Journal of Traditional Chinese Medicine >
Mechanisms of Gualou Beimu Yin (瓜蒌贝母饮) in suppressing the development and metastasis of triple-negative breast cancer: an integrated study based on network pharmacology, transcriptomics, and metabolomics
Received date: 2024-10-26
Accepted date: 2025-02-22
Online published: 2026-01-28
Supported by
National Natural Science Foundation of China: Study on Mechanism of Transdifferentiation of Hepatocellular Carcinoma Cells Induced by Huoxue Ruanjian Traditional Chinese Medicine(82174103)
OBJECTIVE: To identify the antitumor effects of Gualou Beimu Yin (瓜蒌贝母饮, GLBMY) in triple-negative breast cancer (TNBC) and to explore the underlying mechanisms.
METHODS: A mouse model of breast cancer was established and treated with GLBMY. Freeze-dried GLBMY powder was used to treat MDA-MB-231 and BT549 cells to assess the therapeutic efficacy of GLBMY against TNBC. Network pharmacology, transcriptomics and metabolomics were employed to identify the potential mechanism of GLBMY in TNBC treatment. Finally, the main regulating genes and proteins in the enriched pathways were validated by Quantitative real-time polymerase chain reaction (qPCR) and Western blotting analysis to confirm its mechanism.
RESULTS: GLBMY can inhibit the growth of TNBC through apoptosis and necroptosis pathways and inhibit TNBC lung metastasis by inhibiting epithelial-mesenchymal transition (EMT). Network pharmacology has elucidated the most important active ingredients (tubeimoside I, emodin, cucurbitacin, and ursolic acid) and the most critical targets [interleukin-6 (IL6), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 3 (MAPK3)] of GLBMY in treating TNBC. RNA-seq revealed that GLBMY affected the nuclear factor kappa-light-chain-enhancer of activated B cells, rat sarcoma virus, and MAPK signalling pathways. Metabolomics revealed that the metabolites mainly affected by GLBMY were L-(+)-lactic acid, isocitric acid, benzoic acid and indoxyl sulfate. Subsequent experiments demonstrated that GLBMY can inhibit EMT in TNBC through the MAPK/ERK pathway and inhibit the proliferation and progression of TNBC through the IL6-STAT signalling pathway.
CONCLUSIONS: We confirmed that GLBMY inhibits the development and metastasis of TNBC through the MAPK/Erk and IL6-STAT signalling pathways. GLBMY shows promise as a long-term supplementary or alternative therapy for TNBC, offering new insights for TNBC treatment.
Ao JIA , Shuang LIU , Tingting GAO , Haoran ZHANG , Wenyuan GAO , Xiongzhi WU . Mechanisms of Gualou Beimu Yin (瓜蒌贝母饮) in suppressing the development and metastasis of triple-negative breast cancer: an integrated study based on network pharmacology, transcriptomics, and metabolomics[J]. Journal of Traditional Chinese Medicine, 2026 , 46(1) : 149 -159 . DOI: 10.19852/j.cnki.jtcm.2026.01.014
| 1. | Bodai BI, Tuso P. Breast cancer survivorship: a comprehensive review of long-term medical issues and lifestyle recommendations. Perm J Spring 2015; 19: 48-79. |
| 2. | Liu Y, Hu Y, Xue J, et al. Advances in immunotherapy for triple-negative breast cancer. Mol Cancer 2023; 22: 145. |
| 3. | Li B, Shao H, Gao L, Li H, Sheng H, Zhu L. Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a review. Drug Deliv 2022; 29: 2130-61. |
| 4. | Yang Z, Zhang Q, Yu L, Zhu J, Cao Y, Gao X. The signaling pathways and targets of Traditional Chinese Medicine and natural medicine in triple-negative breast cancer. J Ethnopharmacol 2021; 264: 113249. |
| 5. | Lu Y, Ding Y, Wei J, et al. Anticancer effects of Traditional Chinese Medicine on epithelial-mesenchymal transition (EMT) in breast cancer: cellular and molecular targets. Eur J Pharmacol 2021; 907: 174275. |
