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2000
Volume 20, Issue 2
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970

Abstract

Background

(Oliv.) Diels, a renowned traditional Chinese medicine, has gained widespread recognition for its antitumor properties. Further investigation is warranted to determine whether ligustilide (LIG), which is extracted from this plant, can effectively inhibit tumors.

Objectives

We delved into the impact of LIG on cholangiocarcinoma cells, aiming to unravel the mechanisms underlying its effects.

Materials and Methods

Cholangiocarcinoma cells (HuccT1 and RBE) were exposed to varying concentrations of LIG (2, 5, 10, 15, 20 μg/mL) for 24, 48, and 72 h. After identifying differentially expressed genes, stable transcription strains were utilized to explore LIG’s antitumor mechanism. The inhibitory effects of LIG (5 μg/mL, 48 h) were assessed by CCK-8, colony formation, wound healing, transwell migration, western blotting, and immunofluorescence. , experiments in NOG mice (Ac, Ac+LIG; five per group) evaluated LIG’s antiproliferative efficacy (5 mg/kg, intraperitoneal injection, 18-day period).

Results

LIG significantly inhibited cell proliferation and migration with IC 5.08 and 5.77 μg/mL in HuccT1 and RBE cell lines at 48h, increased the expression of E-cadherin while decreased N-cadherin and the protein of PI3K/AKT pathway. Silenced NDRG1 (N-Myc downstream-regulated gene 1) attenuated these effects. , the AC+LIG group (LIG, 5 mg/kg, qd, 18 d) exhibited smaller tumor volumes compared to the Ac group. The expression of Ki-67 was significantly downregulated in the AC+LIG group.

Conclusion

For the first time, our study has revealed that LIG holds therapeutic potential for treating cholangiocarcinoma. These findings hold promise for advancing innovative therapeutic approaches in the treatment of cholangiocarcinoma. LIG may serve as a useful patent for treating CCA.

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2025-07-07
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References

