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Purpose <p>Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy frequently characterized by intrinsic resistance to standard gemcitabine (Gem) chemotherapy. This study aimed to investigate whether andrographolide (Andro) could sensitize intrinsically gemcitabine-resistant ICC cells to gemcitabine and to explore the underlying molecular mechanisms.</p> Methods <p>Naturally Gem-resistant ICC cell lines (HUCCT-1 and QBC-939) were treated with Andro, Gem, or their combination. Synergistic effects were quantified using the Chou-Talalay method. Anti-tumor efficacy was assessed via CCK-8, colony formation, EdU incorporation, wound healing, and Transwell invasion assays. ROS accumulation, apoptosis, mitochondrial membrane potential, and cell-cycle distribution were assessed by fluorescence microscopy and flow cytometry, as appropriate. Molecular targets were identified using molecular docking, RT-qPCR, and Western blotting.</p> Results <p>Andro and Gem exhibited strong synergistic anti-tumor activity (Combination Index &lt; 1.0) in both cell lines. The combination significantly suppressed proliferation, motility, and epithelial-mesenchymal transition. Mechanistically, the synergy was driven by a surge in intracellular ROS, triggering mitochondrial apoptosis and G1/S phase arrest. Furthermore, Ribonucleotide-diphosphate reductase subunit M2 was identified as a candidate molecular target associated with the effects of andrographolide, leading to its downregulation and the subsequent inactivation of the JAK/STAT3 signaling pathway.</p> Conclusion <p>Andrographolide overcomes intrinsic Gem resistance in ICC, potentially through modulation of the RRM2/JAK/STAT3 axis. This combination therapy represents a promising strategy for treating chemoresistant intrahepatic cholangiocarcinoma.</p>

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Synergistic anti-tumor activity of andrographolide and gemcitabine in intrahepatic cholangiocarcinoma through inhibition of RRM2 and the JAK/STAT3 pathway

  • 期刊论文

  • 发表日期：

    2026年5月11日

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  • Qinghang Song,
  • Chunjuan Yu,
  • Fulin Sun,
  • Wenbo Wang,
  • Ziyuan Wen,
  • Ruolan Chen,
  • Yiming Wang,
  • Haoran Wang,
  • Zhenxiang Wang,
  • Bing Li,
  • Lina Yang

摘要

Purpose

Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy frequently characterized by intrinsic resistance to standard gemcitabine (Gem) chemotherapy. This study aimed to investigate whether andrographolide (Andro) could sensitize intrinsically gemcitabine-resistant ICC cells to gemcitabine and to explore the underlying molecular mechanisms.

Methods

Naturally Gem-resistant ICC cell lines (HUCCT-1 and QBC-939) were treated with Andro, Gem, or their combination. Synergistic effects were quantified using the Chou-Talalay method. Anti-tumor efficacy was assessed via CCK-8, colony formation, EdU incorporation, wound healing, and Transwell invasion assays. ROS accumulation, apoptosis, mitochondrial membrane potential, and cell-cycle distribution were assessed by fluorescence microscopy and flow cytometry, as appropriate. Molecular targets were identified using molecular docking, RT-qPCR, and Western blotting.

Results

Andro and Gem exhibited strong synergistic anti-tumor activity (Combination Index < 1.0) in both cell lines. The combination significantly suppressed proliferation, motility, and epithelial-mesenchymal transition. Mechanistically, the synergy was driven by a surge in intracellular ROS, triggering mitochondrial apoptosis and G1/S phase arrest. Furthermore, Ribonucleotide-diphosphate reductase subunit M2 was identified as a candidate molecular target associated with the effects of andrographolide, leading to its downregulation and the subsequent inactivation of the JAK/STAT3 signaling pathway.

Conclusion

Andrographolide overcomes intrinsic Gem resistance in ICC, potentially through modulation of the RRM2/JAK/STAT3 axis. This combination therapy represents a promising strategy for treating chemoresistant intrahepatic cholangiocarcinoma.