1’- Acetoxychavicol acetate Suppresses Osteosarcoma Cell Proliferation through the PI3K Pathway: A Molecular Docking and Cytotoxicity Study
Abstract
Background: This study aims to investigate anticancer properties of 1'-Acetoxychavicol acetate (ACA), a phenylpropanoid substance obtained from the rhizomes of the Alpinia genus, which has been extensively studied. However research on its cytotoxic effects, particularly against osteosarcoma cells, has never been donenot been conducted. The purpose of the research is to investigate the anticancer potential of ACA to support the its development as a novel therapeutic candidate.
Materials and methods: This study assessed ACA’s initial anticancer potential through in vitro cytotoxic tests on normal human osteoblast cells (hFOB) and osteosarcoma cells (MG-63) using the MTT assay. Additionally, bioinformatics analyses, including target prediction, gene ontology, hub gene identification, protein-protein interactions (PPI) network construction, Kyoto encyclopedia of genes and genomes (KEGG) pathways analysis, disease association analysis, and molecular docking, were performed.
Results: The cytotoxicity test on normal hFOB showed an IC50 of 45.05 µM, while in MG-63 osteosarcoma cells, the IC50 was 20.41 µM. In the bioinformatics test, top five target genes identified were SRC, GNAI1, PIK3CD, PIK3CB, PIK3R3. Molecular docking analysis showed that, the native PI3KD ligand showed a strong binding affinity of -10.99 kcal/mol and interacted with more amino acid residues.
Conclusion: Overall, ACA exhibits promise as a treatment option to inhibit osteosarcoma cell proliferation by targeting the PI3K pathway. To develop ACA as a potential osteosarcoma therapeutic candidate, extensive in vitro research is needed.
Keywords: 1-Acetoxychavicol acetate, bioinformatics, cytotoxicity, osteosarcoma, PI3K pathway
Full Text:
PDFReferences
Zhao X, Wu Q, Gong X, Liu J, Ma Y. Osteosarcoma: A review of current and future therapeutic approaches. Biomed Eng Online. 2021; 20(1): 1-14, CrossRef.
Rathore R, Van Tine BA. Pathogenesis and current treatment of osteosarcoma: Perspectives for future therapies. J Clin Med. 2021; 10(6): 1-18, CrossRef.
Van den Boogaard WMC, Komninos DSJ, Vermeij WP. Chemotherapy side-effects: Not all DNA damage is equal. Cancers. 2022; 14(3): 627, CrossRef.
Meiliana A, Dewi NM, Wijaya A. Cancer genetics and epigenetics in cancer risk assesment. Mol Cell Biomed Sci. 2021; 5(2): 41, CrossRef.
Subramaniam B, Arshad NM, Malagobadan S, Misran M, Nyamathulla S, Mun KS, et al. Development and evaluation of 10-acetoxychavicol acetate (ACA)-loaded nanostructured lipid carriers for prostate cancer therapy. Pharmaceutics. 2021; 13(4): 439, CrossRef.
Akiko, Kojima-Yuasa, Isao. Pharmacological effects of 1'-Acetoxychavicol acetate, a major constituent in the rhizomes of Alpinia galanga and Alpinia conchigera. J Med Food. 2020; 23(5): 465-75, CrossRef.
Chauhan VS, Swapna M, Singh A. Phytochemical investigation and cytotoxic activity of methanolic extract of Alpinia galanga. Int J Appl Biol Pharm. 2014; 5(3): 186-9, article.
Suciati A, Maryati. Systematic review: Anticancer potential of active compounds from galangal (Alpinia galanga). In: Proceedings of the 4th International Conference Current Breakthrough in Pharmacy; 2022; Vol 3. Atlantis Press; 2023, CrossRef.
Wulandari F, Fauzi A, Da'i M, Mirzaei M, Maryati, Harismah K. Screening and identification of potential target of 1′-acetoxychavicol acetate (ACA) in acquired lapatinib-resistant breast cancer. Heliyon. 2024; 10(23): e40769, CrossRef.
