Skip to content
2000
Volume 25, Issue 9
  • ISSN: 1871-5206
  • E-ISSN: 1875-5992

Abstract

Background

Irisquinone, an important compound extracted from Semen Irisis, has been used clinically as a radiotherapy sensitizer for lung, oesophageal, head and neck, breast and leukemia cancers. However, the mechanism by which it acts against cancer is still unclear.

Objective

The present study aims to investigate the anti-tumor activity and mechanism of Irisquinone.

Methods

The effect of Irisquinone on cell viability and proliferation was evaluated using the CCK-8 assay. Fluorescence probe (Fast-TRFS) and DTNB assay were used to observe the inhibitory effect of Irisquinone on both intracellular and extracellular thioredoxin reductase (TrxR). The level of reactive oxygen species (ROS) in tumor cells was assessed using the DCFH-DA probe. Annexin V-FITC/PI, staining and microscopy experiments, were used to examine the apoptosis and pyroptosis. Western blotting analyses confirmed that Irisquinone induced apoptosis and pyroptosis in cancer cells by inhibiting TrxR to increase ROS generation.

Results

Our research has shown that Irisquinone has anti-proliferative effects on several cancer cell lines while having low toxicity to normal cells. The amount of ROS induced by inhibition of TrxR activated the BAX (pro-apoptotic protein) and caspase-1(the pro-pyroptotic protein) to induce apoptosis and pyroptosis.

Conclusion

Irisquinone showed anticancer activity through inhibiting TrxR. These results suggested that Irisquinone will be developed to be an anti-tumor drug possibility.

Loading

Article metrics loading...

/content/journals/acamc/10.2174/0118715206339230241202062826
2025-01-15
2025-08-16
Loading full text...

Full text loading...

