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Volume 18, Issue 4
  • ISSN: 2212-7968
  • E-ISSN: 1872-3136

Abstract

Introduction

Gallic acid (GA), a natural phenolic acid, has been reported as an antitumor agent in various cancer cells. Although some mechanisms, such as apoptosis, are well known, the details of other mechanisms, such as their pro-oxidant and autophagy activity, are still considerable.

Methods

The pro-oxidative activity and anti-proliferative activity of GA on HEK 293 and HepG2 cells were measured in the absence and presence of exogenous Cu (II) and Fe (II). Furthermore, colony forming, ROS generation, apoptosis induction, autophagy and mitochondrial membrane potential (MMP) were examined.

Results

HepG2 cells treated with GA + Cu (II) significantly reduced cell viability ( <0.001). GA +Cu (II) induced morphological changes in HepG2 cells and stimulated apoptotic cell death. Moreover, GA +Cu (II) triggered the mitochondrial-dependent apoptotic pathway by increasing intracellular ROS levels and disrupting MMP. Furthermore, GA+ Cu (II) significantly reduced the Plating Efficiency and Surviving Fraction while increasing autophagic vacuoles in the HepG2 cells.

Conclusion

According to our results, GA played a pro-oxidant role in the presence of Cu (II), triggered apoptosis by increased ROS and disruption of MMP. This combination also induced autophagy in HepG2. These effects hold promise for future anticancer research.

© 2024 Bentham Science Publishers
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2025-03-07

