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2000
Volume 20, Issue 5
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970

Abstract

Background

The emergence of drug resistance to oxaliplatin (OXA) is one of the critical obstacles in the therapy of advanced Hepatocellular Carcinoma (HCC). As an ethyl derivative of the natural compound epigallocatechin gallate (epigallocatechin-3-gallate, EGCG), Y was found to be able to enhance the sensitivity of HCC cells to doxorubicin. This study aimed to investigate the effect of Y on oxaliplatin resistance in HCC.

Methods

MTT was used to determine the reversal effect of Y on OXA resistance. To further explore the reversal mechanism, we treated OXA alone or in combination with Y or EGCG in drug-resistant cells and observed the morphological changes of the cells. At the same time, transwell assay was used to detect the invasion and migration ability of cells. Moreover, Real-time PCR and Western blot analysis were performed to determine the expression levels of the miR-338-3p gene, HIF-1α/TWIST proteins, and EMT-related proteins.

Results

We found that Y could inhibit the proliferation of HCC cells and effectively reverse the drug resistance of oxaliplatin-resistant human liver cancer cells (SMMC-7721/OXA) to OXA, and the reversal effect was more significant than that of its lead drug EGCG. Most of the cells in the control group and OXA group showed typical mesenchymal-like cell morphology, while most of the cells in co-administration groups showed typical epithelioid cell morphology, and the ability of the cells to invade and migrate decreased dramatically, particularly in Y plus OXA group. At the same time, Y could up-regulate the EMT epithelial marker protein E-cadherin and down-regulate the interstitial marker protein Vimentin. In addition, in co-administration groups, the expression of miR-338-3p was up-regulated, while the expression of HIF-1α and TWIST was down-regulated.

Conclusion

Y significantly enhanced the susceptibility of drug-resistant cells to OXA, and the process may be related to the regulation of miR-338-3p/HIF-1α / TWIST pathway to inhibit EMT. Therefore, Y could be considered an effective medication resistance reversal agent, which could improve the therapeutic effect for hepatocellular cancer patients.

