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已发表论文
柴胡皂苷D诱导患者来源胆管癌类器官凋亡并增强吉西他滨化疗敏感性的抗肿瘤作用
Authors Han B , Xing G, Du K , Li Y, Liu M, Zheng J, Wang S, Li C, Zhang S, Zhang C, Liu X , Shao Z , Wu W
Received 2 September 2025
Accepted for publication 16 January 2026
Published 22 January 2026 Volume 2026:18 564565
DOI https://doi.org/10.2147/CMAR.S564565
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Kattesh Katti
Bing Han,1,* Guoqiang Xing,1,* Kunkun Du,1,2,* Yanxia Li,3 Min Liu,4 Jie Zheng,4 Shoufeng Wang,4 Canming Li,1 Shupeng Zhang,1,5 Chunyan Zhang,1,3 Xiaozhi Liu,3 Zhijiang Shao,1,2 Wenhan Wu1,6
1Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China; 2Medical College, Tianjin University, Tianjin, People’s Republic of China; 3Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China; 4Department of Pathology, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China; 5College of Clinical Medicine, Medical School of Tianjin University, Tianjin, People’s Republic of China; 6Department of General Surgery, Peking University First Hospital, Beijing, People’s Republic of China
*These authors contributed equally to this work and share first authorship
Correspondence: Zhijiang Shao, Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China, Email shzhj315@126.com Wenhan Wu, Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China, Email wuwenhan88@126.com
Background: Cholangiocarcinoma (CCA), an aggressive malignancy with limited therapeutic options and poor survival rates, poses an urgent clinical challenge necessitating innovative therapeutic strategies. Saikosaponin D (SSd), a bioactive compound derived from Bupleurum, has demonstrated anticancer potential in various malignancies. However, its role in CCA remains unexplored. This study investigated the antitumor effects and potential mechanisms of SSd, both alone and in combination with gemcitabine, utilizing patient-derived cholangiocarcinoma organoids (PDCOs).
Methods: Four PDCO models were established from surgical tumor tissues and metastatic ascites of CCA patients. Histological, immunohistochemical (Cytokeratin 7, Cytokeratin 19 and Ki-67), and immunofluorescence analyses validated the fidelity of organoids to the primary tumors. Drug sensitivity testing evaluated SSd (0.001– 50μM) and gemcitabine alone or in combination (ratios 1:1, 1:2, 1:4) using dose-response curves and combination index (CI) analysis. Apoptosis mechanisms were assessed via TUNEL staining, caspase-3 activity assays, and the JC-1 assay for the mitochondrial membrane potential.
Results: SSd exhibited dose-dependent growth inhibition across PDCOs, with half-maximal inhibitory concentration (IC50) values ranging from 0.9μM to 13μM. Gemcitabine showed IC50 values spanning 0.03μM to 11.1μM. Notably, the SSd-gemcitabine combination at 1:4 ratio demonstrated synergistic effects (CI=0.0005), significantly reducing organoid viability. Ascites-derived PDCOs (eg, CCA182) displayed lower sensitivity to SSd, correlating with prior chemotherapy exposure. Apoptosis induction by SSd was confirmed through increased TUNEL-positive cells, elevated caspase-3 activity, and mitochondrial depolarization. Histological and molecular profiles of PDCOs closely mirrored those of the primary tumors, preserving spatial heterogeneity (eg, glandular structures in tissue-derived PDCOs vs compact morphology in ascites-derived models).
Conclusion: The combination of SSd and gemcitabine exerts a synergistic antitumor effect in patient-derived cholangiocarcinoma organoids through activating caspase-3 and triggering mitochondrial dysfunction-mediated apoptosis.
Keywords: patient-derived cholangiocarcinoma organoids, PDCOs, gemcitabine, Saikosaponin D, SSd, synergistic effect, apoptosis
1Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China; 2Medical College, Tianjin University, Tianjin, People’s Republic of China; 3Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China; 4Department of Pathology, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China; 5College of Clinical Medicine, Medical School of Tianjin University, Tianjin, People’s Republic of China; 6Department of General Surgery, Peking University First Hospital, Beijing, People’s Republic of China
*These authors contributed equally to this work and share first authorship
Correspondence: Zhijiang Shao, Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China, Email shzhj315@126.com Wenhan Wu, Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, People’s Republic of China, Email wuwenhan88@126.com
Background: Cholangiocarcinoma (CCA), an aggressive malignancy with limited therapeutic options and poor survival rates, poses an urgent clinical challenge necessitating innovative therapeutic strategies. Saikosaponin D (SSd), a bioactive compound derived from Bupleurum, has demonstrated anticancer potential in various malignancies. However, its role in CCA remains unexplored. This study investigated the antitumor effects and potential mechanisms of SSd, both alone and in combination with gemcitabine, utilizing patient-derived cholangiocarcinoma organoids (PDCOs).
Methods: Four PDCO models were established from surgical tumor tissues and metastatic ascites of CCA patients. Histological, immunohistochemical (Cytokeratin 7, Cytokeratin 19 and Ki-67), and immunofluorescence analyses validated the fidelity of organoids to the primary tumors. Drug sensitivity testing evaluated SSd (0.001– 50μM) and gemcitabine alone or in combination (ratios 1:1, 1:2, 1:4) using dose-response curves and combination index (CI) analysis. Apoptosis mechanisms were assessed via TUNEL staining, caspase-3 activity assays, and the JC-1 assay for the mitochondrial membrane potential.
Results: SSd exhibited dose-dependent growth inhibition across PDCOs, with half-maximal inhibitory concentration (IC50) values ranging from 0.9μM to 13μM. Gemcitabine showed IC50 values spanning 0.03μM to 11.1μM. Notably, the SSd-gemcitabine combination at 1:4 ratio demonstrated synergistic effects (CI=0.0005), significantly reducing organoid viability. Ascites-derived PDCOs (eg, CCA182) displayed lower sensitivity to SSd, correlating with prior chemotherapy exposure. Apoptosis induction by SSd was confirmed through increased TUNEL-positive cells, elevated caspase-3 activity, and mitochondrial depolarization. Histological and molecular profiles of PDCOs closely mirrored those of the primary tumors, preserving spatial heterogeneity (eg, glandular structures in tissue-derived PDCOs vs compact morphology in ascites-derived models).
Conclusion: The combination of SSd and gemcitabine exerts a synergistic antitumor effect in patient-derived cholangiocarcinoma organoids through activating caspase-3 and triggering mitochondrial dysfunction-mediated apoptosis.
Keywords: patient-derived cholangiocarcinoma organoids, PDCOs, gemcitabine, Saikosaponin D, SSd, synergistic effect, apoptosis