  1. BergquistA. von SethE. Epidemiology of cholangiocarcinoma.Best Pract. Res. Clin. Gastroenterol.201529222123210.1016/j.bpg.2015.02.003 25966423
    [Google Scholar]
  2. SarcognatoS. SacchiD. FassanM. Cholangiocarcinoma.Pathologica2021113315816910.32074/1591‑951X‑252 34294934
    [Google Scholar]
  3. ChoiJ.H. ThungS.N. Recent advances in pathology of intrahepatic cholangiocarcinoma.Cancers2024168153710.3390/cancers16081537 38672619
    [Google Scholar]
  4. HeJ. HuangY. HuangN. JiangJ. Prevalence and predictive value of sarcopenia in surgically treated cholangiocarcinoma: A comprehensive review and meta-analysis.Front. Oncol.202414136384310.3389/fonc.2024.1363843 38571501
    [Google Scholar]
  5. NobreC.C.G. SampaioR.L. XimenesA.C.M. CoelhoG.R. GarciaJ.H.P. Extended left hepatectomy associated with resection of the vena cava and suprahepatic veins by in situ perfusion to treat intrahepatic cholangiocarcinoma.Ann. Hepatobiliary Pancreat. Surg.202428110911310.14701/ahbps.23‑102 38213108
    [Google Scholar]
  6. WeiD. PeslherbeG.H. SelvarajG. WangY. Advances in drug design and development for human therapeutics using artificial intelligence-II.Biomolecules20231312173510.3390/biom13121735
    [Google Scholar]
  7. ShroffR.T. KennedyE.B. BachiniM. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline.J. Clin. Oncol.201937121015102710.1200/JCO.18.02178 30856044
    [Google Scholar]
  8. BelkouzA. WilminkJ.W. Haj MohammadN. Advances in adjuvant therapy of biliary tract cancer: An overview of current clinical evidence based on phase II and III trials.Crit. Rev. Oncol. Hematol.202015110297510.1016/j.critrevonc.2020.102975 32464483
    [Google Scholar]
  9. Abdel-RahmanO. ElsayedZ. ElhalawaniH. Gemcitabine-based chemotherapy for advanced biliary tract carcinomas.Cochrane Database Syst. Rev.201844CD01174610.1002/14651858.CD011746.pub2
    [Google Scholar]
  10. LuviraV. SatitkarnmaneeE. PugkhemA. KietpeerakoolC. LumbiganonP. PattanittumP. Postoperative adjuvant chemotherapy for resectable cholangiocarcinoma.Cochrane Database Syst. Rev.202199CD012814 34515993
    [Google Scholar]
  11. ChenJ. AmoozgarZ. LiuX. Reprogramming the intrahepatic cholangiocarcinoma immune microenvironment by chemotherapy and CTLA-4 blockade enhances Anti–PD-1 therapy.Cancer Immunol. Res.202412440041210.1158/2326‑6066.CIR‑23‑0486 38260999
    [Google Scholar]
  12. WangY. WenN. WangS. Chemotherapy and targeted therapy for advanced biliary tract cancers: An umbrella review.BMC Cancer202323137810.1186/s12885‑023‑10679‑8 37098481
    [Google Scholar]
  13. PropleschR. RieggerC. SimonW. WolframS. Novel composition comprising ligustilide and process for their manufacture. US Patent 20080152730A12008
  14. OrtegaM.J. Parra-TorrejónB. Cano-CanoF. Gómez-JaramilloL. González-MontelongoM.C. ZubíaE. Synthesis and antioxidant/anti-inflammatory activity of 3-arylphthalides.Pharmaceuticals2022155588
    [Google Scholar]
  15. WangS.Z. LiuJ.N. ZhouF.F. WangY.J.P. ZhangP. ChengS.T. Decreased Nrf2 protein level and low sperm quality in intractable spermatocystitis.Asian J. Androl.202426218919410.4103/aja202361 37934170
    [Google Scholar]
  16. ShiozakiM. YoshimuraK. ShibataM. Morphological and biochemical signs of age-related neurodegenerative changes in klotho mutant mice.Neuroscience2008152492494110.1016/j.neuroscience.2008.01.032 18343589
    [Google Scholar]
  17. Hernandez-UnzuetaI. BenedictoA. TelleriaU. SanzE. MárquezJ. Improving the antitumor effect of chemotherapy with ocoxin as a novel adjuvant agent to treat prostate cancer.Nutrients20231511253610.3390/nu15112536 37299500
    [Google Scholar]
  18. JiangX. ZhaoW. ZhuF. Ligustilide inhibits the proliferation of non-small cell lung cancer via glycolytic metabolism.Toxicol. Appl. Pharmacol.202141011533610.1016/j.taap.2020.115336 33212065
    [Google Scholar]
  19. WuY. GuoW. WangT. The comprehensive landscape of prognosis, immunity, and function of the GLI family by pan-cancer and single-cell analysis.Aging20241665123514810.18632/aging.205630 38498906
    [Google Scholar]
  20. ScalesM.K. Velez-DelgadoA. SteeleN.G. Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer.PLoS Genet.2022187e101031510.1371/journal.pgen.1010315 35867772