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References

  1. LiuZ.H. YangC.X. ZhangL. YangC.Y. XuX.Q. Baicalein, as a prooxidant, triggers mitochondrial apoptosis in MCF-7 human breast cancer cells through mobilization of intracellular copper and reactive oxygen species generation.OncoTargets Ther.201912107491076110.2147/OTT.S22281931849483
     [Google Scholar]
  2. SahooBM BanikBK BorahP JainA Reactive oxygen species (ROS): Key components in cancer therapies.Anticancer Agents Med Chem2022222215222
     [Google Scholar]
  3. ShinJ. SongM.H. OhJ.W. KeumY.S. SainiR.K. Pro-oxidant actions of carotenoids in triggering apoptosis of cancer cells: A review of emerging evidence.Antioxidants20209653210.3390/antiox906053232560478
     [Google Scholar]
  4. JomovaK. RaptovaR. AlomarS.Y. AlwaselS.H. NepovimovaE. KucaK. ValkoM. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: Chronic diseases and aging.Arch. Toxicol.202397102499257410.1007/s00204‑023‑03562‑937597078
     [Google Scholar]
  5. SabahiZ. HasanS.M.F. AyatollahiS.A. FarmaniF. AfsariA. MoeinM. Improvement of phenolic compound extraction by using ion exchange chromatography and evaluation of biological activities of polyphenol-enriched fraction of Rosa canina fruits.Iran. J. Pharm. Res.2022211e12655810.5812/ijpr‑12655836942078
     [Google Scholar]
  6. SabahiZ. FarmaniF. SoltaniF. MoeinM. DNA protection, antioxidant and xanthine oxidase inhibition activities of polyphenol-enriched fraction of Berberis integerrima Bunge fruits.Iran. J. Basic Med. Sci.201821441141629796226
     [Google Scholar]
  7. Vaghari-TabariM. FernsG.A. QujeqD. AndevariA.N. SabahiZ. MoeinS. Signaling, metabolism, and cancer: An important relationship for therapeutic intervention.J. Cell. Physiol.202123685512553210.1002/jcp.3027633580511
     [Google Scholar]
  8. FormanH.J. ZhangH. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy.Nat. Rev. Drug Discov.202120968970910.1038/s41573‑021‑00233‑134194012
     [Google Scholar]
  9. León-GonzálezA.J. AugerC. Schini-KerthV.B. Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy.Biochem. Pharmacol.201598337138010.1016/j.bcp.2015.07.01726206193
     [Google Scholar]
  10. LeeW.L. HuangJ.Y. ShyurL.F. Phytoagents for cancer management: Regulation of nucleic acid oxidation, ROS, and related mechanisms.Oxid. Med. Cell. Longev.2013201312210.1155/2013/92580424454991
     [Google Scholar]
  11. JungM. MertensC. TomatE. BrüneB. Iron as a central player and promising target in cancer progression.Int. J. Mol. Sci.201920227310.3390/ijms2002027330641920
     [Google Scholar]
  12. LelièvreP. SanceyL. CollJ.L. DeniaudA. BusserB. The multifaceted roles of copper in cancer: A trace metal element with dysregulated metabolism, but also a target or a bullet for therapy.Cancers (Basel)20201212359410.3390/cancers1212359433271772
     [Google Scholar]
  13. BezerraD. MilitãoG. De MoraisM. De SousaD. The dual antioxidant/prooxidant effect of eugenol and its action in cancer development and treatment.Nutrients2017912136710.3390/nu912136729258206
     [Google Scholar]
  14. ProcházkováD. BoušováI. WilhelmováN. Antioxidant and prooxidant properties of flavonoids.Fitoterapia201182451352310.1016/j.fitote.2011.01.01821277359
     [Google Scholar]
  15. MoeinM. SabahiZ. SoltaniF. Insight into DNA protection ability of medicinal herbs and potential mechanisms in hydrogen peroxide damages model.Asian Pac. J. Trop. Biomed.20188212012910.4103/2221‑1691.225616
     [Google Scholar]
  16. YenG.C. DuhP.D. TsaiH.L. HuangS.L. Pro-oxidative properties of flavonoids in human lymphocytes.Biosci. Biotechnol. Biochem.20036761215122210.1271/bbb.67.121512843645