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References

  1. MöllerK. Safai ZadehE. GörgC. DongY. CuiX. LimA. de MoloC. SerraC. Martín AlgíbezA. BerzigottiA. PiscagliaF. FaissS. DietrichC.F. Focal liver lesions other than hepatocellular carcinoma in cirrhosis: Diagnostic challenges.J. Transl. Int. Med.202310430832710.2478/jtim‑2022‑006836860624
     [Google Scholar]
  2. ZhuR.X. SetoW.K. LaiC.L. YuenM.F. Epidemiology of hepatocellular carcinoma in the Asia-Pacific Region.Gut Liver201610333233910.5009/gnl1525727114433
     [Google Scholar]
  3. RumgayH. ArnoldM. FerlayJ. LesiO. CabasagC.J. VignatJ. LaversanneM. McGlynnK.A. SoerjomataramI. Global burden of primary liver cancer in 2020 and predictions to 2040.J. Hepatol.20227761598160610.1016/j.jhep.2022.08.02136208844
     [Google Scholar]
  4. YangJ.D. HainautP. GoresG.J. AmadouA. PlymothA. RobertsL.R. A global view of hepatocellular carcinoma: Trends, risk, prevention and management.Nat. Rev. Gastroenterol. Hepatol.2019161058960410.1038/s41575‑019‑0186‑y31439937
     [Google Scholar]
  5. ParkJ.W. ChenM. ColomboM. RobertsL.R. SchwartzM. ChenP.J. KudoM. JohnsonP. WagnerS. OrsiniL.S. ShermanM. Global patterns of hepatocellular carcinoma management from diagnosis to death: The BRIDGE Study.Liver Int.20153592155216610.1111/liv.1281825752327
     [Google Scholar]
  6. European Association for Study of LiverEuropean Organisation for Research and Treatment of CancerEASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma.Eur. J. Cancer201248559964110.1016/j.ejca.2011.12.02122424278
     [Google Scholar]
  7. ChenZ. XieH. HuM. HuangT. HuY. SangN. ZhaoY. Recent progress in treatment of hepatocellular carcinoma.Am. J. Cancer Res.20201092993303633042631
     [Google Scholar]
  8. LyuN. WangX. LiJ.B. LaiJ.F. ChenQ.F. LiS.L. DengH-J. HeM. MuL-W. ZhaoM. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: A biomolecular exploratory, randomized, Phase III Trial (FOHAIC-1).J. Clin. Oncol.202240546848010.1200/JCO.21.0196334905388
     [Google Scholar]
  9. QinS. BaiY. LimH.Y. ThongprasertS. ChaoY. FanJ. YangT-S. BhudhisawasdiV. KangW.K. ZhouY. LeeJ.H. SunY. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia.J. Clin. Oncol.201331283501350810.1200/JCO.2012.44.564323980077
     [Google Scholar]
  10. MaL. XuA. KangL. CongR. FanZ. ZhuX. HuoN. LiuW. XueC. JiQ. LiW. ChuZ. KangX. WangY. SunZ. HanY. LiuH. GaoX. HanJ. YouH. ZhaoC. XuX. LSD1-demethylated LINC01134 confers oxaliplatin resistance through SP1-induced p62 transcription in HCC.Hepatology20217463213323410.1002/hep.3207934322883
     [Google Scholar]
  11. DongreA. WeinbergR.A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer.Nat. Rev. Mol. Cell Biol.2019202698410.1038/s41580‑018‑0080‑430459476
     [Google Scholar]
  12. XuZ. ZhangY. DaiH. HanB. Epithelial-mesenchymal transition-mediated tumor therapeutic resistance.Molecules20222715475010.3390/molecules2715475035897925
     [Google Scholar]
  13. LiX. ZhangZ.S. ZhangX.H. YangS.N. LiuD. DiaoC.R. WangH. ZhengF.P. Cyanidin inhibits EMT induced by oxaliplatin via targeting the PDK1-PI3K/Akt signaling pathway.Food Funct.201910259260110.1039/C8FO01611A30672917
     [Google Scholar]
  14. MaJ.L. ZengS. ZhangY. DengG.L. ShenH. Epithelial-mesenchymal transition plays a critical role in drug resistance of hepatocellular carcinoma cells to oxaliplatin.Tumour Biol.20163756177618410.1007/s13277‑015‑4458‑z26614432
     [Google Scholar]
