Skip to content
2000
image of Raddeanoside R13 Inhibits Proliferation, Invasion, and Metastasis of 
Gastric Cancer Cells Based on Network Pharmacology and Experimental Validation

Abstract

Objective

This study aims to explore the potential mechanisms by which Raddeanoside R13 (R13) inhibits the proliferation, invasion, and metastasis of gastric cancer (GC) cells through network pharmacology analysis and experimental validation.

Methods

First, network pharmacology was used to explore the potential mechanisms of R13 in treating GC. The effects of R13 on GC cell proliferation were assessed using CCK-8 and colony formation assays. Apoptosis was measured by flow cytometry, while the effects of R13 on invasion and metastasis were evaluated through wound healing and Transwell invasion assays. Finally, Western blotting was performed to investigate the impact of R13 on the expression of epithelial-to-mesenchymal transition (EMT) markers, PI3K/AKT signaling pathway proteins, and apoptosis-related proteins in GC cells.

Results

A total of 58 potential targets of R13 in the treatment of GC were identified. R13 was found to affect the development of GC by regulating pathways, such as NFKB1, mTOR, apoptosis, and the PI3K-AKT signaling pathway. In vitro experiments confirmed that R13 inhibited the proliferation, invasion, and metastasis of GC cells while promoting apoptosis. Additionally, we found that R13 suppressed the EMT of GC cells and reduced the phosphorylation levels of PI3K, AKT, and mTOR. When this pathway was activated, it partially reversed these effects.

Conclusion

R13 inhibited the proliferation, invasion, and metastasis of GC cells while inducing apoptosis. Furthermore, R13 may suppress the EMT process in GC cells by inhibiting the PI3K/AKT/mTOR signaling pathway. These findings provide a foundation for the potential use of R13 as a therapeutic strategy for GC.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ccdt/10.2174/0115680096379893250523102125
2025-06-02
2025-09-13