| 6. | Ao M, Xiao X, Li Q. Efficacy and safety of compound Kushen injection combined with chemotherapy on postoperative patients with breast cancer: a Meta-analysis of randomized controlled trials. Medicine (Baltimore) 2019; 98: e14024. |
| 7. | Ni L, Zhu X, Gong C, et al. Trichosanthes kirilowii fruits inhibit non-small cell lung cancer cell growth through mitotic cell-cycle arrest. Am J Chin Med 2015; 43: 349-64. |
| 8. | Park SM, Jeon SK, Kim OH, et al. Anti-tumor effects of the ethanolic extract of Trichosanthes kirilowii seeds in colorectal cancer. Chin Med 2019; 14: 43. |
| 9. | Sinha S, Khan S, Shukla S, et al. Cucurbitacin B inhibits breast cancer metastasis and angiogenesis through VEGF-mediated suppression of FAK/MMP-9 signaling axis. Int J Biochem Cell Biol 2016; 77: 41-56. |
| 10. | Wang J, Yang X, Han H, et al. Inhibition of growth and metastasis of triple-negative breast cancer targeted by Traditional Chinese Medicine Tubeimu in orthotopic mice models. Chin J Cancer Res 2018; 30: 112-21. |
| 11. | Kwon SJ, Park SY, Kwon GT, et al. Licochalcone E present in licorice suppresses lung metastasis in the 4T1 mammary orthotopic cancer model. Cancer Prev Res (Phila) 2013; 6: 603-13. |
| 12. | Lin SC, Chu PY, Liao WT, et al. Glycyrrhizic acid induces human MDA-MB-231 breast cancer cell death and autophagy via the ROS-mitochondrial pathway. Oncol Rep 2018; 39: 703-10. |
| 13. | Yuan L, Tang P, Li HJ, et al. Serum from Jiao-Tai-Wan treated rats increases glucose consumption by 3T3-L 1 adipocytes through AMPK pathway signaling. Biosci Rep 2019; 39: 1286. |
| 14. | Zhao C, Ma G, Tao S, et al. Qi-Ju-Di-Huang-Pill delays the progression of diabetic retinopathy. J Ethnopharmacol 2024; 323: 117751. |
| 15. | Hu N, Gao Z, Cao P, et al. Uniform and disperse selenium nanoparticles stabilized by inulin fructans from Codonopsis pilosula and their anti-hepatoma activities. Int J Biol Macromol 2022; 203: 105-15. |
| 16. | Newton K, Strasser A, Kayagaki N, Dixit VM. Cell death. Cell 2024; 187: 235-256. |
| 17. | Yan H, Luo B, Wu X, et al. Cisplatin induces pyroptosis via activation of MEG3/NLRP3/caspase-1/GSDMD pathway in triple-negative breast cancer. Int J Biol Sci 2021; 17: 2606-21. |
| 18. | Sinha S, Sharma S, Sharma A, Vora J, Shrivastava N. Sulforaphane-cisplatin combination inhibits the stemness and metastatic potential of TNBCs via down regulation of sirtuins-mediated EMT signaling axis. Phytomedicine 2021; 84: 153492. |
| 19. | Zhang J, Liu Y, Tan J, et al. Necroptotic virotherapy of oncolytic alphavirus M1 cooperated with doxorubicin displays promising therapeutic efficacy in TNBC. Oncogene 2021; 40: 4783-95. |
| 20. | Al-Bahlani SM, Al-Bulushi KH, Al-Alawi ZM, Al-Abri NY, Al-Hadidi ZR, Al-Rawahi SS. Cisplatin induces apoptosis through the endoplasmic reticulum-mediated, calpain 1 pathway in triple-negative breast cancer cells. Clin Breast Cancer 2017; 17: e103-12. |
| 21. | Ding X, Chi J, Yang X, et al. Cucurbitacin B synergistically enhances the apoptosis-inducing effect of arsenic trioxide by inhibiting STAT3 phosphorylation in lymphoma Ramos cells. Leuk Lymphoma 2017; 58: 2439-51. |
| 22. | Jin ZQ, Hao J, Yang X, et al. Higenamine enhances the antitumor effects of cucurbitacin B in breast cancer by inhibiting the interaction of AKT and CDK2. Oncol Rep 2018; 40: 2127-36. |
| 23. | Jiang SL, Guan YD, Chen XS, et al. Tubeimoside-1, a triterpenoid saponin, induces cytoprotective autophagy in human breast cancer cells in vitro via Akt-mediated pathway. Acta Pharmacol Sin 2019; 40: 919-28. |
