Abstract
Objective
To elucidate the potential targets and mechanisms of Brucea javanica in the treatment of oral squamous cell carcinoma (OSCC) through network pharmacology and molecular docking, supported by clinical data and in vitro experiments.
Methods
Potential targets of Brucea javanica and OSCC-related disease targets were identified via the TCMSP, GeneCards, and OMIM databases. A Venn diagram was employed to obtain the intersection targets, which were considered as the potential targets for Brucea javanica in OSCC treatment. The protein–protein interaction (PPI) network was constructed using the STRING database and Cytoscape 3.7.2 to identify core targets. Gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the intersection targets were conducted using the Metascape database. Molecular docking between the main components of Brucea javanica and core targets was performed using AutoDockTools software. The expression of core targets in clinical samples was analyzed via the GEO database. Finally, the effects of Brucea javanica oil (BJO) on OSCC proliferation, invasion, and migration, as well as the expression of the EGFR/PI3K/AKT signaling pathway, were verified in vitro.
Results
A total of 60 potential targets of Brucea javanica against OSCC were identified, with β-sitosterol and luteolin selected as the primary active components. The five targets with the highest connectivity, AKT1, CASP3, PTGS2, TP53, and EGFR, were identified as core targets. KEGG pathway analysis indicated that the anti-OSCC effects of Brucea javanica are primarily mediated through the PI3K-AKT signaling pathway, JAK-STAT signaling pathway, etc. Molecular docking studies demonstrated strong binding affinities between the main components of Brucea javanica and its core targets. Analysis of clinical samples revealed elevated expression levels of core targets in OSCC samples compared to normal samples. The CCK-8 assay and colony formation assay indicated that BJO effectively inhibited OSCC cell proliferation. The scratch test and Transwell test showed that BJO could inhibit the invasion and migration of oral squamous cell carcinoma. In addition, Western blot and RT-qPCR showed that BJO could down-regulate the expression of EGFR/PI3K/AKT signaling pathway-related proteins and mRNA.
Conclusion
Brucea javanica exhibits multi-target and multi-pathway characteristics in the treatment of oral squamous cell carcinoma, potentially exerting its anti-cancer effects by inhibiting the EGFR/PI3K/AKT signaling pathway.
Supplementary Information
The online version contains supplementary material available at 10.1186/s40001-025-02686-1.
Keywords: Brucea javanica oil, Oral squamous cell carcinoma, Signaling pathway, Network pharmacology
Introduction
Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors in the oral and maxillofacial region [1]. It is a highly invasive and metastatic cancer that often leads to significant morbidity and mortality. Despite advancements in OSCC treatment, including surgery, radiotherapy, and chemotherapy, the 5-year survival rate of patients with OSCC remains below 60% due to tumor metastasis and subsequent recurrence [2]. This poor prognosis is attributed to the complex biological behavior of OSCC, which includes rapid cell proliferation, resistance to apoptosis, and a high potential for local invasion and distant metastasis. Moreover, both surgery and radiotherapy, which are the mainstay treatments for OSCC, are associated with significant functional side effects and the development of drug resistance, further complicating the management of this disease. The incidences and mortalities of oral squamous cell carcinoma have increased in various regions worldwide in recent years, partly due to the abuse of tobacco, alcohol, and betel nut [3]. These lifestyle factors contribute to the development of OSCC by causing chronic inflammation, DNA damage, and genetic mutations in the oral epithelial cells.
In traditional Chinese medicine, oral squamous cell carcinoma is categorized under “tooth rock” and “tongue rock.” Its formation is related to the imbalance of spleen movement, yin deficiency, and blood stasis [4]. According to traditional Chinese medicine theory, the treatment of OSCC should focus on strengthening the body, eliminating evil, promoting qi, and activating blood circulation. This holistic approach aims to restore the balance of the body’s internal environment and enhance the body’s natural defense mechanisms against cancer. Chinese herbal medicine (TCM) is characterized by its multiple targets, minimal side effects, and good efficacy, and has demonstrated promising anti-tumor effects in clinical practice. Brucea javanica, belonging to the Simaroubaceae family, is known for its bitter taste and cold nature, and has the effects of clearing away heat and detoxifying, intercepting malaria, and stopping dysentery. The medicinal part is its dry and ripe fruit, and Brucea javanica oil (BJO) extracted from it has been proven to have anti-cancer effects on various cancers [5, 6], including esophageal cancer [7] and ovarian cancer [8]. However, studies on its effects on oral squamous cell carcinoma are limited.