Suhendi A, Wikantyasning ER, Setyadi G, Wahyuni AS, Da'i M. Acetoxy chavicol acetate (ACA) concentration and cytotoxic activity of Alpinia galanga Extract on HeLa, MCF7 and T47D cancer cell lines. Indones J Cancer Chemoprevention. 2017; 8(2): 81, CrossRef.
Yamanishi Y, Kotera M, Kanehisa M, Goto S. Drug-target interaction prediction from chemical, genomic and pharmacological data in an integrated framework. Bioinformatics. 2010; 26(12): i246-54, CrossRef.
Hermawan A, Wulandari F, Hanif N, Utomo RY, Jenie RI, Ikawati M, et al. Identification of potential targets of the curcumin analog CCA-1.1 for glioblastoma treatment: Integrated computational analysis and in vitro study. Sci Rep. 2022; 12:13928, CrossRef.
Wulandari F, Hanifa M. Integrative Bioinformatics Reveals the Lactate Dehydrogenase B (LDHB) Significance in Colon Adenocarcinoma. Mol Cell Biomed Sci. 2023; 7(2): 98-1088, CrossRef.
Adasme MF, Linnemann KL, Bolz SN, Kaiser F, Salentin S, Haupt VJ, et al. PLIP 2021: Expanding the scope of the protein-ligand interaction profiler to DNA and RNA. Nucleic Acids Res. 2021;49(1): W530-4, CrossRef.
Panghiyangani R, Utami JP, Baitullah MA, Maulida ND. Molecular docking of Citrus amblycarpa active compounds against FTO, leptin, and resistin protein. Mol Cell Biomed Sci. 2023; 7(1): 38-46, CrossRef.
Anggini PW, Amanina SA, Asyura SR, Dion R. In silico study of essential oil of Bambusa vulgaris leaves as an anti beta-lactamase compound. Mol Cell Biomed Sci. 2022; 6(3): 147-54, CrossRef.
Rahmawati J, Maryati M, Yuliani R. Cytotoxic and antiproliferation activity of n-hexane fraction of avocado seed (Percea americana Mill) on T47D cell. Pharmacon. 2022; 19(1): 35-44, CrossRef.
Paré G, Vitry J, Merchant ML, Vaillancourt M, Murru A, Shen Y, et al. The inhibitory receptor CLEC12A regulates PI3K-Akt signaling to inhibit neutrophil activation and cytokine release. Front Immunol. 2021; 12: 650808, CrossRef.
Roskoski R. Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors This paper is dedicated to the memory of Prof. Donald F. Steiner (1930-2014) - Advisor, mentor, and discoverer of proinsulin. Pharmacol Res. 2015; 94: 9-25, CrossRef.
Tan Y, Xu P, Huang S, Yang G, Zhou F, He X, et al. Structural insights into the ligand binding and Gi coupling of serotonin receptor 5-HT5A. Cell Discov. 2022; 8(1): 50, CrossRef.
Huang S, Xu P, Tan Y, You C, Zhang Y, Jiang Y, et al. Structural basis for recognition of anti-migraine drug lasmiditan by the serotonin receptor 5-HT1F-G protein complex. Cell Res. 2021; 31(9): 1036-8, CrossRef.
Soundararajan M, Willard FS, Kimple AJ, Turnbull AP, Ball LJ, Schoch GA, et al. Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits. Proc Natl Acad Sci U S A. 2008; 105(17): 6457-62, CrossRef.
Chantry D, Vojtek A, Kashishian A, Holtzman DA, Wood C, Gray PW, et al. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem. 1997; 272(31): 19236-41, CrossRef.
Fransson S, Uv A, Eriksson H, Andersson MK, Wettergren Y, Bergo M, et al. P37 is a new isoform of PI3K p110 that increases cell proliferation and is overexpressed in tumors. Oncogene. 2012; 31(27): 3277-86, CrossRef.