  15. MaJ. ZengS. ZhangY. DengG. QuY. GuoC. YinL. HanY. CaiC. LiY. WangG. BonkovskyH.L. ShenH. BMP4 promotes oxaliplatin resistance by an induction of epithelial-mesenchymal transition via MEK1/ERK/ELK1 signaling in hepatocellular carcinoma.Cancer Lett.201741111712910.1016/j.canlet.2017.09.04128987388
     [Google Scholar]
  16. Odero-MarahV. HawsawiO. HendersonV. SweeneyJ. Epithelial-Mesenchymal Transition (EMT) and prostate cancer.Adv. Exp. Med. Biol.2018109510111010.1007/978‑3‑319‑95693‑0_630229551
     [Google Scholar]
  17. LinY.T. WuK.J. Epigenetic regulation of epithelial-mesenchymal transition: Focusing on hypoxia and TGF-β signaling.J. Biomed. Sci.20202713910.1186/s12929‑020‑00632‑332114978
     [Google Scholar]
  18. WangH.Y. ZhangX.P. WangW. Regulation of epithelial-to-mesenchymal transition in hypoxia by the HIF-1α network.FEBS Lett.2022596333834910.1002/1873‑3468.1425834905218
     [Google Scholar]
  19. YangM.H. WuM.Z. ChiouS.H. ChenP.M. ChangS.Y. LiuC.J. TengS-C. WuK-J. Direct regulation of TWIST by HIF-1α promotes metastasis.Nat. Cell Biol.200810329530510.1038/ncb169118297062
     [Google Scholar]
  20. HaM. KimV.N. Regulation of microRNA biogenesis.Nat. Rev. Mol. Cell Biol.201415850952410.1038/nrm383825027649
     [Google Scholar]
  21. LuY. ChanY.T. WuJ. FengZ. YuanH. LiQ. XingT. XuL. ZhangC. TanH-Y. LeeT.K-W. FengY. WangN. CRISPR/Cas9 screens unravel miR-3689a-3p regulating sorafenib resistance in hepatocellular carcinoma via suppressing CCS/SOD1-dependent mitochondrial oxidative stress.Drug Resist. Updat.20237110101510.1016/j.drup.2023.10101537924725
     [Google Scholar]
  22. XuH. ZhaoL. FangQ. SunJ. ZhangS. ZhanC. LiuS. ZhangY. MiR-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1α.PLoS One2014912e11556510.1371/journal.pone.011556525531114
     [Google Scholar]
  23. SugitaY. FurukawaT. Effect of green tea and tea catechin on the visual motion processing for optokinetic responses in mice.Neuroscience2022501425110.1016/j.neuroscience.2022.08.01335987428
     [Google Scholar]
  24. AlamM. AliS. AshrafG.M. BilgramiA.L. YadavD.K. HassanM.I. Epigallocatechin 3-gallate: From green tea to cancer therapeutics.Food Chem.202237913213510.1016/j.foodchem.2022.13213535063850
     [Google Scholar]
  25. ZhouJ. LiR. JiaY. WangY. LiuJ. PanichayupakaranantP. ChenH. Recent progress in natural anticancer agents discovery from tea (Camellia sinensis): A review.Recent Patents Anticancer Drug Discov.202217434335710.2174/157489281666621120815581134879813
     [Google Scholar]
  26. ZhongX. DiZ. XuY. LiangQ. FengK. ZhangY. DiL. WangR. Mineral medicine: From traditional drugs to multifunctional delivery systems.Chin. Med.20221712110.1186/s13020‑022‑00577‑935144660
     [Google Scholar]
  27. MckinneyC. Compositions for treatment of fibroids.WO Patent 20231678782023
  28. DouQ.P. NamS. SmithD.M. Tea polyphenol esters and analogs thereof for cancer prevention and treatment.WO Patent 6713506B22004
  29. HanxiZ. EGCG drug combination and medical application thereof.CN Patent 113350333A2021
  30. TuS-H. KuC-Y. ChenC-S. HuangC-S. LeeC-H. ChenL-C. Use of tea polyphenols for treating and/or preventing nicotine or nicotine-derived compounds or estrogen induced breast cancer.US Patent 20122088722012
  31. YoungC.S. Novel antioxidant, anti-inflammatory and lipid metabolism promoting synergistic nano-drug delivery system.CN Patent 116832051A2019