Therefore, the present study aims to elucidate the potential mechanisms of Brucea javanica in treating OSCC through a comprehensive approach that integrates network pharmacology, molecular docking, and in vitro experimental validation. This multi-faceted strategy is expected to provide novel insights into the therapeutic effects of Brucea javanica on OSCC and lay a solid foundation for its future clinical application in the management of this challenging disease.
Materials and methods
Acquisition of active components and targets in Brucea Javanica
The Traditional Chinese Medicine System Pharmacology (TCMSP) database (https://old.tcmsp-e.com/tcmsp.php) was used to search for the active ingredients of Brucea javanica, with oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18 as the screening criteria.
Acquisition of OSCC disease targets
Using “Oral squamous cell carcinoma” as the search term in GeneCards (https://www.genecards.org/), Online Mendelian Inheritance in Man (OMIM, https://omim.org/), and Therapeutic target database (https://db.idrblab.net/Therapeutic target database), the results from both databases were integrated, eliminating duplicate entries. The refined results were then imported into the UniProt database (https://www.uniprot.org/) to obtain standardized gene names for relevant targets. Targets lacking gene names were excluded, resulting in a set of unique targets associated with OSCC.
Target acquisition for Brucea Javanica in the treatment of OSCC
The potential targets of Brucea javanica and OSCC disease targets were input into the Bioinformatics platform (https://www.bioinformatics.com.cn/) to create a Venn diagram, identifying the potential targets of Brucea javanica for OSCC treatment.
Constructing the “drug–target–main ingredient” regulatory network and PPI network
Cytoscape 3.7.2 software was used to construct the “drug–target–main component” relationship network. The intersection targets were imported into the STRING database (https://cn.string-db.org/), with the species set as “homo sapiens.” The interaction targets between Brucea javanica and OSCC were obtained and imported into Cytoscape 3.7.2 for topological analysis, selecting the top five core targets based on the highest degree value.
GO and KEGG enrichment analysis
The drug–disease intersection targets were imported into the Metascape database (https://metascape.org), with the species set as “homo sapiens” and “P < 0.05” as the screening condition. The top ten GO enrichment analysis items and the signaling pathways of KEGG enrichment analysis were imported into the Bioinformatics platform.
Molecular docking validation
The PDB structure of the intersection target was obtained from the protein database PDB (https://www.rcsb.org/). The ligand was removed using PyMOL software, followed by hydrogenation and charge calculation using AutoDock software. The mol2 structures of the drug active ingredients were obtained from the TCMSP database, and molecular ligand docking was performed in AutoDock to find the structural output with the lowest binding free energy, which was visualized in PyMOL.
Bioinformatics clinical data analysis
Referring to Li’s method [9], the GSE30784 dataset was downloaded from the GEO database (https://www.ncbi.nlm.nih.gov/geo/) to analyze the expression of core targets in normal mucosal tissues and oral squamous cell carcinoma tissues.
Cell culture
Oral squamous cell carcinoma cells (Cal27 cells) were purchased from Wuhan Boyuan Biotechnology Co., Ltd. and cultured in DMEM medium containing 10% fetal bovine serum. The cells were maintained in a constant temperature incubator at 37 ℃ with 5% CO₂. BJO was provided by Shenyang Yaoda Pharmaceutical Co., with an initial concentration of 100 mg/mL (> 99% purity).
CCK-8 assay
Cal27 cells in the logarithmic growth phase were digested with trypsin and evenly seeded in a 96-well plate at 5000 cells per well. Blank, control, and experimental groups were established, with four replicate wells in each group. After overnight attachment, Brucea javanica oil at different concentrations (0, 3.125, 6.25, 12.5, 25, 50 mg/ml) was added to the culture for 24 h. Subsequently, 10 μL of CCK-8 reagent was added to each well and incubated at 37 ℃ for approximately 2 h. Finally, the absorbance value of each well at 450 nm was measured using a microplate reader.
Colony formation experiment
Cal27 cells were seeded at 2500 cells per well in six-well plates. After cell adhesion, Brucea javanica oil at different concentrations was added and cultured for approximately 10 days. The colonies formed were fixed with paraformaldehyde, washed with PBS, stained with 0.1% crystal violet solution, photographed, and counted using Image-J software.
Wound-healing assay
A suspension containing 2.5 × 105 cells/mL was prepared. Three horizontal lines were drawn every 0.5 cm on the back of the 6-well plate with a marker pen. The suspension was evenly spread in the 6-well plate with 2 ml per well. On the second day, a 200 μL gun tip was used to create a scratch perpendicular to the horizontal line on the back, and the plate was cleaned three times with PBS. Photographs were taken, after which 2 ml of low serum medium containing 6.25 and 25 mg/ml BJO concentrations were added, and the cells were cultured in a cell incubator for 24 h. On the third day, photos were taken again after washing with PBS. The scratch area of cells at 0 and 24 h was calculated using Image-J software.