  • From This Site

    /content/journals/ccdt/10.2174/0115680096379893250523102125
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Smyth E.C. Nilsson M. Grabsch H.I. van Grieken N.C.T. Lordick F. Gastric cancer. Lancet 2020 396 10251 635 648 10.1016/S0140‑6736(20)31288‑5 32861308
    [Google Scholar]
  2. Yang W.J. Zhao H.P. Yu Y. Wang J.H. Guo L. Liu J.Y. Pu J. Lv J. Updates on global epidemiology, risk and prognostic factors of gastric cancer. World J. Gastroenterol. 2023 29 16 2452 2468 10.3748/wjg.v29.i16.2452 37179585
    [Google Scholar]
  3. Johnston F.M. Beckman M. Updates on management of gastric cancer. Curr. Oncol. Rep. 2019 21 8 67 10.1007/s11912‑019‑0820‑4 31236716
    [Google Scholar]
  4. Arnold M. Park J.Y. Camargo M.C. Lunet N. Forman D. Soerjomataram I. Is gastric cancer becoming a rare disease? A global assessment of predicted incidence trends to 2035. Gut 2020 69 5 823 829 10.1136/gutjnl‑2019‑320234 32001553
    [Google Scholar]
  5. Ito Y. Miyashiro I. Ishikawa T. Akazawa K. Fukui K. Katai H. Nunobe S. Oda I. Isobe Y. Tsujitani S. Ono H. Tanabe S. Fukagawa T. Suzuki S. Kakeji Y. Sasako M. Bilchik A. Fujita M. Determinant factors on differences in survival for gastric cancer between the united states and Japan using nationwide databases. J. Epidemiol. 2021 31 4 241 248 10.2188/jea.JE20190351 32281553
    [Google Scholar]
  6. Van Cutsem E. Sagaert X. Topal B. Haustermans K. Prenen H. Gastric cancer. Lancet 2016 388 10060 2654 2664 10.1016/S0140‑6736(16)30354‑3 27156933
    [Google Scholar]
  7. Diepenbruck M. Christofori G. Epithelial–mesenchymal transition (EMT) and metastasis: Yes, no, maybe? Curr. Opin. Cell Biol. 2016 43 7 13 10.1016/j.ceb.2016.06.002 27371787
    [Google Scholar]
  8. Lan Q. Tan X. He P. Li W. Tian S. Dong W. TRIM11 promotes proliferation, migration, invasion and EMT of gastric cancer by activating β-Catenin signaling. OncoTargets Ther. 2021 14 1429 1440 10.2147/OTT.S289922 33658804
    [Google Scholar]
  9. Pastushenko I. Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 2019 29 3 212 226 10.1016/j.tcb.2018.12.001 30594349
    [Google Scholar]
  10. Wu Y.J. Lin S.H. Din Z.H. Su J.H. Liu C.I. Sinulariolide inhibits gastric cancer cell migration and invasion through downregulation of the EMT process and suppression of FAK/PI3K/AKT/mTOR and MAPKs signaling pathways. Mar. Drugs 2019 17 12 668 10.3390/md17120668 31783709
    [Google Scholar]
  11. Barrett D. Brown V.I. Grupp S.A. Teachey D.T. Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr. Drugs 2012 14 5 299 316 10.2165/11594740‑000000000‑00000 22845486
    [Google Scholar]
  12. Sharma V.R. Gupta G.K. Sharma A.K. Batra N. Sharma D.K. Joshi A. Sharma A.K. PI3K/Akt/mTOR intracellular pathway and breast cancer: Factors, mechanism and regulation. Curr. Pharm. Des. 2017 23 11 1633 1638 10.2174/1381612823666161116125218 27848885
    [Google Scholar]
  13. Narayanankutty A. PI3K/ Akt/ mTOR pathway as a therapeutic target for colorectal cancer: A review of preclinical and clinical evidence. Curr. Drug Targets 2019 20 12 1217 1226 10.2174/1389450120666190618123846 31215384
    [Google Scholar]
  14. Deng S. Shanmugam M.K. Kumar A.P. Yap C.T. Sethi G. Bishayee A. Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer 2019 125 8 1228 1246 10.1002/cncr.31978 30748003
    [Google Scholar]
  15. Prieto-Domínguez N. Garcia-Mediavilla M.V. Sanchez-Campos S. Mauriz J.L. Gonzalez-Gallego J. Autophagy as a molecular target of flavonoids underlying their protective effects in human disease. Curr. Med. Chem. 2018 25 7 814 838 10.2174/0929867324666170918125155 28925866
    [Google Scholar]
  16. Li Y. Zou M. Han Q. Deng L. Weinshilboum R.M. Therapeutic potential of triterpenoid saponin anemoside B4 from Pulsatilla chinensis. Pharmacol. Res. 2020 160 105079 10.1016/j.phrs.2020.105079 32679180
    [Google Scholar]