    [Google Scholar]
  21. DrasinD.J. RobinT.P. FordH.L. Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity.Breast Cancer Res.201113622610.1186/bcr3037 22078097
    [Google Scholar]
  22. ThieryJ.P. AcloqueH. HuangR.Y.J. NietoM.A. Epithelial-mesenchymal transitions in development and disease.Cell2009139587189010.1016/j.cell.2009.11.007 19945376
    [Google Scholar]
  23. LiaoT.T. YangM.H. Hybrid epithelial/mesenchymal state in cancer metastasis: Clinical significance and regulatory mechanisms.Cells20209362310.3390/cells9030623 32143517
    [Google Scholar]
  24. SinhaD. SahaP. SamantaA. BishayeeA. Emerging concepts of hybrid epithelial-to-mesenchymal transition in cancer progression.Biomolecules20201011156110.3390/biom10111561 33207810
    [Google Scholar]
  25. CasalinoL. VerdeP. Multifaceted roles of DNA methylation in neoplastic transformation, from tumor suppressors to EMT and metastasis.Genes202011892210.3390/genes11080922 32806509
    [Google Scholar]
  26. BandyopadhyayS. PaiS.K. GrossS.C. The Drg-1 gene suppresses tumor metastasis in prostate cancer.Cancer Res.200363817311736 12702552
    [Google Scholar]
  27. BaeD.H. JanssonP.J. HuangM.L. The role of NDRG1 in the pathology and potential treatment of human cancers.J. Clin. Pathol.2013661191191710.1136/jclinpath‑2013‑201692 23750037
    [Google Scholar]
  28. EllenT.P. KeQ. ZhangP. CostaM. NDRG1, a growth and cancer related gene: Regulation of gene expression and function in normal and disease states.Carcinogenesis20072912810.1093/carcin/bgm200 17916902
    [Google Scholar]
  29. HosoiF. IzumiH. KawaharaA. N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kappaB kinase beta expression.Cancer Res.200969124983499110.1158/0008‑5472.CAN‑08‑4882 19491262
    [Google Scholar]
  30. WangY.Y. ZhouY.Q. XieJ.X. MAOA suppresses the growth of gastric cancer by interacting with NDRG1 and regulating the Warburg effect through the PI3K/AKT/mTOR pathway.Cell. Oncol.20234651429144410.1007/s13402‑023‑00821‑w 37249744
    [Google Scholar]
  31. (a XieQ. ZhangL. XieL. Z‐ligustilide: A review of its pharmacokinetics and pharmacology.Phytother. Res.20203481966199110.1002/ptr.666232135035
    [Google Scholar]
  32. (b AminA. AwadB. Crocin-sorafenib combination therapy for liver cancer.US Patent 10933076B22019
  33. AminA. Prevention of liver cancer with safranal-based formulations.U.S. Patent 10912741B22019
  34. Amin Amr franal-sorafenib combination therapy for liver cancer.U.S. Patent US10912741B22019
  35. LangF. QuJ. YinH. Apoptotic cell death induced by Z-Ligustilidein human ovarian cancer cells and role of NRF2.Food Chem. Toxicol.201812163163810.1016/j.fct.2018.09.041 30243965
    [Google Scholar]
  36. BotrosS.R. MatoukA.I. AminA. HeebaG.H. Comparative effects of incretin-based therapy on doxorubicin-induced nephrotoxicity in rats: The role of SIRT1/Nrf2/NF-κB/TNF-α signaling pathways.Front. Pharmacol.202415135302910.3389/fphar.2024.1353029 38440177
    [Google Scholar]
  37. ZhangB. WuD. HuL. Ligustilide inhibits the proliferation of human osteoblastoma MG63 cells through the TLR4-ERK pathway.Life Sci.202228811899310.1016/j.lfs.2020.118993 33545202
    [Google Scholar]
  38. LiZ.Q. ZhangG.S. LiuR.Q. Anti-glioma effects of ligustilide or n-butylphthalide on their own and the synergistic effects with temozolomide via PI3K/Akt signaling pathway.OncoTargets Ther.20231698399410.2147/OTT.S432901 38021448
    [Google Scholar]
  39. ArpinatiL. Scherz-ShouvalR. From gatekeepers to providers: Regulation of immune functions by cancer-associated fibroblasts.Trends Cancer20239542144310.1016/j.trecan.2023.01.007 36870916
    [Google Scholar]
  40. Sánchez-RamírezD. Mendoza-RodríguezM.G. AlemánO.R. Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression.World J. Gastrointest. Oncol.20241651705172410.4251/wjgo.v16.i5.1705 38764833
    [Google Scholar]
  41. MilosevicV. ÖstmanA. Interactions between cancer-associated fibroblasts and T-cells: Functional crosstalk with targeting and biomarker potential.Ups. J. Med. Sci.2024129e1071010.48101/ujms.v129.10710 38863724
    [Google Scholar]
