Mangosteen Peel Extract (Garcinia mangostana L.) as a Potential Complementary of Leukemia Therapy: In Vitro and In Silico Studies

Marisca Evalina  Gondokesumo; Arina  Novilla; Sijani  Prahastuti; Fadhilah Haifa  Zahiroh; Hanna Sari Widya  Kusuma; Wahyu  Widowati; Rizal  Azis; Dhanar Septyawan  Hadiprasetyo; Aris Muhammad  Nurjamil; Wahyu  Surakusumah; Khoerotul Nur Fadhilah  Adha

doi:10.5614/j.math.fund.sci.2025.57.2.3

Authors

Marisca Evalina Gondokesumo Faculty of Pharmacy, University of Surabaya, Universitas Surabaya, Surabaya 60284, Indonesia
Arina Novilla Medical Laboratory Technology Study Program, Universitas Jenderal Achmad Yani, Cimahi 40531, Indonesia
Sijani Prahastuti Faculty of Medicine, Maranatha Christian University, Bandung 40164, Indonesia
Fadhilah Haifa Zahiroh Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung 40163, Indonesia
Hanna Sari Widya Kusuma Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung 40163, Indonesia
Wahyu Widowati Faculty of Medicine, Maranatha Christian University, Bandung 40164, Indonesia
Rizal Azis Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung 40163, Indonesia
Dhanar Septyawan Hadiprasetyo Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung 40163, Indonesia
Aris Muhammad Nurjamil Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung 40163, Indonesia
Wahyu Surakusumah Biology Study Program, Faculty of Mathematics and Science Education, Universitas Pendidikan Indonesia, Bandung 40154, Indonesia
Khoerotul Nur Fadhilah Adha Biology Study Program, Faculty of Mathematics and Science Education, Universitas Negeri Jakarta, Jakarta 13220, Indonesia

DOI:

https://doi.org/10.5614/j.math.fund.sci.2025.57.2.3

Keywords:

anticancer, cytotoxicity, Garcinia mangostana, HL-60 cell, leukemia

Abstract

Leukemia is caused by abnormal white blood cell proliferation that leads to disruption of conventional blood cell functions. Mangosteen (Garcinia mangostana L.) contains phytochemical compounds with strong anticancer properties, according to various cancer studies. This study investigated the potential of mangosteen peel extract (MPE) as an anti-leukemia agent through molecular docking of LC-MS-identified compounds against FLT-1 and AKT proteins, followed by in vitro evaluation on HL-60 cells, namely cytotoxic (WST-8 assay), ROS levels and senescence (flow cytometry), and then FLT1 and AKT gene expression (qRT-PCR). LC-MS identified ?-mangostin, ?-mangostin, ?-mangostin, mangostinone, and epicatechin as the main compounds. Molecular docking revealed strong binding affinities from ?8.5 to ?9.9 kcal/mol against AKT, and from ?9.0 to ?9.9 kcal/mol against FLT-1. MPE (500 g/mL) decreased cell viability and increased inhibition of HL-60 cells. Intracellular ROS levels decreased significantly at 0.6, 1.2, and 2.4 g/mL MPE. MPE induced cell senescence especially at 1.2 and 2.4 g/mL. Gene expression analysis revealed downregulation of AKT at 1.2 and 2.4 g/mL and FLT1 at 2.4 g/mL. These findings suggest that MPE may exert multifactorial anti-leukemic mechanisms, including apoptosis, ROS modulation, senescence induction, and regulation of AKT and FLT1 expression.

References

Hoseini, S.S., Espinosa-Cotton, M., Guo, H.F. & Cheung, N.K.V., Overcoming Leukemia Heterogeneity by Combining T Cell Engaging Bispecific Antibodies, Journal for Immunotherapy of Cancer, 8(2), e001626, 2020.

Heidari-Foroozan, M., Saeedi Moghaddam, S., Keykhaei, M., Shobeiri, P., Azadnajafabad, S., Esfahani, Z. & Farzadfar, F., Regional and National Burden of Leukemia and Its Attributable Burden to Risk Factors in 21 Countries and Territories of North Africa and Middle East, 1990?2019: Results From the GBD Study 2019, Journal of Cancer Research and Clinical Oncology, 149(8), pp. 4149-4161, 2023.

Du, M., Chen, W., Liu, K., Wang, L., Hu, Y., Mao, Y. & Ye, D., The Global Burden of Leukemia and Its Attributable Factors in 204 Countries and Territories: Findings from The Global Burden of Disease 2019 Study and Projections to 2030, Journal of Oncology, 2022(1), 1612702, 2022.