     [Google Scholar]
  17. LeeY.S. Role of NADPH oxidase-mediated generation of reactive oxygen species in the mechanism of apoptosis induced by phenolic acids in HepG2 human hepatoma cells.Arch. Pharm. Res.200528101183118910.1007/BF0297298416276977
     [Google Scholar]
  18. KiruthigaC. DeviK.P. NabaviS.M. BishayeeA. Autophagy: A potential therapeutic target of polyphenols in hepatocellular carcinoma.Cancers (Basel)202012356210.3390/cancers1203056232121322
     [Google Scholar]
  19. LiuX. WangN. HeZ. ChenC. MaJ. LiuX. DengS. XieL. Diallyl trisulfide inhibits osteosarcoma 143B cell migration, invasion and EMT by inducing autophagy.Heliyon2024105e2668110.1016/j.heliyon.2024.e2668138434350
     [Google Scholar]
  20. AfshariA MoeinM AfsariA SabahiZ. Antiproliferative effects of ferulic, coumaric, and caffeic acids in HepG2 cells by hTERT downregulation.Adv. Pharmacol. Pharmaceut. Sci.202220221850732
     [Google Scholar]
  21. Madrigal-MatuteJ. CuervoA.M. Regulation of liver metabolism by autophagy.Gastroenterology2016150232833910.1053/j.gastro.2015.09.04226453774
     [Google Scholar]
  22. HaghshenasM. FirouzabadiN. AkbarizadehA.R. RashediniaM. Combination of metformin and gallic acid induces autophagy and apoptosis in human breast cancer cells.Res. Pharm. Sci.202318666367510.4103/1735‑5362.38995639005566
     [Google Scholar]
  23. KulikovA.V. LuchkinaE.A. GogvadzeV. ZhivotovskyB. Mitophagy: Link to cancer development and therapy.Biochem. Biophys. Res. Commun.2017482343243910.1016/j.bbrc.2016.10.08828212727
     [Google Scholar]
  24. GheenaS. EzhilarasanD. Syringic acid triggers reactive oxygen species–mediated cytotoxicity in HepG2 cells.Hum. Exp. Toxicol.201938669470210.1177/096032711983917330924378
     [Google Scholar]
  25. WangX. CaoJ. LiZ. XuR. GuoY. PuF. XiaoX. DuH. HeJ. LuS. Co-amorphous mixture of erlotinib hydrochloride and gallic acid for enhanced antitumor effects.J. Drug Deliv. Sci. Technol.20249110520010.1016/j.jddst.2023.105200
     [Google Scholar]
  26. KowalskiS. KarskaJ. TotaM. SkinderowiczK. KulbackaJ. Drąg-ZalesińskaM. Natural compounds in non-melanoma skin cancer: Prevention and treatment.Molecules202429372810.3390/molecules2903072838338469
     [Google Scholar]
  27. LuY. JiangF. JiangH. WuK. ZhengX. CaiY. KatakowskiM. ChoppM. ToS.S.T. Gallic acid suppresses cell viability, proliferation, invasion and angiogenesis in human glioma cells.Eur. J. Pharmacol.20106412-310210710.1016/j.ejphar.2010.05.04320553913
     [Google Scholar]
  28. Rezaei-SereshtH. CheshomiH. FalanjiF. Movahedi-MotlaghF. HashemianM. MireskandariE. Cytotoxic activity of caffeic acid and gallic acid against MCF-7 human breast cancer cells: An in silico and in vitro study.Avicenna J. Phytomed.20199657458631763216
     [Google Scholar]
  29. RashediniaM. NasrollahiA. ShafaghatM. MomeniS. IranpakF. SaberzadehJ. ArabsolgharR. SabahiZ. Syringic acid induces cancer cell death in the presence of Cu (II) ions via pro-oxidant activity.Asian Pac. J. Trop. Biomed.202212627027810.4103/2221‑1691.345519
     [Google Scholar]
  30. FarmaniF. SabahiZ. Protective Effects of Anthocyanin Fraction of Berberis integerrima Bunge Fruits against H2O2 Induced Cytotoxicity in MCF7 and HepG2 Cells.J. Young Pharm.201810328829110.5530/jyp.2018.10.64
     [Google Scholar]
  31. MontaseriH. AlipourS. VakilinezhadM. Development, evaluation and optimization of superparamagnetite nanoparticles prepared by co-precipitation method.Res. Pharm. Sci.201712427428210.4103/1735‑5362.21204428855938