  32. PetrelliR.P. Multicomponent composition comprising epigallocatechin gallate and saffron dry extract, and its use in the prevention and treatment of parkinson's disease.WO Patent 20231395142023
  33. MachinA. Potential neuroprotection of camellia sinensis with its EGCG active ingredient as a therapy of thrombotic infark stroke.WO Patent 20221806222022
  34. CaoY. Inhibition of angiogenesis with epigallocatechin-3-gallate.AU Patent 2567300A2000
  35. HanxiZ. Application of EGCG (epigallocatechin gallate) composition in preparation of medicine for treating novel coronavirus.CN Patent 116077560A2023
  36. HonggangZ. Application of gallocatechin gallate in preparation of medicine for treating new coronavirus or sepsis.CN Patent 113855667A2021
  37. AndreevnaLM ValerevichEA AleksandrovnaZO NikolaevichLV MikhajlovnaVA SergeevnaVT Method for producing prophylactic antiviral composition based on epigallocatechin-3-gallate (EGCG).RU Patent 2771898C12022
  38. HuanC GuoT LiuJ XuW GaoS Application of EGCG in the preparation for the prevention and/or treatment of the PRV infection, preparation for the prevention and/or treatment of PRV infection.AU Patent 2020103362A42021
  39. NezamiM Compositions and methods for preventing and/or treating viral infection.WO Patent 20212627492021
  40. OuB.N. LiaoZ.Z. LiangG. TangA.Z. Synthesis and reversal activity of multidrug resistance of hepatocellular carcinoma of (−)-epigallocatechin gallate analogues.Chin. J. Nat. Med.20119427427910.1016/S1875‑5364(11)60064‑2
     [Google Scholar]
  41. LiangG. TangA. LinX. LiL. ZhangS. HuangZ. TangH. LiQ.Q. Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer.Int. J. Oncol.201037111112320514403
     [Google Scholar]
  42. AlmatroodiS.A. AlmatroudiA. KhanA.A. AlhumaydhiF.A. AlsahliM.A. RahmaniA.H. Potential therapeutic targets of Epigallocatechin Gallate (EGCG), the most abundant catechin in green tea, and its role in the therapy of various types of cancer.Molecules20202514314610.3390/molecules2514314632660101
     [Google Scholar]
  43. LeeM.J. MaliakalP. ChenL. MengX. BondocF.Y. PrabhuS. LambertG. MohrS. YangC.S. Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans: Formation of different metabolites and individual variability.Cancer Epidemiol. Biomarkers Prev.20021110 Pt 11025103212376503
     [Google Scholar]
  44. YinZ. ZhengT. HoC.T. HuangQ. WuQ. ZhangM. Improving the stability and bioavailability of tea polyphenols by encapsulations: A review.Food Sci. Hum. Wellness202211353755610.1016/j.fshw.2021.12.011
     [Google Scholar]
  45. ChengC.T. Nanoparticle complex with defined sizes.CA Patent 3196651A12022
  46. JianP. Tea extract EGCG prodrug based on quinone oxidoreductase as well as preparation method and application of tea extract EGCG prodrug.CN Patent 114195767A2022
  47. Jong-HoK. Epigallocatechin gallate derivative as well as preparation method and application thereof.CN Patent 117304158A2023
  48. WenY. ZhaoR. GuptaP. FanY. ZhangY. HuangZ. LiX. SuY. LiaoL. XieY-A. YangD. ChenZ-S. LiangG. The epigallocatechin gallate derivative Y6 reverses drug resistance mediated by the ABCB1 transporter both in vitro and in vivo. Acta Pharm. Sin. B20199231632310.1016/j.apsb.2018.10.00130972279
     [Google Scholar]
  49. ZhaoR.Q. WenY. GuptaP. LeiZ.N. CaiC.Y. LiangG. YangD-H. ChenZ-S. XieY-A. Y6, an epigallocatechin gallate derivative, reverses ABCG2-mediated mitoxantrone resistance.Front. Pharmacol.20199154510.3389/fphar.2018.0154530687102
     [Google Scholar]