  17. Liu Z.M. Yang X.L. Jiang F. Pan Y.C. Zhang L. Matrine involves in the progression of gastric cancer through inhibiting miR‐93‐5p and upregulating the expression of target gene AHNAK. J. Cell. Biochem. 2020 121 3 2467 2477 10.1002/jcb.29469 31736157
    [Google Scholar]
  18. Zhou Y. Xu Q. Shang J. Lu L. Chen G. Crocin inhibits the migration, invasion, and epithelial‐mesenchymal transition of gastric cancer cells via miR‐320/KLF5/HIF‐1α signaling. J. Cell. Physiol. 2019 234 10 17876 17885 10.1002/jcp.28418 30851060
    [Google Scholar]
  19. Min L. Fang M. Resistance reverse effect of anemoside B4 and tetrandrine on oxaliplatin-resistant human colon cancer cells and the mechanism. Chin. J. Cancer 2015 25 01 38 44
    [Google Scholar]
  20. Ma C.Y. Zhang B.Y. Deng B.L. Effect mechanism of modified baitouwengtang treating colorectal cancer by regulating SF1R/STING/TBK1 signaling to polarize phenotype of tumor-associated macrophages (TAMs). J. Chin. Exp. Formulae. 2023 29 17 96 108 10.13422/j.cnki.syfjx.20230815
    [Google Scholar]
  21. Wen-Cai Ye Nine-Ning Ji Shou-Xun Zhao Jing-Han Liu Tao Ye McKervey M.A. Stevenson P. Triterpenoids from Pulsatilla chinensis. Phytochemistry 1996 42 3 799 802 10.1016/0031‑9422(96)00043‑X 8768325
    [Google Scholar]
  22. Zhong J. Tan L. Chen M. He C. Pharmacological activities and molecular mechanisms of Pulsatilla saponins. Chin. Med. 2022 17 1 59 10.1186/s13020‑022‑00613‑8 35606807
    [Google Scholar]
  23. Zhang L. Naeem A. Wei S. Li Z. Zang Z. Wang M. Liu Y. Su D. PPTS inhibits the TGF- β 1-Induced epithelial-mesenchymal transition in human colorectal cancer SW480 cells. Evid. Based Complement. Alternat. Med. 2019 2019 1 10 10.1155/2019/2683534 31662772
    [Google Scholar]
  24. Liang Y. Xu X. Yu H. Li L. Hong T. Ji Q. Feng Y. Jin S. Song Y. Guo J. Zheng Z. Ye Q. Yang S. Raddeanoside R13 inhibits breast cancer cell proliferation, invasion, and metastasis. Tumour Biol. 2016 37 7 9837 9847 10.1007/s13277‑015‑4748‑5 26810189
    [Google Scholar]
  25. Barthomeuf C. Debiton E. Mshvildadze V. Kemertelidze E. Balansard G. In vitro activity of hederacolchisid A1 compared with other saponins from Hedera colchica against proliferation of human carcinoma and melanoma cells. Planta Med. 2002 68 8 672 675 10.1055/s‑2002‑33807 12221585
    [Google Scholar]
  26. Wang Y.E. Xu K. Yue W.H. Xu Q-M. You B-G. Zhang M-Y. Zhu Z-C. Yang S-L. Liu Y-L. Li K-P. Hederacolchiside A1 suppresses proliferation of tumor cells by inducing apoptosis through modulating PI3K/Akt/mTOR signaling pathway. Chin. Herb. Med. 2018 10 2 215 222 10.1016/j.chmed.2018.03.007
    [Google Scholar]
  27. Liu W.K. Ho J.C.K. Cheung F.W.K. Liu B.P.L. Ye W.C. Che C.T. Apoptotic activity of betulinic acid derivatives on murine melanoma B16 cell line. Eur. J. Pharmacol. 2004 498 1-3 71 78 10.1016/j.ejphar.2004.07.103 15363977
    [Google Scholar]
  28. LoRusso P.M. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J. Clin. Oncol. 2016 34 31 3803 3815 10.1200/JCO.2014.59.0018 27621407
    [Google Scholar]
  29. Shanmugam V. Ramanathan R.K. Lavender N.A. Sinari S. Chadha M. Liang W.S. Kurdoglu A. Izatt T. Christoforides A. Benson H. Phillips L. Baker A. Murray C. Hostetter G. Von Hoff D.D. Craig D.W. Carpten J.D. Whole genome sequencing reveals potential targets for therapy in patients with refractory KRASmutated metastatic colorectal cancer. BMC Med. Genomics 2014 7 1 36 10.1186/1755‑8794‑7‑36 24943349
    [Google Scholar]
  30. Zhu X. Li Z. Li T. Long F. Lv Y. Liu L. Liu X. Zhan Q. Osthole inhibits the PI3K/AKT signaling pathway via activation of PTEN and induces cell cycle arrest and apoptosis in esophageal squamous cell carcinoma. Biomed. Pharmacother. 2018 102 502 509 10.1016/j.biopha.2018.03.106 29579711
    [Google Scholar]
  31. Li H. Prever L. Hirsch E. Gulluni F. Targeting PI3K/AKT/mTOR signaling pathway in breast cancer. Cancers 2021 13 14 3517 10.3390/cancers13143517 34298731
    [Google Scholar]