| 24. | Peng Y, Zhong Y, Li G. Tubeimoside-1 suppresses breast cancer metastasis through downregulation of CXCR4 chemokine receptor expression. BMB Rep 2016; 49: 502-7. |
| 25. | Zou G, Zhang X, Wang L, et al. Herb-sourced emodin inhibits angiogenesis of breast cancer by targeting VEGFA transcription. Theranostics 2020; 10: 6839-53. |
| 26. | Zhang Y, Ma X, Li H, et al. Identifying the effect of ursolic acid against triple-negative breast cancer: coupling network pharmacology with experiments verification. Front Pharmacol 2021; 12: 685773. |
| 27. | Sharma R, Yadav V, Jha S, Dighe S, Jain S. Unveiling the potential of ursolic acid modified hyaluronate nanoparticles for combination drug therapy in triple negative breast cancer. Carbohydr Polym 2024; 338: 122196. |
| 28. | Guerra ?R, Paulino AF, Castro MM, Oliveira H, Duarte MF, Duarte IF. Triple negative breast cancer and breast epithelial cells differentially reprogram glucose and lipid metabolism upon treatment with triterpenic acids. Biomolecules 2020; 10: 1163. |
| 29. | Lan M, Lu W, Zou T, et al. Role of inflammatory micro-environment: potential implications for improved breast cancer nano-targeted therapy. Cell Mol Life Sci 2021; 78: 2105-29. |
| 30. | Liu J, Liu L, Yagüe E, et al. GGNBP2 suppresses triple-negative breast cancer aggressiveness through inhibition of IL6/STAT3 signaling activation. Breast Cancer Res Treat 2019; 174: 65-78. |
| 31. | Lee H, Jeong AJ, Ye SK. Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep 2019; 52: 415-23. |
| 32. | Chen L, Guo P, He Y, et al. HCC-derived exosomes elicit HCC progression and recurrence by epithelial-mesenchymal transition through MAPK/ERK signalling pathway. Cell Death Dis 2018; 9: 513. |
| 33. | Zhang T, Yang J, Sun Y, et al. Interleukin-6 and hypoxia synergistically promote emt-mediated invasion in epithelial ovarian cancer via the IL6/STAT3/HIF-1α feedback loop. Anal Cell Pathol 2023; 2023: 8334881. |
| 34. | Ito-Kureha T, Koshikawa N, Yamamoto M, et al. Tropomodulin 1 expression driven by NF-κB enhances breast cancer growth. Cancer Res 2015; 75: 62-72. |
| 35. | Shah S, Brock EJ, Ji K, Mattingly RR. Ras and Rap1: a tale of two GTPases. Semin Cancer Biol 2019; 54: 29-39. |
| 36. | Pohl SG, Brook N, Agostino M, Arfuso F, Kumar AP, Dharmarajan A. Wnt signaling in triple-negative breast cancer. Oncogenesis 2017; 6: e310. |
| 37. | Li H, Liang J, Wang J, et al. Mex3a promotes oncogenesis through the RAP1/MAPK signaling pathway in colorectal cancer and is inhibited by hsa-miR-6887-3p. Cancer Commun 2021; 41: 472-91. |
| 38. | Mazzio E, Mack N, Badisa RB, Soliman KFA. Triple isozyme lactic acid dehydrogenase inhibition in fully viable MDA-MB-231 cells induces cytostatic effects that are not reversed by exogenous lactic acid. Biomolecules 2021; 11: 1751. |
| 39. | Yue P, Lopez-Tapia F, Paladino D, et al. Hydroxamic acid and benzoic acid-based STAT3 inhibitors suppress human glioma and breast cancer phenotypes In vitro and in vivo. Cancer Res 2016; 76: 652-63. |
| 40. | Yang J, Li H, Zhang C, Zhou Y. Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways. JCI Insight 2022; 7: 145475. |
| 41. | Yang R, Yuan BC, Ma YS, Zhou S, Liu Y. The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharm Biol 2017; 55: 5-18. |
| 42. | Yu TX, Ma RD, Yu LJ. Structure-activity relationship of tubeimosides in anti-inflammatory, antitumor, and antitumor-promoting effects. Acta Pharmacol Sin 2001; 22: 463-8. |
| 43. | Wang Y, Sun X, Yang Q, Guo C. Cucurbitacin Ⅱb attenuates cancer cachexia induced skeletal muscle atrophy by regulating the IL6/STAT3/FoxO signaling pathway. Phytother Res 2023; 37: 3380-93. |
/
| 〈 |
|
〉 |