  50. WenY. ZhaoR.Q. ZhangY.K. GuptaP. FuL.X. TangA.Z. LiuB-M. ChenZ-S. YangD-H. LiangG. Effect of Y6, an epigallocatechin gallate derivative, on reversing doxorubicin drug resistance in human hepatocellular carcinoma cells.Oncotarget2017818297602977010.18632/oncotarget.1596428423656
     [Google Scholar]
  51. XieD.Y. ZhuK. RenZ.G. ZhouJ. FanJ. GaoQ. A review of 2022 Chinese clinical guidelines on the management of hepatocellular carcinoma: Updates and insights.Hepatobiliary Surg. Nutr.202312221622810.21037/hbsn‑22‑46937124695
     [Google Scholar]
  52. SunJ. MaoF. LiuC. ZhangF. JiangD. GuoW. HuoL. ZhouL. LauW.Y. ShiJ. ChengS. Combined FOLFOX4 with all-trans retinoic acid versus FOLFOX4 with placebo in treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: A randomized, double-blind comparative study.Signal Transduct. Target. Ther.20238136810.1038/s41392‑023‑01604‑337752117
     [Google Scholar]
  53. FarhanM. Green tea catechins: Nature’s way of preventing and treating cancer.Int. J. Mol. Sci.202223181071310.3390/ijms23181071336142616
     [Google Scholar]
  54. JingF. LiX. JiangH. SunJ. GuoQ. Combating drug resistance in hepatocellular carcinoma: No awareness today, no action tomorrow.Biomed. Pharmacother.202316711556110.1016/j.biopha.2023.11556137757493
     [Google Scholar]
  55. GiannelliG. KoudelkovaP. DituriF. MikulitsW. Role of epithelial to mesenchymal transition in hepatocellular carcinoma.J. Hepatol.201665479880810.1016/j.jhep.2016.05.00727212245
     [Google Scholar]
  56. ThieryJ.P. AcloqueH. HuangR.Y.J. NietoM.A. Epithelial-mesenchymal transitions in development and disease.Cell2009139587189010.1016/j.cell.2009.11.00719945376
     [Google Scholar]
  57. ZhuH. WangD. ZhangL. XieX. WuY. LiuY. ShaoG. SuZ. Upregulation of autophagy by hypoxia-inducible factor-1α promotes EMT and metastatic ability of CD133+ pancreatic cancer stem-like cells during intermittent hypoxia.Oncol. Rep.201432393594210.3892/or.2014.329824994549
     [Google Scholar]
  58. ComerfordK.M. WallaceT.J. KarhausenJ. LouisN.A. MontaltoM.C. ColganS.P. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene.Cancer Res.200262123387339412067980
     [Google Scholar]
  59. FuJ. ChenY. CaoJ. LuoT. QianY.W. YangW. RenY-B. SuB. CaoG-W. YangY. YanY-Q. ShenF. WuM-C. FengG-S. WangH-Y. p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1α pathways.Hepatology201153118119210.1002/hep.2401521254169
     [Google Scholar]
  60. HuangD. CaoL. XiaoL. SongJ.X. ZhangY.J. ZhengP. ZhengS.G. Hypoxia induces actin cytoskeleton remodeling by regulating the binding of CAPZA1 to F-actin via PIP2 to drive EMT in hepatocellular carcinoma.Cancer Lett.201944811712710.1016/j.canlet.2019.01.04230742939
     [Google Scholar]
  61. YangM.H. WuK.J. TWIST activation by hypoxia inducible factor-1 (HIF-1): Implications in metastasis and development.Cell Cycle20087142090209610.4161/cc.7.14.632418635960
     [Google Scholar]
  62. YangJ. WeinbergR.A. Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis.Dev. Cell200814681882910.1016/j.devcel.2008.05.00918539112
     [Google Scholar]
  63. QinY. LiuH.J. LiM. ZhaiD.H. TangY.H. YangL. QiaoK.L. YangJ.H. ZhongW.L. ZhangQ. LiuY.R. YangG. SunT. YangC. Salidroside improves the hypoxic tumor microenvironment and reverses the drug resistance of platinum drugs via HIF-1α signaling pathway.EBioMedicine201838253610.1016/j.ebiom.2018.10.06930396856
     [Google Scholar]