  32. Duan Y. Haybaeck J. Yang Z. Therapeutic potential of PI3K/AKT/mTOR pathway in gastrointestinal stromal tumors: Rationale and progress. Cancers 2020 12 10 2972 10.3390/cancers12102972 33066449
    [Google Scholar]
  33. Tan Z. Recent advances in the surgical treatment of advanced gastric cancer: A review. Med. Sci. Monit. 2019 25 3537 3541 10.12659/MSM.916475 31080234
    [Google Scholar]
  34. Che G. Yin J. Wang W. Luo Y. Chen Y. Yu X. Wang H. Liu X. Chen Z. Wang X. Chen Y. Wang X. Tang K. Tang J. Shao W. Wu C. Sheng J. Li Q. Liu J. Circumventing drug resistance in gastric cancer: A spatial multi-omics exploration of chemo and immuno-therapeutic response dynamics. Drug Resist. Updat. 2024 74 101080 10.1016/j.drup.2024.101080 38579635
    [Google Scholar]
  35. Dutta S. Mahalanobish S. Saha S. Ghosh S. Sil P.C. Natural products: An upcoming therapeutic approach to cancer. Food Chem. Toxicol. 2019 128 240 255 10.1016/j.fct.2019.04.012 30991130
    [Google Scholar]
  36. Xue S. Zhou Y. Zhang J. Xiang Z. Liu Y. Miao T. Liu G. Liu B. Liu X. Shen L. Zhang Z. Li M. Miao Q. Anemoside B4 exerts anti-cancer effect by inducing apoptosis and autophagy through inhibiton of PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Am. J. Transl. Res. 2019 11 4 2580 2589 31105864
    [Google Scholar]
  37. Wang K. Tu Y. Wan J.B. Chen M. He C. Synergistic anti-breast cancer effect of pulsatilla saponin D and camptothecin through interrupting autophagic–lysosomal function and promoting p62-mediated ubiquitinated protein aggregation. Carcinogenesis 2020 41 6 804 816 10.1093/carcin/bgz140 31504230
    [Google Scholar]
  38. Xu Y. Lu Y. Influence of pulsatilla saponin on proliferation, migration and invasion of gastric cancer HGC-27 cells and its possible mechanism. J Pract Clin Med 2023 27 09 32 38
    [Google Scholar]
  39. Khorasani B.S. The PI3K/Akt/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur. J. Pharmacol. 2021 898 173983 10.1016/j.ejphar.2021.173983 33647255
    [Google Scholar]
  40. Gonzalez D.M. Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci. Signal. 2014 7 344 re8 10.1126/scisignal.2005189 25249658
    [Google Scholar]
  41. Wang Z. Lv J. Li X. Lin Q. The flavonoid Astragalin shows anti‐tumor activity and inhibits PI3K/AKT signaling in gastric cancer. Chem. Biol. Drug Des. 2021 98 5 779 786 10.1111/cbdd.13933 34396710
    [Google Scholar]
  42. Chen W. Zhang Y. Gu X. Qian P. Liu W. Shu P. Qi Ling decoction reduces gastric cancer cell metastasis by inhibiting MMP-9 through the PI3K/Akt signaling pathway. Am. J. Transl. Res. 2021 13 5 4591 4602 34150039
    [Google Scholar]
  43. Skommer J. Wlodkowic D. Deptala A. Larger than life: Mitochondria and the Bcl-2 family. Leuk. Res. 2007 31 3 277 286 10.1016/j.leukres.2006.06.027 16911824
    [Google Scholar]
  44. Marsden V.S. O’Connor L. O’Reilly L.A. Silke J. Metcalf D. Ekert P.G. Huang D.C.S. Cecconi F. Kuida K. Tomaselli K.J. Roy S. Nicholson D.W. Vaux D.L. Bouillet P. Adams J.M. Strasser A. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature 2002 419 6907 634 637 10.1038/nature01101 12374983
    [Google Scholar]
  45. Einat H. Yuan P. Manji H. Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: Further support for the involvement of mitochondrial function in anxiety disorders. Behav. Brain Res. 2005 165 2 172 180 10.1016/j.bbr.2005.06.012 16095731
    [Google Scholar]
/content/journals/ccdt/10.2174/0115680096379893250523102125
Loading
Raddeanoside R13 Inhibits Proliferation, Invasion, and Metastasis of 
Gastric Cancer Cells Based on Network Pharmacology and Experimental Validation
Bentham Science Publishers ; https://doi.org/10.2174/0115680096379893250523102125
/content/journals/ccdt/10.2174/0115680096379893250523102125
/content/journals/ccdt/10.2174/0115680096379893250523102125
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: invasion ; epithelial-mesenchymal transition ; raddeanoside R13 ; metastasis ; Gastric cancer

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test