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. 2023 Sep 15;102(37):e34835.
doi: 10.1097/MD.0000000000034835.

Molecular mechanism of oroxyli semen against triple-negative breast cancer verified by bioinformatics and in vitro experiments

Lulu Chen  1 , Aishen Yang  2 , Yangan Li  3 , Xin Liu  4 , Wei Jiang  5 , Kehui Hu  3
Affiliations

Molecular mechanism of oroxyli semen against triple-negative breast cancer verified by bioinformatics and in vitro experiments

Lulu Chen et al. Medicine (Baltimore). .

Abstract

Objective: This study aimed to use network pharmacology to predict the therapeutic mechanism of oroxyli semen (OS) on triple-negative breast cancer (TNBC) and validate it through in vitro experiments.

Methods: The active ingredients and target proteins of OS were retrieved from the Traditional Chinese Medicine Systems Pharmacology database, and the TNBC-related target genes were obtained from the GeneCards database. The overlapping genes were used to construct a protein-protein interaction (PPI) network via the String database. Furthermore, we employed an online bioinformatics analysis platform (https://www.bioinformatics.com.cn/) to perform gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses to evaluate biological processes, molecular functions, and cellular components and generate simulated signal pathways. Additionally, molecular docking was used to evaluate the binding ability of small molecule drugs and signaling pathway targets. CCK8 assay was conducted to detect the effect of small molecule drugs on TNBC cell viability, and Western Blot was utilized to verify the expression of AKT, VEGF, and hypoxia-inducible factor 1-alpha (HIF-1α) proteins.

Results: Fifteen active ingredients and 166 therapeutic targets of OS were obtained from the Traditional Chinese Medicine Systems Pharmacology database. The Venn diagram revealed that 163 targets were related to TNBC. The protein-protein interaction network analysis identified AKT1, IL-6, JUN, vascular endothelial growth factor A (VEGFA), CASP3, and HIF-1α as potential core targets through which OS may treat TNBC. Furthermore, the molecular docking results indicated that the active ingredient chryseriol in OS had good binding ability with VEGFA, and HIF-1α. CCK8 assay results indicated that chryseriol inhibited the viability of MDA-MB-231 and BT-20 cells. Western Blot demonstrated that chryseriol intervention led to a decrease in VEGFA, and HIF-1α protein expression compared with the control group (P < .05), increased the cleaved PARP.

Conclusion: OS may exert its therapeutic effects on TNBC through multiple cellular signaling pathways. Chryseriol, the active component of OS, can enhance the apoptosis of TNBC cells by targeting VEGFA/HIF-1α pathway. This study provided new insights into the potential therapeutic mechanism of OS for TNBC and may aid in the development of novel therapeutic approaches for TNBC.

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Conflict of interest statement

The authors have no funding and conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Venn diagram of OS and TNBC. The red color represents the targets of TNBC, the green color represents the targets of OS, and the dark red color in the middle represents the common targets.
Figure 2.
Figure 2.
Network of active ingredients and targets of OS. The green nodes represent the target genes of TNBC, and the purple nodes represent the active ingredients.
Figure 3.
Figure 3.
Constructing PPI network and selecting core genes: (A) PPI network diagram of OS-TNBC common targets. PPI = protein-protein interaction. (B) Twenty key targets selected by PPI topology analysis based on degree. The horizontal axis represents the value of degree, and the vertical axis represents the specific target name.
Figure 4.
Figure 4.
Functional enrichment analysis: (A) GO enrichment analysis. (B) KEGG enrichment analysis.
Figure 5.
Figure 5.
KEGG simulated signaling pathway analysis.
Figure 6.
Figure 6.
Molecular docking. (A) Molecular docking model of chryseriol with VEGFA. (B) Molecular docking model of chryseriol with HIF-1α.
Figure 7.
Figure 7.
In vitro experiments. (A) Cell viability assay. MDA-MB-231, BT20 cells were treated with 0, 5, 10, 15, 20 μmol/L chryseriol for 48 hours, and cell survival rate was detected by CCK-8 assay. *P < .05, compared with 0 μmol/L group, #P < .05, compared with 0 μmol/L group. (B) Western blot showed that the expression of VEGFA, HIF-1α and cleaved PARP were decreased after treatment of MDA-MB-231 and BT20 cells with 20 μmol/L chryseriol for 48 hours.
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