     [Google Scholar]
  32. FatehiR. RashediniaM. AkbarizadehA.R. zamaniM. FirouzabadiN. Metformin enhances anti-cancer properties of resveratrol in MCF-7 breast cancer cells via induction of apoptosis, autophagy and alteration in cell cycle distribution.Biochem. Biophys. Res. Commun.202364413013910.1016/j.bbrc.2022.12.06936641965
     [Google Scholar]
  33. Combination of NDRG2 overexpression, X-ray radiation and docetaxel enhances apoptosis and inhibits invasiveness properties of LNCaP cells. Zarei, M.A.; Dehbidi, G.R.; Takhshid, M.A., Eds.;Urologic Oncology: Seminars and Original Investigations.AmsterdamElsevier2020
     [Google Scholar]
  34. FatehiR. NouraeiM. PanahiyanM. RashediniaM. FirouzabadiN. Modulation of ACE2/Ang1-7/Mas and ACE/AngII/AT1 axes affects anticancer properties of sertraline in MCF-7 breast cancer cells.Biochem. Biophys. Rep.20243810173810.1016/j.bbrep.2024.10173838831897
     [Google Scholar]
  35. RashediniaM. SaberzadehJ. KhodaeiF. Mashayekhi SardoeiN. AlimohammadiM. ArabsolgharR. Effect of sodium benzoate on apoptosis and mitochondrial membrane potential after aluminum toxicity in PC-12 cell line.Iranian J. Toxicol.202014423724410.32598/IJT.10.4.677.1
     [Google Scholar]
  36. MengX. XiaC. YeQ. NieX. tert -Butyl- p -benzoquinone induces autophagy by inhibiting the Akt/mTOR signaling pathway in RAW 264.7 cells.Food Funct.20201154193420110.1039/D0FO00281J32352125
     [Google Scholar]
  37. LohiteshK. ChowdhuryR. MukherjeeS. Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: An insight.Cancer Cell Int.20181814410.1186/s12935‑018‑0538‑729568237
     [Google Scholar]
  38. González-BártulosM. Aceves-LuqueroC. QualaiJ. CussóO. MartínezM.A. Fernández de MattosS. MenéndezJ.A. VillalongaP. CostasM. RibasX. MassaguerA. Pro-oxidant activity of amine-pyridine-based iron complexes efficiently kills cancer and cancer stem-like cells.PLoS One2015109e013780010.1371/journal.pone.013780026368127
     [Google Scholar]
  39. NurG. NazıroğluM. DeveciH.A. Synergic prooxidant, apoptotic and TRPV1 channel activator effects of alpha-lipoic acid and cisplatin in MCF-7 breast cancer cells.J. Recept. Signal Transduct. Res.201737656957710.1080/10799893.2017.136912128849985
     [Google Scholar]
  40. KimSJ KimHS SeoYR Understanding of ROS-inducing strategy in anticancer therapy.Oxid. Med. Cell Longev.201920195381692
     [Google Scholar]
  41. KohanR. CollinA. GuizzardiS. Tolosa de TalamoniN. PicottoG. Reactive oxygen species in cancer: A paradox between pro- and anti-tumour activities.Cancer Chemother. Pharmacol.202086111310.1007/s00280‑020‑04103‑232572519
     [Google Scholar]
  42. WangY. YuL. DingJ. ChenY. Iron Metabolism in Cancer.Int. J. Mol. Sci.20182019510.3390/ijms2001009530591630
     [Google Scholar]
  43. YangY. FanH. GuoZ. Modulation of metal homeostasis for cancer therapy.ChemPlusChem2024896e20230062410.1002/cplu.20230062438315756
     [Google Scholar]
  44. KoedrithP. SeoY.R. Advances in carcinogenic metal toxicity and potential molecular markers.Int. J. Mol. Sci.201112129576959510.3390/ijms1212957622272150
     [Google Scholar]
  45. ZhangP. SadlerP.J. Redox‐active metal complexes for anticancer therapy.Eur. J. Inorg. Chem.20172017121541154810.1002/ejic.201600908
     [Google Scholar]
  46. SabahiZ FarmaniF MousavinoorE MoeinM. Valorization of waste water of Rosa damascena oil distillation process by ion exchange chromatography.Sci. World J.20202020540949310.1155/2020/5409493
     [Google Scholar]
