by resisting the action of androgen. European Journal of Pharmacology, 907, 174251. doi:10.1016/j.ejphar.2021.174251
Wongso, H. (2022). Natural product-based radiopharmaceuticals: Focus on curcumin and its analogs, flavonoids, and marine peptides. Journal of Pharmaceutical Analysis, 12(3), 380-393. doi:10.1016/j.jpha.2021.07.006
Wongso, H., Nuraeni, W., & Rosyidiah, E. (2022). Efficient and Practical Radiosynthesis of Novel [131I]-Xanthine and [131I]-Hypoxanthine. Atom Indonesia, 48(3), 185. doi:10.17146/aij.2022.1233
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Yang, Q., Fung, K. M., Day, W. V., Kropp, B. P., & Lin, H. K. (2005). Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival. Cancer Cell International, 5(1), 8. doi:10.1186/1475-2867-5-8
Bohl, C. E., Miller, D. D., Chen, J., Bell, C. E., & Dalton, J. T. (2005). Structural basis for accommodation of nonsteroidal ligands in the androgen receptor. Journal of Biological Chemistry, 280(45), 37747-37754. doi:10.1074/jbc.M507464200
Cardinale, J., Roscher, M., Schafer, M., Geerlings, M., Benesova, M., Bauder-Wust, U., Remde, Y., Eder, M., Novakova, Z., Motlova, L., Barinka, C., Giesel, F. L., & Kopka, K. (2020). Development of PSMA-1007-Related Series of (18)F-Labeled Glu-Ureido-Type PSMA Inhibitors. Journal of Medicinal Chemistry, 63(19), 10897-10907. doi:10.1021/acs.jmedchem.9b01479
Crocetto, F., di Zazzo, E., Buonerba, C., Aveta, A., Pandolfo, S. D., Barone, B., Trama, F., Caputo, V. F., Scafuri, L., Ferro, M., Cosimato, V., Fusco, F., Imbimbo, C., & Di Lorenzo, G. (2021). Kaempferol, Myricetin and Fisetin in Prostate and Bladder Cancer: A Systematic Review of the Literature. Nutrients, 13(11). doi:10.3390/nu13113750
D.A. Case, K. Belfon, I.Y. Ben-Shalom, S.R. Brozell, D.S. Cerutti, T.E. Cheatham, V.W.D. Cruzeiro, T.A. Darden, R.E. Duke, G. Giambasu, M.K. Gilson, H. Gohlke, A.W. Goetz, R. Harris, S. Izadi, S.A. Izmailov, K. Kasavajhala, A. Kovalenko, R. Krasny, T. Kurtzman, T.S. Lee, S. LeGrand, P. Li, C. Lin, J. Liu, T. Luchko, R. Luo, V. Man, K.M. Merz, Y. Miao, O. Mikhailovskii, G. Monard, H. Nguyen, A. Onufriev, F. Pan, S. Pantano, R. Qi, D.R. Roe, A. Roitberg, C. Sagui, S. Schott-Verdugo, J. Shen, C.L. Simmerling, N.R. Skrynnikov, J. Smith, J. Swails, R.C. Walker, J. Wang, L. Wilson, R.M. Wolf, X. Wu, Y. Xiong, Y. Xue, D.M. York, & Kollman, P. A. (2020). AMBER 2020, University of California, San Francisco.
Damasuri, A. R., Sholikhah, E. N., & Mustofa. (2020). Cytotoxicity of ((E)-1-(4-aminophenyl)-3-phenylprop-2-en-1-one)) on HeLa cell line. Indonesian Journal of Pharmacology and Therapy, 1(2). doi:10.22146/ijpther.606
Debela, D. T., Muzazu, S. G., Heraro, K. D., Ndalama, M. T., Mesele, B. W., Haile, D. C., Kitui, S. K., & Manyazewal, T. (2021). New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Medicine, 9, 20503121211034366. doi:10.1177/20503121211034366
Hanif, N., Murni, A., Tanaka, C., & Tanaka, J. (2019). Marine Natural Products from Indonesian Waters. Marine Drugs, 17(6). doi:10.3390/md17060364
J. Zhao, L. Xu, J. Sun, M. Song, L. Wang, S. Yuan, Y. Zhu, Z. Wan, S. Larsson, K. Tsilidis, M. Dunlop, H. Campbell, I. Rudan, P. Song, E. Theodoratou, K. Ding, & X. Li. (2023). Global trends in incidence, death, burden and risk factors of early- onset cancer from 1990 to 2019. BMJ Oncology, 2, e000049. doi:10.1136/
Menez, R., Michel, S., Muller, B. H., Bossus, M., Ducancel, F., Jolivet-Reynaud, C., & Stura, E. A. (2008). Crystal structure of a ternary complex between human prostate-specific antigen, its substrate acyl intermediate and an activating antibody. Journal of Molecular Biology, 376(4), 1021-1033. doi:10.1016/j.jmb.2007.11.052
Mosmann, T. (1983). Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays. Journal of lmmunological Methods, 65, 55-63.
