In Vitro Evaluation of 4-Methoxyresorcinol and Kaempferol 7-ORutinoside and Their Radioiodinated Derivatives in MCF-7, MDA-MB-231, and LNCaP Cell Lines
Keywords:
Melia azedarach L., anticancer, radioiodination, cellular uptake, computational analysis
Abstract
The global population is currently experiencing high rates of mortality due to the growing burden of cancer. Efforts on the development of new potent anticancer agents are necessary. Therefore, this study aimed to evaluate the anticancer activity of two flavonoids, including 4-methoxyresorcinol (MRC) and kaempferol 7-O-rutinoside (K7R), isolated from Melia azedarach L. leaves. Anticancer activity was evaluated in vitro against MCF-7, MDA-MB-231, and LNCaP cell lines. Radioiodination was performed with iodine-131 as well as computational studies to assess the feasibility of the isolated compounds as natural product-based radiopharmaceuticals for diagnosing and managing cancer. The results showed that MRC and K7R had moderate anticancer activity against MCF-7, MDA-MB-231, and LNCaP cell lines with IC50 values ranging from 154.75 to 1962.66 µM. Cellular uptake investigations found that the highest cellular accumulation of [131I]-4-methoxyresorcinol (MRCI) was observed in MCF-7 (3.17 ± 0.11%) after 24 hours of incubation, approximately 20-fold greater than the control group uptake (iodine-131). Meanwhile, [131I]-kaempferol 7-O-rutinoside (K7RI) showed the highest uptake in MCF-7 (3.05 ± 0.9%) post-one hour of incubation, which was around 23-folds higher than iodine-131 uptake. In conclusion, both MRC and K7R were identified as potential anticancer drugs, which could be further developed into 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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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
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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
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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
2025-12-08
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). In Vitro Evaluation of 4-Methoxyresorcinol and Kaempferol 7-ORutinoside and Their Radioiodinated Derivatives in MCF-7, MDA-MB-231, and LNCaP Cell Lines. Indonesian Journal of Pharmacy, 36(4), 777-787. https://doi.org/10.22146/ijp.10877
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Research Article