Alkhaldy, H.Y., Assiri, A.M., Fatima, S. & Owaidah, T., Isotretinoin Is Active in The Initial Management of Acute Pro-myelocytic Leukemia, Leukemia Research Reports, 14, 100220, 2020.

Demirci Saadet, E. & Sahin, U., Evaluation of Hematological Parameters in Patients Using Systemic Isotretinoin with Diagnosis of Acne Vulgaris, Journal of Cosmetic Dermatology, 22(3), pp. 1077-1082, 2023.

Draghici, C.C., Miulescu, R.G., Petca, R.C., Petca, A., Dumitra?cu, M.C. & ?andru, F., Teratogenic Effect of Isotretinoin in Both Fertile Females and Males, Experimental and Therapeutic Medicine, 21(5), pp. 1-5, 2021.

Widowati, W., Laksmitawati, D.R., Wargasetia, T.L., Afifah, E., Amalia, A., Arinta, Y. & Suciati, T., Mangosteen Peel Extract (Garcinia mangostana L.) as Protective Agent in Glucose-induced Mesangial Cell as In Vitro Model of Diabetic Glomerulosclerosis, Iranian Journal of Basic Medical Sciences, 21(9), pp. 972-977, 2018.

Janardhanan, S., Mahendra, J., Mahendra, L. & Devarajan, N., Cytotoxic Effects of Mangosteen Pericarp Extracts on Oral Cancer and Cervical Cancer Cells, Asian Pacific Journal of Cancer Prevention: APJCP, 21(9), 2577, 2020.

Chen, R., Zhang, H., Liu, P., Wu, X. & Chen, B., Gambogenic Acid Synergistically Potentiates Bortezomib-induced Apoptosis in Multiple Myeloma, Journal of Cancer, 8(5), 839, 2017.

Kurniadewi, F., Aqilah, A.S., Kartika, I.R., Nurjayadi, M., Hermawati, E. & Danova, A., Garciniaxanthone E and 12b?Hydroxy?des?D?garcigerrin A from The Tree Bark Garcinia dulcis and Their Inhibitory Properties Against Receptor Tyrosine Kinases, Jurnal Kimia Valensi, 10(1), pp. 20-26, 2024.

Li, J., Nie, X., Panthakarn Rangsinth, Wu, X., Zheng, C., Cheng, Y., Shiu, P.H., Li, R., Lee, S.M., Fu, C., Zhang, J. & Leung, G.P., Structure and Activity Relationship Analysis of Xanthones from Mangosteen: Identifying Garcinone E As A Potent Dual EGFR and VEGFR2 Inhibitor, Phytomedicine, 122, 155140, 2024.

Kurniadewi, F., Palah, L.M., Kartika, I.R., Nurjayadi, M., Hermawati, E. & Danova, A., Isolation, Characterization, and Evaluation of Xanthone Derivatives from Garcinia mangostana Twigs as Tyrosine Kinase Inhibitors with Potential EGFR Selectivity, Advanced Journal of Chemistry, Section A, 8(6), pp. 1027-1042, 2025.

Jiang, N., Dai, Q., Su, X., Fu, J., Feng, X. & Peng, J., Role of PI3K/AKT Pathway in Cancer: The Framework of Malignant Behavior, Molecular Biology Reports, 47(6), pp. 4587-4629, 2020.

Ostini, A. & Mourtada-Maarabouni, M., Investigation into the Role of Long-Non-Coding RNA MIAT in Leukemia, Non-Coding RNA, 9(4), 47, 2023.

Corzo Prada, L., Urue, C., Leal-Garc, E., Barreto, A., Ballesteros-Ramez, R., Rodruez-Pardo, V. & Fiorentino, S., Doxorubicin Activity Is Modulated by Traditional Herbal Extracts in a 2D and 3D Multicellular Sphere Model of Leukemia, Pharmaceutics, 15(6), pp. 1690, 2023.

Ye, X., Wang, L., Yang, X., Yang, J., Zhou, J., Lan, C. & Zeng, J., Integrated Chemical Characterization, Network Pharmacology, and Transcriptomics to Explore the Mechanism of Sesquiterpenoids Isolated from Gynura divaricata (L.) DC Against Chronic Myelogenous Leukemia, Pharmaceuticals, 15(11), 1435, 2022.

Widowati, W., Prahastuti, S., Hidayat, M., Hasianna, S.T., Wahyudianingsih, R., Eltania, T.F. & Kusuma, H.S.W., Detam 1 Black Soybean Against Cisplatin-Induced Acute Renal Failure in Rat Models via Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Potential, Journal of Traditional and Complementary Medicine, 12(4), pp. 426-435, 2022.