Transwell assay
The Transwell chamber was coated with Matrigel matrix gel in advance (not needed for migration experiments). A serum-free cell suspension at 2 × 105 cells/ml was prepared, with 6.25 and 25 mg/ml concentrations of BJO added. 200 μL was placed in the chamber. The lower chamber was cultured with 20% fetal bovine serum medium for 48 h, then cleaned with PBS, fixed with paraformaldehyde, and stained with 1% crystal violet. The number of invaded and migrated cells was counted under a microscope.
Western blot experiments
Cal27 cells in the logarithmic growth phase were cultured with 6.25 and 25 mg/ml BJO for 24 h. The cells were lysed with cell lysate and PMSF on ice for 20 min, collected, centrifuged at 4 ℃ for 15 min, and the supernatant was removed. The sample was loaded onto a gel, transferred to a membrane, blocked, incubated with primary antibody at 4 ℃ overnight, washed with TBST, treated with secondary antibody, shaken at room temperature for 1 h, washed again, developed with ECL working solution, and analyzed using Image-J software.
RT-qPCR
Cells were cultured with BJO at concentrations of 6.25 and 25 mg/ml for 24 h. The cells were collected, RNA was extracted using a total RNA extraction kit, and the RNA concentration was measured using an ultra-micro nucleic acid protein analyzer. The RNA was then reverse transcribed to cDNA for RT-qPCR analysis. β-Actin was used as an internal control to calculate the relative expression of target genes.
Data statistics and processing
GraphPad Prism 9.1 was used for statistical plotting. T-tests were employed to compare two groups, and one-way ANOVA was used to detect differences between multiple groups followed by Bonferroni’s post-hoc test. P < 0.05 was considered statistically significant.
Results
Collection and screening of Brucea Javanica active ingredients
The active ingredients of Brucea javanica were obtained from the TCMSP database, and 15 ingredients were identified based on the screening conditions (Table 1). After further screening, only luteolin and beta-sitosterol were identified as having relevant drug targets. Therefore, we selected them as the active ingredients for network pharmacology screening.
Table 1.
The active ingredients of Brucea Javanica
| Mol ID | Molecule name | OB (%) | DL |
|---|---|---|---|
| MOL000358 | Beta-sitosterol | 36.91 | 0.75 |
| MOL000006 | Luteolin | 36.16 | 0.25 |
| MOL008068 | Bruceoside A_qt | 31.05 | 0.75 |
| MOL008073 | Brusatol | 45.69 | 0.75 |
| MOL008077 | Yadanzioside B | 46.16 | 0.31 |
| MOL008089 | Yadanzioside H | 62.77 | 0.32 |
| MOL008091 | Yadanzioside I | 61.13 | 0.38 |
| MOL008093 | Yadanzioside J | 38.7 | 0.3 |
| MOL008097 | Yadanzioside L | 31.37 | 0.27 |
| MOL008099 | Yadanzioside M | 45.04 | 0.23 |
| MOL008105 | Yadanzioside P | 58.76 | 0.29 |
| MOL008108 | Yadanzioside C_qt | 31.8 | 0.66 |
| MOL008109 | Yadanzioside D | 55.76 | 0.65 |
| MOL008110 | Bruceoside B | 56.54 | 0.32 |
| MOL008112 | Bruceine C | 31.38 | 0.66 |
Acquisition of targets at the intersection of Brucea javanica and OSCC
A total of 67 potential targets of Brucea javanica were obtained from the TCMSP database, and 6332 disease targets of OSCC were obtained from the disease database. After taking the intersection, a Venn diagram was drawn to obtain 60 potential targets of Brucea javanica for the treatment of OSCC, as shown in Fig 1A.
Fig. 1.
A Venn diagram of Brucea javanica and OSCC; B Brucea javanica, main ingredients and their corresponding target genes; C PPI network; D GO enrichment analysis; E KEGG enrichment analysis bubble plot
Construction of “TCM-target-major component” network and PPI network
As shown in Fig 1B, the “TCM-target-active component” regulatory network was constructed using Cytoscape 3.7.2. The intersection targets were imported into STRING to construct the PPI network, which showed 60 nodes and 728 edges between proteins. The more connections between nodes, the stronger the interaction is. The top five core targets with the highest degree were AKT1, CASP3, PTGS2, TP53, and EGFR (Fig 1C).