Nasim, N., Sandeep, I. S., & Mohanty, S. (2022). Plant-derived natural products for drug discovery: current approaches and prospects. Nucleus (Calcutta), 65(3), 399-411. doi:10.1007/s13237-022-00405-3
Niu, Y., Yeh, S., Miyamoto, H., Li, G., Altuwaijri, S., Yuan, J., Han, R., Ma, T., Kuo, H. C., & Chang, C. (2008). Tissue prostate-specific antigen facilitates refractory prostate tumor progression via enhancing ARA70-regulated androgen receptor transactivation. Cancer Research, 68(17), 7110-7119. doi:10.1158/0008-5472.CAN-07-6507
Nugraha, A. S., Firli, L. N., Hendra, R., Keller, P. A., Purwoko, R. Y., Idrus, H. H., Ritawidya, R., Febrian, M. B., Mahendra, I., Kurniawan, A., Forentin, A. M., Susilo, V. Y., Kusumaningrum, C. E., Setiadi, Y., & Wongso, H. (2023). Anticancer activity of Indonesian Melia azedarach L.: Phyto-chemistry, in vitro and in silico studies. Journal of Biologically Active Products from Nature, 13(1), 12-26. doi:10.1080/22311866.2023.2172079
Nugrahaa, A. S., & Keller, P. A. (2011). Revealing Indigenous Indonesian Traditional Medicine: Anti-infective Agents. Natural Product Communications, 6, 1956-1966.
Panche, A. N., Diwan, A. D., & Chandra, S. R. (2016). Flavonoids: an overview. Journal of Nutritional Science, 5, e47. doi:10.1017/jns.2016.41
Petrov, S. A., Yusubov, M. S., Beloglazkina, E. K., & Nenajdenko, V. G. (2022). Synthesis of Radioiodinated Compounds. Classical Approaches and Achievements of Recent Years. International Journal of Molecular Sciences, 23(13789), 1-41. doi:10.3390/genes1030413
Rizvi, S. A. A., Einstein, G. P., Tulp, O. L., Sainvil, F., & Branly, R. (2022). Introduction to Traditional Medicine and Their Role in Prevention and Treatment of Emerging and Re-Emerging Diseases. Biomolecules, 12(10). doi:10.3390/biom12101442
Shahbaz, M., Imran, M., Alsagaby, S. A., Naeem, H., Al Abdulmonem, W., Hussain, M., Abdelgawad, M. A., El-Ghorab, A. H., Ghoneim, M. M., El-Sherbiny, M., Atoki, A. V., & Awuchi, C. G. (2023). Anticancer, antioxidant, ameliorative and therapeutic properties of kaempferol. International Journal of Food Properties, 26(1), 1140-1166. doi:10.1080/10942912.2023.2205040
Trott, O., & Olson, A. J. (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), 455-461. doi:10.1002/jcc.21334
Tungmunnithum, D., Thongboonyou, A., Pholboon, A., & Yangsabai, A. (2018). Flavonoids and Other Phenolic Compounds from Medicinal Plants for Pharmaceutical and Medical Aspects: An Overview. Medicines (Basel), 5(3). doi:10.3390/medicines5030093
Ullah, A., Munir, S., Badshah, S. L., Khan, N., Ghani, L., Poulson, B. G., Emwas, A. H., & Jaremko, M. (2020). Important Flavonoids and Their Role as a Therapeutic Agent. Molecules, 25(22). doi:10.3390/molecules25225243
Wang, X., Yang, Y., An, Y., & Fang, G. (2019). The mechanism of anticancer action and potential clinical use of kaempferol in the treatment of breast cancer. Biomedicine & Pharmacotherapy, 117, 109086. doi:10.1016/j.biopha.2019.109086
Wang, X., Zhu, J., Yan, H., Shi, M., Zheng, Q., Wang, Y., Zhu, Y., Miao, L., & Gao, X. (2021). Kaempferol inhibits benign prostatic hyperplasia by resisting the action of androgen. European Journal of Pharmacology, 907, 174251. doi:10.1016/j.ejphar.2021.174251
Wongso, H. (2022). Natural product-based radiopharmaceuticals: Focus on curcumin and its analogs, flavonoids, and marine peptides. Journal of Pharmaceutical Analysis, 12(3), 380-393. doi:10.1016/j.jpha.2021.07.006
Wongso, H., Nuraeni, W., & Rosyidiah, E. (2022). Efficient and Practical Radiosynthesis of Novel [131I]-Xanthine and [131I]-Hypoxanthine. Atom Indonesia, 48(3), 185. doi:10.17146/aij.2022.1233
Xiong, G., Wu, Z., Yi, J., Fu, L., Yang, Z., Hsieh, C., Yin, M., Zeng, X., Wu, C., Lu, A., Chen, X., Hou, T., & Cao, D. (2021). ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Research, 49(W1), W5-W14. doi:10.1093/nar/gkab255
Yang, Q., Fung, K. M., Day, W. V., Kropp, B. P., & Lin, H. K. (2005). Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival. Cancer Cell International, 5(1), 8. doi:10.1186/1475-2867-5-8
Published
2025-04-30
How to Cite
Wongso, H., Rochmantika , P., Forentin, A. M., Susilo , V. Y., Febrian , M. B., Mahendra , I., Kurniawan , A., Kusumaningrum, C. E., Rizaludin , A., Setiadi, Y., & Nugraha , A. S. (2025). Anticancer Activity, Radiolabelling, Cellular Uptake, and Computational Analysis of [131I]-4-methoxyresorcinol and [131I]-kaempferol 7-O-rutinoside. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.10877
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Research Article
