Schisanhenol Inhibits the Proliferation of Hepatocellular Carcinoma Cells by Targeting Programmed Cell Death-ligand 1 via the STAT3 Pathways.

IF 3 4区医学 Q3 CHEMISTRY, MEDICINAL Anti-cancer agents in medicinal chemistry Pub Date : 2025-01-01 DOI:10.2174/0118715206349131241121091834

Zhihong Zhang, Yiwen Zhong, Xu Han, Xueyang Hu, Yuhan Wang, Lei Huang, Siying Li, Ziqing Li, Chunmei Wang, He Li, Jinghui Sun, Wenyue Zhuang, Mengyang Wang, Jianguang Chen, Wei Liu, Chang Liu, Xin Guo, Siyu Yuan, Jiping Wu

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Abstract

Background: Programmed cell death-ligand 1 (PD-L1) is overexpressed in tumor cells, which promotes tumor cell survival and cell proliferation and causes tumor cells to escape T-cell killing. Schisanhenol, a biphenyl cyclooctene lignin-like compound, was extracted and isolated from the plant named Schisandra rubriflora (Franch.).

Purpose: In this work, we studied the anticancer potential of schisanhenol and explored whether schisanhenol mediated its effect by inhibiting the expression of PD-L1 in vitro and in vivo.

Materials and methods: In vitro, we performed western blot, immunofluorescence, immunoprecipitation, and colony formation assays to study the proteins, genes, and pathways related to the anti-tumour activity of schisanhenol. In vivo, we explored the antitumor activity of schisanhenol through orthotopic liver transplantation and subcutaneous transplantation tumor models of hepatocellular carcinoma (HCC) cells.

Results: We found that schisanhenol decreased the viability of HCC cells. It inhibited the expression of programmed cell death ligand-1 (PD-L1), which plays a pivotal role in tumorigenesis. Subsequently, schisanhenol suppressed the expression of PD-L1 by decreasing the activation of STAT3. Furthermore, we found that schisanhenol inhibited the activation of STAT3 via JAK/STAT3 (T705), Src/STAT3 (T705), and PI3K/AKT/mTOR/STAT3 (S727) pathways. Colony formation tests showed that schisanhenol suppressed cell proliferation by inhibiting PD-L1. Schisanhenol also enhanced cytotoxic T lymphocytes (CTL) activity and regained their ability to kill tumour cells in co-culture. Finally, in vivo observation confirmed the antitumor activity of schisanhenol.

Conclusion: Schisanhenol inhibits the proliferation of HCC cells by targeting PD-L1 via the STAT3 pathways. These findings prove that schisanhenol is a valuable candidate for HCC therapeutics and reveal previously unknown characteristics of schisanhenol.

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五味子酚通过STAT3通路靶向程序性细胞死亡配体1抑制肝癌细胞增殖

背景：程序性细胞死亡配体1 （Programmed cell death-ligand 1, PD-L1）在肿瘤细胞中过表达，促进肿瘤细胞存活和细胞增殖，使肿瘤细胞逃避t细胞的杀伤。五味子酚（Schisanhenol）是一种从法国植物五味子（Schisandra rubriflora）中分离得到的联苯环烯木质素类化合物。目的：研究五味子酚的抗癌潜力，探讨五味子酚是否通过抑制体内和体外PD-L1的表达来调节其抗癌作用。材料和方法：在体外，我们采用western blot、免疫荧光、免疫沉淀、菌落形成等方法研究五味子酚抗肿瘤活性的相关蛋白、基因和途径。在体内，我们通过原位肝移植和皮下移植肝癌细胞肿瘤模型，探讨五味子酚的抗肿瘤活性。结果：我们发现五味子酚降低了肝癌细胞的活力。它抑制了程序性细胞死亡配体-1 （PD-L1）的表达，PD-L1在肿瘤发生中起着关键作用。随后，五味子酚通过降低STAT3的激活来抑制PD-L1的表达。此外，我们发现五味子酚通过JAK/STAT3 （T705）、Src/STAT3 （T705）和PI3K/AKT/mTOR/STAT3 （S727）途径抑制STAT3的激活。菌落形成实验表明五味子酚通过抑制PD-L1抑制细胞增殖。五味子酚还能增强细胞毒性T淋巴细胞（CTL）的活性，恢复其杀伤肿瘤细胞的能力。最后，通过体内观察证实了五味子酚的抗肿瘤活性。结论：五味子酚通过STAT3通路靶向PD-L1抑制HCC细胞增殖。这些发现证明五味子酚是HCC治疗的有价值的候选药物，并揭示了五味子酚以前未知的特性。

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来源期刊

Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL

CiteScore

5.10

自引率

3.60%

发文量

323

审稿时长

4-8 weeks

期刊介绍： Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.