GO function and KEGG enrichment analysis
GO biological process analysis showed that the targets of Brucea javanica acting on OSCC were involved in the response to exogenous stimulation, positive and negative regulation of apoptosis process, and other biological processes (Fig 1D). Eighteen signal pathways were screened by KEGG enrichment analysis. The larger the − log₁₀(p-value) value, the more likely the mechanisms pathway were to act on OSCC (Fig 1E).
Molecular docking
The top five targets in the PPI network, AKT1, CASP3, PTGS2, TP53, EGFR, and the two active components of Brucea javanica, luteolin and beta-sitosterol, were selected for molecular docking and visualized in PyMOL (Fig 2A, B). It has been shown that the lower binding energy of the receptor to the ligand, the better affinity and the more stable conformation is [10].
Fig. 2.
A, B Beta-sitosterol and Luteolin molecular docking maps to core targets; C expression of core targets EGFR and AKT1 in clinical data
Expression of core targets in clinical samples
45 normal oral mucosa samples and 167 oral squamous cell carcinoma samples were collected through the GSE30784 dataset. The core targets EGFR and AKT1 were up-regulated in cancer samples compared with normal samples, and the difference was statistically significant (Fig 2C).
Effect of Brucea Javanica oil on the proliferation of oral squamous cell carcinoma Cal27 cells
CCK-8 was used to detect the effect of BJO on the proliferation of OSCC. As shown in Fig 3A, when the BJO concentration was 6.25, 12.5, 25, and 50 mg/ml, the cell viability was significantly different compared with the control group, indicating that BJO can inhibit OSCC.
Fig. 3.
A, B CCK-8 assay and colony formation assay showed that BJO inhibited the proliferation of OSCC. C, D Wound-healing assay and Transwell assay were used to detect the invasion and migration of Brucea javanica oil on oral squamous cell carcinoma. All values are expressed as mean ± SEM, n = 3. Compared to the control group, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001
Brucea javanica oil inhibits invasion and migration of oral squamous cell carcinoma
Based on the results of the CCK-8 assay, 25 and 6.25 mg/ml were selected as the high and low concentrations of BJO for OSCC treatment. The colony formation assay showed that BJO reduced the cloning efficiency of OSCC (Fig 3B). The effects of BJO on the invasion and migration of OSCC were evaluated by scratch assay and Transwell assay. The results of the wound healing assay showed that the migration ability of BJO-treated cells was weakened, and the migration ability decreased with increasing BJO concentration. Similarly, Transwell invasion and migration assays showed that the number of BJO-treated cells passing through the chamber also decreased with increasing doses (Fig. 3C, D).
Effect of Brucea Javanica oil on protein and mRNA expression of the EGFR/PI3 K/AKT pathway
As shown in Fig. 4A–D, Brucea javanica oil inhibited the protein expression of EGFR, PI3K, P-PI3K, AKT, and P-AKT, as well as the mRNA expression of EGFR, PI3K, and AKT, consistent with the predicted results of network pharmacology and clinical data analysis.
Fig. 4.
A Effects of Brucea javanica oil on protein expression related to the EGFR/PI3K/AKT signaling pathway. B–D Effects of Brucea javanica oil on mRNA expression related to the EGFR/PI3 K/AKT signaling pathway. All values are expressed as mean ± SEM, n = 3. Compared to the control group, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001
Discussion
Network pharmacology provides a theoretical basis for the development and application of traditional Chinese medicine by constructing drug–target and gene–disease networks and systematically exploring the multi-target and multi-pathway action modes of traditional Chinese medicine [11]. Our group has previously shown that Brucea javanica oil can inhibit tongue squamous cell invasion and metastasis by regulating the miR-138–EZH2 pathway [12]. Therefore, this study was designed to further explore the potential mechanisms of Brucea javanica in the treatment of oral squamous cell carcinoma through network pharmacology and to provide theoretical and experimental support.
The main active ingredients of Brucea javanica, identified through screening in the drug target database, are β-sitosterol and luteolin. β-Sitosterol is a white crystalline substance with anti-inflammatory, antibacterial, and anti-tumor effects [13]. Studies have shown that β-sitosterol can increase the level of reactive oxygen species (ROS) in the cytoplasm and promote the expression of gp91phox in oral squamous cell carcinoma cells, thereby inducing cell apoptosis [14]. Luteolin is a natural flavonoid with antiviral, antioxidant, and anti-tumor pharmacological effects [15]. Gao found that luteolin may inhibit the proliferation of OSCC by down-regulating the p53-PLK1 signaling pathway and reducing cell energy metabolism [16]. Wang found that luteolin could inhibit the invasion and migration of OSCC by inhibiting the secretion of gelatinases MMP-2 and MMP-9 [17]. Yang’s study showed that luteolin inhibited cell growth by inducing G1 phase arrest [18]. Based on the above results, it can be seen that the main components of Brucea javanica cannot only inhibit the proliferation, invasion, and migration of OSCC but also induce cell apoptosis.