Wee S, Wiederschain D, Maira SM, Loo A, Miller C, deBeaumont R, et al. PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A. 2008;105(35): 13057-62.
Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, et al. Essential roles of PI(3)K-p110β in cell growth, metabolism and tumorigenesis. Nature. 2008; 454(7205): 776-9, CrossRef.
Czupalla C, Culo M, Müller EC, Brock C, Reusch HP, Spicher K, et al. Identification and characterization of the autophosphorylation sites of phosphoinositide 3-kinase isoforms beta and gamma. J Biol Chem. 2003; 278(13): 11536-45, CrossRef.
Abidin Z. Peran jalur phosphatidyl-inositol-3-kinase (pi3k) dalam resistensi kemoterapi pada kanker. Qanun Medika. 2018; 2(1): 80-90, CrossRef.
Castanedo GM, Blaquiere N, Beresini M, Bravo B, Brightbill H, Chen J, et al. Structure-based design of tricyclic NF-κB inducing kinase (NIK) inhibitors that have high selectivity over phosphoinositide-3-kinase (PI3K). J Med Chem. 2017; 60(2): 627-40, CrossRef.
Liew SK, Azmi MN, In LLA, Awang K, Nagoor NH. Anti-proliferative, apoptotic induction, and anti-migration effects of hemi-synthetic 1'S-1'-acetoxychavicol acetate analogs on MDA-MB-231 breast cancer cells. Drug Des Devel Ther. 2017; 11: 2763-76, CrossRef.
Misawa T, Dodo K, Ishikawa M, Hashimoto Y, Sagawa M, Kizaki M, et al. Structure-activity relationships of benzhydrol derivatives based on 1′-acetoxychavicol acetate (ACA) and their inhibitory activities on multiple myeloma cell growth via inactivation of the NF-κB pathway. Bioorg Med Chem. 2015; 23(9): 2241-6, CrossRef.
Awang K, Azmi MN, Aun LI, Aziz AN, Ibrahim H, Nagoor NH. The apoptotic effect of 1's-1'-acetoxychavicol acetate from Alpinia conchigera on human cancer cells. Molecules. 2010; 15(11): 8048-59, CrossRef.
Ji Z, Shen J, Lan Y, Yi Q, Liu H. Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies. MedComm. 2023; 4(4): e308, CrossRef.
Parkinson GN, Vines D, Driscoll PC, Djordjevic S. Crystal structures of PI3K-C2α PX domain indicate conformational change associated with ligand binding. BMC Struct Biol. 2008; 8: 13, CrossRef.
Tian Z, Niu X, Yao W. Receptor tyrosine kinases in osteosarcoma treatment: Which is the key target. Front Oncol. 2020, CrossRef.
Wulandari F, Utami W, Rohana E, Rizqy Prabhata WR. Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) therapy in lung cancer. J Res Pharm. 2021; 1(1): 24-31, CrossRef.
Karim BK, Tsamarah DF, Zahira A, Rosandi NF, Swarga KF, Aulifa DL, et al. In-Silico Study of Active Compounds in Guava Leaves (Psidium guajava L.) as Candidates for Breast Anticancer Drugs. Indonesian Journal of Biological Pharmacy. 2023; 3(3): 194-209, CrossRef.
Lipinski CA. Physicochemical properties and the discovery of orally active drugs: Technical and people issues. Molecular informatics: Confronting complexity. 2003; 59-78, article.
Pollastri MP. Overview on the Rule of Five. Curr Protoc Pharmacol. 2010; Chapter 9: Unit 9.12, CrossRef.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46(1-3): 3-26, CrossRef.
DOI: https://doi.org/10.21705/mcbs.v9i2.640
Copyright (c) 2025 Cell and BioPharmaceutical Institute
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Indexed by:
Cell and BioPharmaceutical Institute
