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Molecular mechanism of Spatholobi Caulis treatment for cholangiocarcinoma based on network pharmacology, molecular docking, and molecular dynamics simulation

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Abstract

Cholangiocarcinoma (CCA) is a type of malignant tumor originating from the intrahepatic, periportal, or distal biliary system. The treatment means for CCA is limited, and its prognosis is poor. Spatholobi Caulis (SC) is reported to have effects on anti-inflammatory and anti-tumor, but its role in CCA is unclear. First, the potential molecular mechanism of SC for CCA treatment was explored based on network pharmacology, and the core targets were verified by molecular docking and molecular dynamics simulation. Then, we explored the inhibitory effect of SC on the malignant biological behavior of CCA in vitro and in vivo and also explored the related signaling pathways. The effect of combination therapy of SC and cisplatin (DDP) in CCA was also explored. Finally, we conducted a network pharmacological study and simple experimental verification on luteolin, one of the main components of SC. Network pharmacology analysis showed that the core targets of SC on CCA were AKT1, CASP3, MYC, TP53, and VEGFA. Molecular docking and molecular dynamics simulation indicated a good combination between the core target protein and the corresponding active ingredients. In vitro, SC inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of CCA cells. In vivo experiments, the results were consistent with in vitro experiments, and there was no significant hepatorenal toxicity of SC at our dosage. Based on KEGG enrichment analysis, we found PI3K/AKT signaling pathway might be the main signaling pathway of SC action on CCA by using AKT agonist SC79. To explore whether SC was related to the chemotherapy sensitivity of CCA, we found that SC combined with DDP could more effectively inhibit the progression of cholangiocarcinoma. Finally, we found luteolin may inhibit the proliferation and invasion of CCA cells. Our study demonstrates for the first time that SC inhibits the progression of CCA by suppressing EMT through the PI3K-AKT signaling pathway, and SC could enhance the effectiveness of cisplatin therapy for CCA.

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Data and materials are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the following organizations: Hunan Provincial Natural Science Foundation (no. 2022JJ30339), Project of Hunan Provincial Health Commission (no. 202204013663, no. 202204013536 and no.202204014077), Excellent Youth Project of Hunan Provincial Education Department (no. 21B0036), Natural Science Foundation of Changsha (no. kq2007075).

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Author notes

  1. Xu Chen and Bo Sun contributed equally.

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61 Jiefang West Road, Changsha, 410005, Hunan, People’s Republic of China

    Xu Chen, Bo Sun, Zhangtao Yu, Yuhang Li & Chuang Peng

  2. The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, 410007, Hunan, People’s Republic of China

    Jia Zeng

  3. The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, Gansu, People’s Republic of China

    Jie Liu & Zhiguo Tan

Authors
  1. Xu Chen
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  2. Bo Sun
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  3. Jia Zeng
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  4. Zhangtao Yu
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  5. Jie Liu
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  6. Zhiguo Tan
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  8. Chuang Peng
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Contributions

All authors contributed to the study conception and design. Xu Chen and Bo Sun performed the material preparation and data collection; Zhiguo Tan and Jie Liu contributed significantly to the date analysis and manuscript preparation; Xu Chen and Jia Zeng wrote the first draft of the manuscript; Yuhang Li and Zhangtao Yu contributed to the conception of the study; Xu Chen, Bo Sun and Chuang Peng helped perform the analysis with constructive discussions. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Zhiguo Tan, Yuhang Li or Chuang Peng.

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The animal study was reviewed and approved by the Hunan Province Experimental Animal Management Committee.

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The authors have declared that no competing interest exists.

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Chen, X., Sun, B., Zeng, J. et al. Molecular mechanism of Spatholobi Caulis treatment for cholangiocarcinoma based on network pharmacology, molecular docking, and molecular dynamics simulation. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-02985-0

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