To further screen core targets, a PPI network was constructed, which included AKT1, CASP3, PTGS2, TP53, and EGFR. This indicates that Brucea javanica has multiple targets in the treatment of OSCC. Molecular docking results showed that β-sitosterol and luteolin, the main components of Brucea javanica, had strong binding energy with the core targets AKT1, CASP3, PTGS2, TP53, and EGFR, suggesting that they may be effective targets of Brucea javanica in the treatment of OSCC. GO functional enrichment results obtained a variety of biological processes, such as response to exogenous stimulation and positive and negative regulation of apoptosis. KEGG pathway analysis showed that the PI3K–AKT signaling pathway was mainly enriched in Brucea javanica treatment of OSCC. The GEO database was used to verify the expression of EGFR and AKT1 in normal individuals and OSCC patients. It was found that the expression of EGFR and AKT1 in OSCC patients was significantly higher than that in normal individuals, suggesting that Brucea javanica may exert its effects by down-regulating EGFR. As a member of the tyrosine kinase family, EGFR is involved in key cellular processes, including proliferation, anti-apoptosis, and differentiation [19]. The down-regulation of EGFR expression can inhibit the activity of the PI3K/AKT signaling pathway and affect downstream signaling pathways [20]. In addition, some studies have shown that clinical monoclonal antibody drugs targeting EGFR can increase the apoptosis of OSCC induced by radiation. During radiotherapy, EGFR signal transduction is increased, which can stimulate the PI3K-AKT signaling pathway [21]. These results indicate that the EGFR/PI3K/AKT signaling pathway plays an important role in the treatment of OSCC. This study also has some limitations, such as the lack of animal experiment to verify. In the future, we will continue to construct a mouse OSCC model and further explore and verify the upstream and downstream pathways of EGFR/PI3K/AKT pathway.
In conclusion, the present study used network pharmacology to screen the core targets and signaling pathways of Brucea javanica in the treatment of OSCC and verified that Brucea javanica may exert its anti-cancer effects by inhibiting the EGFR/PI3K/AKT signaling pathway through in vitro experiments. These results provide an experimental basis for the treatment of OSCC with Brucea javanica.
Supplementary Information
Author contributions
M.L., J.Z., Y.L., and Y.M. proposed the study conception and design. Y.L., Y.M., and Y.S. completed the practical work. Y.L., Y.M., Y.S., and J.Z. collected the data. H.W. contributed to the data analysis. M.L., J.Z., Y.L., Y.M., and H.W. contributed to data interpretation. J.Z., Y.L., M.L., Y.M., Y.S., and H.W. prepared the manuscript’s initial draft. M.L., J.Z., Y.L., Y.M., H.W., L.J., J.Z., and W.W. critically reviewed and edited the manuscript’s intellectual content. All the authors reviewed the manuscript.
Funding
This work was supported in part by grants from the National Nature Science Foundation of China (NSFC82060887, NSFC82360958), the Jiangxi Province Natural Science Foundation (20224 ACB206039, 20181BAB205039, 2023BAB206153), the Jiangxi Administration of Traditional Chinese Medicine General Project (2024 A0167, 2023131211, 2020 A0295), the Science and Technology Research Project of Jiangxi Provincial Department of Education (202410312, 202210743), the Key Discipline Construction Fund of Jiangxi University of Traditional Chinese Medicine (2023jzzdxk004), the Jiangxi Provincial Administration of Traditional Chinese Medicine Key Research Laboratory of Oral Diseases of Traditional Chinese Medicine (No.2022.8), and the Science and Technology Program of Jiangxi Provincial Administration of Traditional Chinese Medicine (2024 A0167).
Availability of data
No datasets were generated or analyzed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Mingkang Li and Juan Zhan have contributed equally to this work and are the co-first authors.
Contributor Information
YiSen Shao, Email: shaoyisen@jxutcm.edu.cn.
Wei Wang, Email: wangwei42@jxutcm.edu.cn.
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Associated Data
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Supplementary Materials
Data Availability Statement
No datasets were generated or analyzed during the current study.