PO.CH01.05 · 化学
网络药理学揭示穿心莲联合乳铁蛋白治疗胰腺癌的功能成分与分子机制
Network pharmacology reveals functional components and molecular mechanisms of andrographis combined with lactoferrin in pancreatic cancer treatment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：胰腺癌（PC）仍是最致命的恶性肿瘤，凸显出对新型治疗策略的需求。天然植物来源的生物活性化合物因其安全性、可负担性以及靶向调控细胞生长的多条通路的能力，作为潜在抗癌药物受到越来越多的关注。网络药理学已成为阐明各类生物活性化合物多靶点、多通路机制的有力手段，为其在复杂疾病中的协同治疗潜力提供理论见解。在天然药物中，穿心莲（Andro）和乳铁蛋白（Lf）已显示出强效的抗癌特性。然而，二者潜在的协同相互作用及其内在机制在很大程度上仍未被探索。
方法：本研究中，我们考察了Andro和Lf对PC细胞系（MIA-PaCa-2和BxPC-3）的协同抗癌作用，并探讨了其联合活性所依赖的生长调控通路。通过细胞活力、迁移和侵袭实验评估其抗增殖和抗侵袭活性。利用网络药理学和通路富集分析，我们进一步鉴定了与这两种化合物在PC中协同作用相关的关键靶点和信号通路。随后，采用患者来源的3D肿瘤类器官对细胞培养实验的结果进行了验证。
结果：Andro与Lf联合处理表现出显著的协同抗肿瘤活性，明显抑制PC细胞的活力、增殖、迁移和侵袭。网络药理学鉴定出13,778个疾病相关靶点和164个推测的药物靶点，其中PC与联合治疗之间存在148个重叠靶点。值得注意的是，AKT1成为核心节点，表明PC进展与Andro和Lf的药理活性之间存在密切关联。通路富集分析进一步表明，该联合的协同作用主要与PI3K-AKT信号通路相关（P <0.05），并伴随细胞内钙水平的显著下降。与之一致，在TCGA数据集中，AKT1在PC组织中的表达显著高于正常组织（FC = 1.24，P <0.05）。最后，在3D类器官模型中，联合处理表现出更强的抗癌活性，显著减少类器官的数量和大小（P <0.05），凸显其治疗潜力。
结论：本研究提供了证据，表明Andro与Lf在PC中的协同抗癌作用是通过PI3K-AKT信号通路及对细胞内钙水平的调节介导的，凸显其作为联合治疗策略的应用前景。
查看英文原文 English abstract
Background: Pancreatic cancer (PC) remains the most lethal malignancies, underscoring the need for novel therapeutic strategies. Natural plant-derived bioactive compounds have garnered increasing attention as potential anticancer agents due to their safety, affordability, and ability to target multiple pathways regulating cellular growth. Network pharmacology has emerged as a powerful approach to elucidate the multi-target and multi-pathway mechanisms of various bioactive compounds, offering theoretical insights into their synergistic therapeutic potential in complex diseases. Among natural agents, Andrographis (Andro) and Lactoferrin (Lf) have shown potent anticarcinogenic properties. However, their potential synergistic interactions and the underlying mechanisms remain largely unexplored.
Methods: In this study, we investigated the synergistic anticancer effects of Andro and Lf on PC cell lines (MIA-PaCa-2 and BxPC-3), and explored growth-regulatory pathways underlying their combined activities. Cell viability, migration, and invasion assays were performed to evaluate the antiproliferative and anti-invasive activities. Using Network pharmacology and pathway enrichment analyses, we further identified key targets and signaling pathways associated with the synergistic effects of these two compounds in PC. Subsequently, the findings from cell-culture experiments were validated using patient-derived 3D tumor organoids.
Results: The combined treatment with Andro and Lf demonstrated marked synergistic anti-tumor activity, significantly suppressing cell viability, proliferation, migration, and invasion in PC cells. Network pharmacology identified 13,778 disease-related targets and 164 putative drug targets, with 148 overlapping targets between PC and the combination treatment were deciphered. Notably, AKT1 emerged as a central node, indicating strong associations between PC progression and the pharmacological activity of Andro and Lf. Pathway enrichment analyses further indicated that the synergistic effects of the combination were predominantly linked to the PI3K-AKT signaling pathway ( P <0.05) and accompanied by a significant reduction in intracellular calcium levels. Consistently, AKT1 expression was significantly higher in PC tissues compared with normal tissues in the TCGA dataset (FC = 1.24, P <0.05). Finally, in 3D organoid models, the combined treatment showed stronger anticancer activity, significantly reducing organoid number and size ( P <0.05), highlighting its therapeutic potential.
Conclusion: Our study provides evidence that the synergistic anticancer effects of Andro and Lf in PC are mediated via the PI3K-AKT signaling pathway and modulation of intracellular calcium levels, highlighting their promise as a combinatorial therapeutic strategy.
利益披露 Disclosure
Y. Li, None..
W. Weng, None..
A. Goel, None.