  64. ZhaoX. LuY. NieY. FanD. MicroRNAs as critical regulators involved in regulating epithelial- mesenchymal transition.Curr. Cancer Drug Targets201313993594410.2174/1568009611313666009924168189
     [Google Scholar]
  65. FangY. ZhangX. HuangH. ZengZ. The interplay between noncoding RNAs and drug resistance in hepatocellular carcinoma: The big impact of little things.J. Transl. Med.202321136910.1186/s12967‑023‑04238‑937286982
     [Google Scholar]
  66. LiJ. BaoH. HuangZ. LiangZ. WangM. LinN. NiC. XuY. Little things with significant impact: miRNAs in hepatocellular carcinoma.Front. Oncol.202313119107010.3389/fonc.2023.119107037274242
     [Google Scholar]
  67. ZengT. LuoL. HuangY. YeX. LinJ. Upregulation of miR-138 Increases Sensitivity to Cisplatin in Hepatocellular Carcinoma by Regulating EZH2.BioMed Res. Int.20212021666591810.1155/2021/666591833748276
     [Google Scholar]
  68. RenW.W. LiD.D. ChenX. LiX.L. HeY.P. GuoL.H. LiuL-N. SunL-P. ZhangX-P. MicroRNA-125b reverses oxaliplatin resistance in hepatocellular carcinoma by negatively regulating EVA1A mediated autophagy.Cell Death Dis.20189554710.1038/s41419‑018‑0592‑z29749374
     [Google Scholar]
  69. CaoF. YinL.X. miR-122 enhances sensitivity of hepatocellular carcinoma to oxaliplatin via inhibiting MDR1 by targeting Wnt/β-catenin pathway.Exp. Mol. Pathol.2019106344310.1016/j.yexmp.2018.10.00930539797
     [Google Scholar]
  70. XuZ. SunY. WangD. SunH. LiuX. SNHG16 promotes tumorigenesis and cisplatin resistance by regulating miR-338-3p/PLK4 pathway in neuroblastoma cells.Cancer Cell Int.202020123610.1186/s12935‑020‑01291‑y32536824
     [Google Scholar]
  71. HanJ. LiJ. TangK. ZhangH. GuoB. HouN. HuangC. miR-338-3p confers 5-fluorouracil resistance in p53 mutant colon cancer cells by targeting the mammalian target of rapamycin.Exp. Cell Res.2017360232833610.1016/j.yexcr.2017.09.02328928082
     [Google Scholar]
  72. ShanY. LiX. YouB. ShiS. ZhangQ. YouY. MicroRNA-338 inhibits migration and proliferation by targeting hypoxia-induced factor 1α in nasopharyngeal carcinoma.Oncol. Rep.20153441943195210.3892/or.2015.419526260688
     [Google Scholar]
  73. YangX. ZiX.H. LncRNA SNHG1 alleviates OGD induced injury in BMEC via miR-338/HIF-1α axis.Brain Res.2019171417418110.1016/j.brainres.2018.11.00330414401
     [Google Scholar]
  74. QianW. HuangT. FengW. Circular RNA HIPK3 promotes EMT of cervical cancer through sponging miR-338-3p to up-regulate HIF-1α.Cancer Manag. Res.20201217718710.2147/CMAR.S23223532021434
     [Google Scholar]
  75. WeiH. CaoC. WeiX. MengM. WuB. MengL. WeiX. GuS. LiH. Circular RNA circVEGFC accelerates high glucose-induced vascular endothelial cells apoptosis through miR-338-3p/HIF-1α/VEGFA axis.Aging (Albany NY)20201214143651437510.18632/aging.10347832680978
     [Google Scholar]
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Epigallocatechin Gallate Derivative Y6 Reverses Oxaliplatin Resistance in Hepatocellular Carcinoma via Targeting the MiR-338-3p/HIF-1α/TWIST Axis to Inhibit EMT
Recent Patents on Anti-Cancer Drug Discovery 20, 753 (2025); https://doi.org/10.2174/0115748928293750240619092747
/content/journals/pra/10.2174/0115748928293750240619092747
/content/journals/pra/10.2174/0115748928293750240619092747
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  • Article Type:     Research Article
Keyword(s): EMT; epigallocatechin-3-gallate (EGCG); miR-338-3p; oxaliplatin-resistance; resistance reversal agent; Y6

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