  47. SturmB. GoldenbergH. Scheiber-MojdehkarB. Transient increase of the labile iron pool in HepG2 cells by intravenous iron preparations.Eur. J. Biochem.2003270183731373810.1046/j.1432‑1033.2003.03759.x12950256
     [Google Scholar]
  48. BadhaniB. SharmaN. KakkarR. Gallic acid: A versatile antioxidant with promising therapeutic and industrial applications.RSC Advances2015535275402755710.1039/C5RA01911G
     [Google Scholar]
  49. SabahiZ KhoshnoudMJ HosseiniS KhoshraftarF RashediniaM. Syringic acid attenuates cardiomyopathy in Streptozotocin-induced diabetic rats.Adv Pharmacol Pharm Sci.20212021501809210.1155/2021/
     [Google Scholar]
  50. YilmazB.S. Antimicrobial and anticancer activity of gallic acid–Cu(II) hybrid nanoflowers and gallic acid–Zn(II) hybrid nanoflowers.J. Inorg. Organometallic Polym. Mater.202420242
     [Google Scholar]
  51. MuK. YaoY. WangD. KittsD.D. Prooxidant capacity of phenolic acids defines antioxidant potential.Biochim. Biophys. Acta, Gen. Subj.20231867713037110.1016/j.bbagen.2023.13037137121280
     [Google Scholar]
  52. SakihamaY. CohenM.F. GraceS.C. YamasakiH. Plant phenolic antioxidant and prooxidant activities: Phenolics-induced oxidative damage mediated by metals in plants.Toxicology20021771678010.1016/S0300‑483X(02)00196‑812126796
     [Google Scholar]
  53. RajashekarC.B. Dual role of plant phenolic compounds as antioxidants and prooxidants.Am. J. Plant Sci.2023141152810.4236/ajps.2023.141002
     [Google Scholar]
  54. EghbaliferizS. IranshahiM. Prooxidant activity of polyphenols, flavonoids, anthocyanins and carotenoids: Updated review of mechanisms and catalyzing metals.Phytother. Res.20163091379139110.1002/ptr.564327241122
     [Google Scholar]
  55. AndrésC.M.C. Pérez de la LastraJ.M. JuanC.A. PlouF.J. Pérez-LebeñaE. Polyphenols as antioxidant/pro-oxidant compounds and donors of reducing species: Relationship with human antioxidant metabolism.Processes (Basel)2023119277110.3390/pr11092771
     [Google Scholar]
  56. do CarmoM.A.V. GranatoD. AzevedoL. Antioxidant/pro-oxidant and antiproliferative activities of phenolic-rich foods and extracts: A cell-based point of view.Adv Food Nutr Res.202198253280
     [Google Scholar]
  57. LabieniecM. GabryelakT. Study of interactions between phenolic compounds and H2O2 or Cu(II) ions in B14 Chinese hamster cells.Cell Biol. Int.2006301076176810.1016/j.cellbi.2006.05.01316820308
     [Google Scholar]
  58. FarhanM. El OirdiM. AatifM. NahviI. MuteebG. AlamM.W. Soy isoflavones induce cell death by copper-mediated mechanism: Understanding its anticancer properties.Molecules2023287292510.3390/molecules2807292537049690
     [Google Scholar]
  59. FarhanM. RizviA. AliF. AhmadA. AatifM. MalikA. AlamM.W. MuteebG. AhmadS. NoorA. SiddiquiF.A. Pomegranate juice anthocyanidins induce cell death in human cancer cells by mobilizing intracellular copper ions and producing reactive oxygen species.Front. Oncol.20221299834610.3389/fonc.2022.99834636147917
     [Google Scholar]
  60. YenG.C. DuhP.D. TsaiH.L. Antioxidant and pro-oxidant properties of ascorbic acid and gallic acid.Food Chem.200279330731310.1016/S0308‑8146(02)00145‑0
     [Google Scholar]
  61. ChiaY.C. RajbanshiR. CalhounC. ChiuR.H. Anti-neoplastic effects of gallic acid, a major component of Toona sinensis leaf extract, on oral squamous carcinoma cells.Molecules201015118377838910.3390/molecules1511837721081858
     [Google Scholar]
  62. BarikS.K. DehuryB. RussellW.R. MoarK.M. CruickshankM. ScobbieL. HoggardN. Analysis of polyphenolic metabolites from in vitro gastrointestinal digested soft fruit extracts identify malvidin-3-glucoside as an inhibitor of PTP1B.Biochem. Pharmacol.202017811410910.1016/j.bcp.2020.11410932569626