  42. ZengH. HouY. ZhouX. Cancer-associated fibroblasts facilitate premetastatic niche formation through lncRNA SNHG5-mediated angiogenesis and vascular permeability in breast cancer.Theranostics202212177351737010.7150/thno.74753 36438499
    [Google Scholar]
  43. Cabrerizo-GranadosD. PeñaR. PalaciosL. Snail1 expression in endothelial cells controls growth, angiogenesis and differentiation of breast tumors.Theranostics202111167671768410.7150/thno.61881 34335957
    [Google Scholar]
  44. WanX. GuanS. HouY. FOSL2 promotes VEGF-independent angiogenesis by transcriptionnally activating Wnt5a in breast cancer-associated fibroblasts.Theranostics202111104975499110.7150/thno.55074 33754039
    [Google Scholar]
  45. YanY. WangL.F. WangR.F. Role of cancer-associated fibroblasts in invasion and metastasis of gastric cancer.World J. Gastroenterol.201521339717972610.3748/wjg.v21.i33.9717 26361418
    [Google Scholar]
  46. RebeloR. XavierC.P.R. GiovannettiE. VasconcelosM.H. Fibroblasts in pancreatic cancer: Molecular and clinical perspectives.Trends Mol. Med.202329643945310.1016/j.molmed.2023.03.002 37100646
    [Google Scholar]
  47. MaH. LiL. DouG. Z-ligustilide restores tamoxifen sensitivity of ERα negative breast cancer cells by reversing MTA1/IFI16/HDACs complex mediated epigenetic repression of ERα.Oncotarget2017817293282934510.18632/oncotarget.16440 28415616
    [Google Scholar]
  48. XuL. HuangF. ZhangY. Chuanxiong Rhizoma inhibits brain metastasis of lung cancer through multiple active ingredients acting on multiple targets, pathways and biological functions.Nan Fang Yi Ke Da Xue Xue Bao202141913191328 34658345
    [Google Scholar]
  49. OlejarzW. BasakG. Emerging therapeutic targets and drug resistance mechanisms in immunotherapy of hematological malignancies.Cancers20231524576510.3390/cancers15245765 38136311
    [Google Scholar]
  50. GengP. ZhaoJ. LiQ. Z-ligustilide combined with cisplatin reduces plpp1-mediated phospholipid synthesis to impair cisplatin resistance in lung cancer.Int. J. Mol. Sci.202324231704610.3390/ijms242317046 38069368
    [Google Scholar]
  51. XuD. FuJ. LiuX. ELABELA-APJ axis enhances mesenchymal stem cell proliferation and migration via the METTL3/PI3K/AKT pathway.Acta Nat2024161111118 38698964
    [Google Scholar]
  52. NakaharaY. ItoH. NamikawaH. a tumor suppressor gene, N-myc downstream-regulated gene 1 (NDRG1), in gliomas and glioblastomas.Brain Sci.202212447310.3390/brainsci12040473 35448004
    [Google Scholar]
  53. ItoH. WatariK. ShibataT. Bidirectional regulation between NDRG1 and GSK3β controls tumor growth and is targeted by differentiation inducing factor-1 in glioblastoma.Cancer Res.202080223424810.1158/0008‑5472.CAN‑19‑0438 31723002
    [Google Scholar]
  54. FengY. RenY. ZhangX. Metabolites of traditional Chinese medicine targeting PI3K/AKT signaling pathway for hypoglycemic effect in type 2 diabetes.Front. Pharmacol.202415137371110.3389/fphar.2024.1373711 38799166
    [Google Scholar]
  55. YangG. HuangL. JiaH. NDRG1 enhances the sensitivity of cetuximab by modulating EGFR trafficking in colorectal cancer.Oncogene202140415993600610.1038/s41388‑021‑01962‑8 34385595
    [Google Scholar]
  56. WeiM. ZhangY. YangX. Claudin‐2 promotes colorectal cancer growth and metastasis by suppressing NDRG1 transcription.Clin. Transl. Med.20211112e66710.1002/ctm2.667 34965023
    [Google Scholar]
  57. LimS.C. GeletaB. MalekiS. RichardsonD.R. KovačevićŽ. The metastasis suppressor NDRG1 directly regulates androgen receptor signaling in prostate cancer.J. Biol. Chem.2021297610141410.1016/j.jbc.2021.101414 34785213
    [Google Scholar]
  58. GeletaB. ToutF.S. LimS.C. Targeting Wnt/tenascin C-mediated cross talk between pancreatic cancer cells and stellate cells via activation of the metastasis suppressor NDRG1.J. Biol. Chem.2022298310160810.1016/j.jbc.2022.101608 35065073
    [Google Scholar]
  59. SongY. GuoJ.F. LanP.S. WangM. DuQ.Y. Investigation of the pan-cancer property of FNDC1 and its molecular mechanism to promote lung adenocarcinoma metastasis.Transl. Oncol.20244410195310.1016/j.tranon.2024.101953 38593585
    [Google Scholar]