Widowati, W., Darsono, L., Lucianus, J., Setiabudi, E., Obeng, S.S., Stefani, S. & Rizal, R., Butterfly Pea Flower (Clitoria ternatea L.) Extract Displays Antidiabetic Effects Through Antioxidant Activity, Reduced Hepatic GSK-3?, and Pancreatic Glycogen in Diabetes Mellitus and Dyslipidemia Rats, Journal of King Saud University-Science, 35(4), 102579, 2023.

Priyandoko, D., Widowati, W., Kusuma, H.S.W., Afifah, E., Wijayanti, C.R., Rizal, R. & Utomo, D.H., Inflammation-Inhibitory Activity of Green Tea, Soybean, and Guava Extracts During SARS-CoV-2 Infection Through TNF Protein in Cytokine Storm, Computational Biology and Chemistry, 105, pp. 107898, 2023.

Banerjee P, Kemmler E, Dunkel M. & Preissner R., ProTox 3.0: A Webserver for the Prediction of Toxicity of Chemicals, Nucleic Acids Research, 52(W1), pp. W513-W520, 2024.

Lister, I.N.E., Ginting, C.N., Girsang, E., Nataya, E.D., Azizah, A.M. & Widowati, W., Hepatoprotective Properties of Red Betel (Piper crocatum Ruiz and Pav) Leaf Extract Toward H?O?-Induced HepG2 Cells via Anti-Inflammatory, Antinecrotic, and Antioxidant Potency, Saudi Pharmaceutical Journal, 28(10), pp. 1182-1189, 2020.

Widowati, W., Murti, H., Widyastuti, H., Laksmitawati, D.R., Rizal, R., Kusuma, H.S.W. & Bachtiar, I., Decreased Inhibition of Proliferation and Induction of Apoptosis in Breast Cancer Cell Lines (T47D and MCF7) Following Treatment with Conditioned Medium Derived from Hypoxia-Treated Wharton?s Jelly MSCs Compared with Normoxia-Treated MSCs, International Journal of Hematology-Oncology and Stem Cell Research, 15(2), 77, 2021.

Abdullah, M.Z., Bakar, L.M., Othman, N., Taher, M., Rasad, M.S.B.A., Foong, F.H.N. & Ichwan, S.J.A., Anti-cancer Activities of ?-Mangostin Against Oral Squamous Cell Carcinoma, Journal of International Dental and Medical Research, 15(1), pp. 81-87, 2022.

Nauman, M.C. & Johnson, J.J., The Purple Mangosteen (Garcinia mangostana): Defining The Anticancer Potential of Selected Xanthones, Pharmacological Research, 175, 106032, 2022.

Amjad, M.T., Chidharla, A. & Kasi, A., Cancer Chemotherapy, StatPearls Publishing, Treasure Island (FL), 2024.

Zhang, C., Yu, G. & Shen, Y., The Naturally Occurring Xanthone ?-Mangostin Induces ROS-Mediated Cytotoxicity in Non-Small Cell Lung Cancer Cells, Saudi Journal of Biological Sciences, 25(6), pp. 1090-1095, 2018.

Li, K., Wu, L., Chen, Y., Li, Y., Wang, Q., Li, M. & Wang, Z., Cytotoxic and Antiproliferative Effects of ?-Mangostin on Rat C6 Glioma Cells Depend on Oxidative Stress Induction via PI3K/AKT/mTOR Pathway Inhibition, Drug Design, Development and Therapy, pp. 5315-5324, 2020.

Kim, M., Chin, Y.W. & Lee, E.J., ?, ?-Mangostins Induce Autophagy and Show Synergistic Effects with Gemcitabine in Pancreatic Cancer Cell Lines, Biomolecules & Therapeutics, 25(6), 609, 2017.

Lez-Garc, J., Lehock M., Humpolek, P. & Sa, P., HaCaT Keratinocytes Response on Antimicrobial Atelocollagen Substrates: Extent of Cytotoxicity, Cell Viability, and Proliferation, Journal of Functional Biomaterials, 5(2), pp. 43-57, 2014.

Kalick, L. S., Khan, H. A., Maung, E., Baez, Y., Atkinson, A. N., Wallace, C. E. & Bishayee, A., Mangosteen for Malignancy Prevention and Intervention: Current Evidence, Molecular Mechanisms, and Future Perspectives, Pharmacological Research, 188, 106630, 2023.

Diab, K.A., Shafik, R.E. & Yasuda, S., In Vitro Antioxidant and Antiproliferative Activities of Novel Orange Peel Extract and Its Fractions on Leukemia HL-60 Cells, Asian Pacific Journal of Cancer Prevention, 16(16), pp 7053-7060, 2015.