     [Google Scholar]
  63. AgarwalC. TyagiA. AgarwalR. Gallic acid causes inactivating phosphorylation of cdc25A/cdc25C-cdc2 via ATM-Chk2 activation, leading to cell cycle arrest, and induces apoptosis in human prostate carcinoma DU145 cells.Mol. Cancer Ther.20065123294330210.1158/1535‑7163.MCT‑06‑048317172433
     [Google Scholar]
  64. ZorovaL.D. PopkovV.A. PlotnikovE.Y. SilachevD.N. PevznerI.B. JankauskasS.S. BabenkoV.A. ZorovS.D. BalakirevaA.V. JuhaszovaM. SollottS.J. ZorovD.B. Mitochondrial membrane potential.Anal. Biochem.2018552505910.1016/j.ab.2017.07.00928711444
     [Google Scholar]
  65. KroemerG. GalluzziL. BrennerC. Mitochondrial membrane permeabilization in cell death.Physiol. Rev.20078719916310.1152/physrev.00013.200617237344
     [Google Scholar]
  66. ZorovD.B. JuhaszovaM. SollottS.J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release.Physiol. Rev.201494390995010.1152/physrev.00026.201324987008
     [Google Scholar]
  67. DengS. ShanmugamM.K. KumarA.P. YapC.T. SethiG. BishayeeA. Targeting autophagy using natural compounds for cancer prevention and therapy.Cancer201912581228124610.1002/cncr.3197830748003
     [Google Scholar]
  68. JosifovskaN. AlbertR. NagymihályR. LytvynchukL. MoeM.C. KaarnirantaK. VerébZ.J. PetrovskiG. Resveratrol as inducer of autophagy, pro-survival, and anti-inflammatory stimuli in cultured human RPE cells.Int. J. Mol. Sci.202021381310.3390/ijms2103081332012692
     [Google Scholar]
  69. GanguliA. ChoudhuryD. DattaS. BhattacharyaS. ChakrabartiG. Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis.Biochimie2014107Pt B33834910.1016/j.biochi.2014.10.00125308836
     [Google Scholar]
  70. LeeY.J. KimN.Y. SuhY.A. LeeC. Involvement of ROS in curcumin-induced autophagic cell death.Korean J. Physiol. Pharmacol.20111511710.4196/kjpp.2011.15.1.121461234
     [Google Scholar]
  71. WenM. WuJ. LuoH. ZhangH. Galangin induces autophagy through upregulation of p53 in HepG2 cells.Pharmacology2012895-624725510.1159/00033704122507894
     [Google Scholar]
  72. AugusteS. YanB. MaginaR. XueL. NetoC. GuoM. Cranberry extracts and cranberry polyphenols induce mitophagy in human fibroblast cells.Food Biosci.20245710354910.1016/j.fbio.2023.103549
     [Google Scholar]
  73. KameyamaK. MotoyamaK. TanakaN. YamashitaY. HigashiT. ArimaH. Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin.Int. J. Nanomedicine2017123433344610.2147/IJN.S13348228496320
     [Google Scholar]
  74. LiuJ. WuY. MengS. XuP. LiS. LiY. HuX. OuyangL. WangG. Selective autophagy in cancer: Mechanisms, therapeutic implications, and future perspectives.Mol. Cancer20242312210.1186/s12943‑024‑01934‑y38262996
     [Google Scholar]
  75. WangJ. ZhengF. WangD. YangQ. Regulation of ULK1 by WTAP/IGF2BP3 axis enhances mitophagy and progression in epithelial ovarian cancer.Cell Death Dis.20241519710.1038/s41419‑024‑06477‑038286802
     [Google Scholar]
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Prooxidant Activity of Gallic Acid by Promote Reactive Oxygen Species, Apoptosis and Autophagy in HepG2 Cells In Vitro
Curr Chem Biol 18, 259 (2024); https://doi.org/10.2174/0122127968314625241015155536
/content/journals/ccb/10.2174/0122127968314625241015155536
/content/journals/ccb/10.2174/0122127968314625241015155536
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  • Article Type:     Research Article
Keyword(s): apoptosis; autophagy; copper; Gallic acid; pro-oxidant; reactive oxygen specious

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