  60. SivasankarS. XieB. Engineering the interactions of classical cadherin cell–cell adhesion proteins.J. Immunol.2023211334334910.4049/jimmunol.2300098 37459190
    [Google Scholar]
  61. ZhangN. HäringM. WolfF. GroßhansJ. KongD. Dynamics and functions of E-cadherin complexes in epithelial cell and tissue morphogenesis.Mar. Life Sci. Technol.20235458560110.1007/s42995‑023‑00206‑w 38045551
    [Google Scholar]
  62. KoiralaR. PriestA.V. YenC.F. Inside-out regulation of E-cadherin conformation and adhesion.Proc. Natl. Acad. Sci. USA202111830e210409011810.1073/pnas.2104090118 34301871
    [Google Scholar]
  63. ChenZ. SunJ. LiT. RETRACTED: Iron chelator-induced up-regulation of Ndrg1 inhibits proliferation and EMT process by targeting Wnt/β-catenin pathway in colon cancer cells.Biochem. Biophys. Res. Commun.2018506111412110.1016/j.bbrc.2018.10.054 30340826
    [Google Scholar]
  64. LiuW. YueF. ZhengM. The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.Oncotarget20156118851887410.18632/oncotarget.3316 25860930
    [Google Scholar]
  65. ZhongJ. HuaY. ZouS. WangB. Juglone triggers apoptosis of non-small cell lung cancer through the reactive oxygen species -mediated PI3K/Akt pathway.PLoS One2024195e029992110.1371/journal.pone.0299921 38814975
    [Google Scholar]
  66. HuaR. PeiY. GuH. SunY. HeY. Antitumor effects of flavokawain-B flavonoid in gemcitabine-resistant lung cancer cells are mediated via mitochondrial-mediated apoptosis, ROS production, cell migration and cell invasion inhibition and blocking of PI3K/AKT Signaling pathway.JBUON2020251262267 32277640
    [Google Scholar]
  67. YangY. HuY.E. ZhaoM.Y. JiangY.F. FuX. YouF.M. Decursin affects proliferation, apoptosis, and migration of colorectal cancer cells through PI3K/Akt signaling pathway.Zhongguo Zhongyao Zazhi202348923342342 37282862
    [Google Scholar]
  68. National tumor quality control center; Tumor pathology committee of china anti-cancer association; Boao institute of oncology innovation.Zhonghua Zhong Liu Za Zhi2022447673692 35880333
    [Google Scholar]
  69. QuanY.C. WangL.Y. WangZ.Y. GaoW. CheF.Y. Effect of REG3A on proliferation and invasion of glioma cells by regulating PI3K/Akt signaling pathway.Zhonghua Zhong Liu Za Zhi2023458642650 37580268
    [Google Scholar]
  70. MaZ. ZhangW. WuY. Cyclophilin A inhibits A549 cell oxidative stress and apoptosis by modulating the PI3K/Akt/mTOR signaling pathway.Biosci. Rep.2021411BSR2020321910.1042/BSR20203219 33393627
    [Google Scholar]
  71. LiX.Q. ChengX.J. WuJ. WuK.F. LiuT. Targeted inhibition of the PI3K/AKT/mTOR pathway by (+)-anthrabenzoxocinone induces cell cycle arrest, apoptosis, and autophagy in non-small cell lung cancer.Cell. Mol. Biol. Lett.20242915810.1186/s11658‑024‑00578‑6 38649803
    [Google Scholar]
  72. LiuB. YanY. ZhangL. Radix Actinidiae chinensis induces the autophagy and apoptosis in renal cell carcinoma cells.Eur. J. Med. Res.202429129110.1186/s40001‑024‑01881‑w 38764054
    [Google Scholar]
  73. LiK YouG JiangK Root extract of Hemsleya amabilis Diels suppresses renal cell carcinoma cell growth through inducing apoptosis and G2/M phase arrest via PI3K/AKT signaling pathway.J Ethnopharmacol 2024318Pt B117014
    [Google Scholar]
  74. GuoY. JiangL. LuoS. Network analysis and basic experiments on the inhibition of renal cancer proliferation and migration by alpinetin through PI3K/AKT/mTOR pathway.Curr. Mol. Med.202424113414410.2174/1566524023666230522145226 37221689
    [Google Scholar]
  75. WangY. MangX. LiD. ChenY. CaiZ. TanF. Piezoeletric cold atmospheric plasma induces apoptosis and autophagy in human hepatocellular carcinoma cells through blocking glycolysis and AKT/mTOR/HIF-1α pathway.Free Radic. Biol. Med.202320813415210.1016/j.freeradbiomed.2023.07.036 37543168
    [Google Scholar]
  76. BouabdallahS. Al-MaktoumA. AminA. Steroidal saponins: Naturally occurring compounds as inhibitors of the hallmarks of cancer.Cancers 20231515390010.3390/cancers15153900 37568716
    [Google Scholar]
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  • Article Type:
    Research Article
Keyword(s): cholangiocarcinoma; EMT; Ligustilide; malignant tumor; proliferation; signal pathway
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