Zhamanbayeva, G.T., Aralbayeva, A.N., Murzakhmetova, M.K., Tuleukhanov, S.T. & Danilenko, M., Cooperative Antiproliferative and Differentiation-Enhancing Activity of Medicinal Plant Extracts in Acute Myeloid Leukemia Cells, Biomedicine & Pharmacotherapy, 82, pp. 80-89, 2016.

Yuvanatemiya, V., Srean, P., Klangbud, W. K., Venkatachalam, K., Wongsa, J., Parametthanuwat, T. & Charoenphun, N., A Review of the Influence of Various Extraction Techniques and the Biological Effects of Xanthones from Mangosteen (Garcinia mangostana L.) Pericarps, Molecules, 27(24), 8775, 2022.

Subarnbhesaj, A., Miyauchi, M., Chanbora, C., Mikuriya, A., Nguyen, P. T., Furusho, H. & Takata, T., Roles of VEGF-Flt-1 Signaling in Malignant Behaviors of Oral Squamous Cell Carcinoma, PLoS One, 12(11), 0187092, 2017.

Wang, F., Yamauchi, M., Muramatsu, M., Osawa, T., Tsuchida, R. & Shibuya, M., RACK1 Regulates VEGF/Flt1-Mediated Cell Migration via Activation of the PI3K/Akt Pathway, Journal of Biological Chemistry, 286(11), pp. 9097-9106, 2011.

Meng, X.Y., Zhang, H.X., Mezei, M. & Cui, M., Molecular Docking: A Powerful Approach for Structure-Based Drug Discovery, Current Computer-Aided Drug Design, 7(2), pp. 146-157, 2011.

Das, D.R., Kumar, D., Kumar, P. & Dash, B.P., Molecular Docking and Its Application in the Search for Antisickling Agents from Carica papaya, Journal of Applied Biology and Biotechnology, 8(01), pp. 105-116, 2020.

Varshan, I. & Sankar, S., Molecular Docking Analysis of Hydroxyclavicol and Eugenol from Betel Leaves Against the Outer Membrane Protein (OmpH) of Dialister pneumosintes: ADMET Properties, Cureus, 16(2), pp. 1-8, 2024.

Fatimawali, Tallei, T.E., Kepel, B.J., Bodhi, W., Manampiring, A.E. & Nainu, F. Molecular Insight into the Pharmacological Potential of Clerodendrum minahassae Leaf Extract for Type-2 Diabetes Management Using a Network Pharmacology Approach, Medicina, 59(11), 1899, 2023.

Dong, C., Zhang, N.J. & Zhang, L.J., Oxidative Stress in Leukemia and Antioxidant Treatment, Chinese Medical Journal, 134(16), pp. 1897-1907, 2021.

Fadil Amrulloh, L.S.W., Harmastuti, N., Prasetiyo, A. & Herowati, R., Analysis of Molecular Docking and Dynamics Simulation of Mahogany (Swietenia macrophylla King) Compounds Against the PLpro Enzyme SARS-COV-2, Pharmacy & Pharmaceutical Sciences Journal, 10(3), pp. 347-359, 2023.

Seo, S., Choi, J., Park, S. & Ahn, J., Binding Affinity Prediction for Protein?Ligand Complexes Using a Deep Attention Mechanism Based on Intermolecular Interactions, BMC Bioinformatics, 22(1), pp. 1-15, 2021.

Tallei, T.E., Tumilaar, S.G., Niode, N.J., Fatimawali, F., Kepel, B.J., Idroes, R. & Emran, T.B., Potential of Plant Bioactive Compounds as SARS-CoV-2 Main Protease (Mpro) and Spike (S) Glycoprotein Inhibitors: A Molecular Docking Study, Scientifica, 2020(1), 6307457, 2020.

Ferenczy, G.G. & Kellermayer, M., Contribution of Hydrophobic Interactions to Protein Mechanical Stability, Computational and Structural Biotechnology Journal, 20, pp. 1946-1956, 2022.

Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J., Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings, Advanced Drug Delivery Reviews, 23(1-3), pp. 3-25, 1997.

Asano, D., Takakusa, H. & Nakai, D., Oral Absorption of Middle-to-Large Molecules and Its Improvement, with A Focus on New Modality Drugs, Pharmaceutics, 16(1), 47, 2023.

Doak, B.C., Zheng, J., Dobritzsch, D. & Kihlberg, J., How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets, Journal of Medicinal Chemistry, 59(6), pp. 2312-2327, 2015.

Kenny, P.W., Hydrogen Bond Donors in Drug Design, Journal of Medicinal Chemistry, 65(21), pp. 14261-14275, 2022.