References

  1. NordbergJ. ArnérE.S.J. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system.Free Radic. Biol. Med.200131111287131210.1016/S0891‑5849(01)00724‑911728801
    [Google Scholar]
  2. CortassaS. O’RourkeB. AonM.A. Redox-Optimized ROS Balance and the relationship between mitochondrial respiration and ROS.Biochim. Biophys. Acta Bioenerg.20141837228729510.1016/j.bbabio.2013.11.00724269780
    [Google Scholar]
  3. MohammadiF. SoltaniA. GhahremanlooA. JavidH. HashemyS.I. The thioredoxin system and cancer therapy: A review.Cancer Chemother. Pharmacol.201984592593510.1007/s00280‑019‑03912‑431367788
    [Google Scholar]
  4. PengS. YuS. ZhangJ. ZhangJ. 6-shogaol as a novel thioredoxin reductase inhibitor induces oxidative-stress-mediated apoptosis in HeLa cells.Int. J. Mol. Sci.2023245496610.3390/ijms2405496636902397
    [Google Scholar]
  5. ZhangJ. LiY. DuanD. YaoJ. GaoK. FangJ. Inhibition of thioredoxin reductase by alantolactone prompts oxidative stress-mediated apoptosis of HeLa cells.Biochem. Pharmacol.2016102344410.1016/j.bcp.2015.12.00426686580
    [Google Scholar]
  6. ArnérE.S.J. Focus on mammalian thioredoxin reductases — Important selenoproteins with versatile functions.Biochim. Biophys. Acta, Gen. Subj.20091790649552610.1016/j.bbagen.2009.01.01419364476
    [Google Scholar]
  7. ZhangJ. ZhangB. LiX. HanX. LiuR. FangJ. Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update.Med. Res. Rev.201939153910.1002/med.2150729727025
    [Google Scholar]
  8. JohnsonS.S. LiuD. EwaldJ.T. Robles-PlanellsC. PulliamC. ChristensenK.A. BayanboldK. WelsB.R. SolstS.R. O’DorisioM.S. MendaY. SpitzD.R. FathM.A. Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth.Cancer Biol. Ther.2024251238252410.1080/15384047.2024.238252439054566
    [Google Scholar]
  9. JiaJ. XuG. ZhuD. LiuH. ZengX. LiL. Advances in the functions of thioredoxin system in central nervous system diseases.Antioxid. Redox Signal.2022384-6ars.2022.007910.1089/ars.2022.007935761787
    [Google Scholar]
  10. SöderbergA. SahafB. RosénA. Thioredoxin reductase, a redox-active selenoprotein, is secreted by normal and neoplastic cells: presence in human plasma.Cancer Res.20006082281228910786696
    [Google Scholar]
  11. HellfritschJ. KirschJ. SchneiderM. FluegeT. WortmannM. FrijhoffJ. DagnellM. FeyT. EspositoI. KölleP. PogodaK. AngeliJ.P.F. IngoldI. KuhlencordtP. ÖstmanA. PohlU. ConradM. BeckH. Knockout of mitochondrial thioredoxin reductase stabilizes prolyl hydroxylase 2 and inhibits tumor growth and tumor-derived angiogenesis.Antioxid. Redox Signal.2015221193895010.1089/ars.2014.588925647640
    [Google Scholar]
  12. WelshS.J. BellamyW.T. BriehlM.M. PowisG. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis.Cancer Res.200262175089509512208766
    [Google Scholar]
  13. ChenY. CaiJ. JonesD.P. Mitochondrial thioredoxin in regulation of oxidant‐induced cell death.FEBS Lett.200658028-296596660210.1016/j.febslet.2006.11.00717113580
    [Google Scholar]
  14. DuanD. GuoX. TianJ. LiM. JinX. WangZ. WangL. YanY. XiaoJ. SongP. WangX. Targeting thioredoxin reductase by eupalinilide B promotes apoptosis of colorectal cancer cells in vitro and in vivo.Chem. Biol. Interact.202439911113710.1016/j.cbi.2024.11113738977166
    [Google Scholar]
  15. WangX. LiX. ZhangX. WangX. YangJ. LiuG. Design, synthesis and biological evaluation of novel curcumin-fluorouracil hybrids as potential anti-cancer agents.Biochem. Pharmacol.2024230Pt 111655910.1016/j.bcp.2024.11655939326677
    [Google Scholar]
  16. SeitzR. TümenD. KunstC. HeumannP. SchmidS. KandulskiA. MüllerM. GülowK. Exploring the thioredoxin system as a therapeutic target in cancer: Mechanisms and implications.Antioxidants2024139107810.3390/antiox1309107839334737
    [Google Scholar]
  17. ChenY. YinH. SunJ. ZhangG. ZhangY. ZengH. TrxR/Trx inhibitor butaselen ameliorates pulmonary fibrosis by suppressing NF-κB/TGF-β1/Smads signaling.Biomed. Pharmacother.202316911582210.1016/j.biopha.2023.11582237944440
    [Google Scholar]
  18. BjørklundG. ZouL. WangJ. ChasapisC.T. PeanaM. Thioredoxin reductase as a pharmacological target.Pharmacol. Res.202117410585410.1016/j.phrs.2021.10585434455077
    [Google Scholar]
  19. LeiH. WangG. ZhangJ. HanQ. Inhibiting TrxR suppresses liver cancer by inducing apoptosis and eliciting potent antitumor immunity.Oncol. Rep.20184063447345710.3892/or.2018.674030272318
    [Google Scholar]
  20. MukherjeeA. MartinS.G. The thioredoxin system: A key target in tumour and endothelial cells.Br. J. Radiol.200881special_issue_1S57S6810.1259/bjr/3418043518819999
    [Google Scholar]
  21. KimS.J. MiyoshiY. TaguchiT. TamakiY. NakamuraH. YodoiJ. KatoK. NoguchiS. High thioredoxin expression is associated with resistance to docetaxel in primary breast cancer.Clin. Cancer Res.200511238425843010.1158/1078‑0432.CCR‑05‑044916322305
    [Google Scholar]
  22. TonissenK.F. Di TrapaniG. Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy.Mol. Nutr. Food Res.20095318710310.1002/mnfr.20070049218979503
    [Google Scholar]
  23. JavvadiP. HertanL. KosoffR. DattaT. KolevJ. MickR. TuttleS.W. KoumenisC. Thioredoxin reductase-1 mediates curcumin-induced radiosensitization of squamous carcinoma cells.Cancer Res.20107051941195010.1158/0008‑5472.CAN‑09‑302520160040
    [Google Scholar]
  24. ZhangB. ZhangJ. PengS. LiuR. LiX. HouY. HanX. FangJ. Thioredoxin reductase inhibitors: A patent review.Expert Opin. Ther. Pat.201727554755610.1080/13543776.2017.127257627977313
    [Google Scholar]
  25. Chinese MedicineChinese Matea Medica.Shanghai, ChinaShanghai Science and Technology Press1999
    [Google Scholar]
  26. Luobusan, Mongolian Pharmacy.HohhotInner Mongolia People's Publishing House2006
    [Google Scholar]
  27. ZhaiR.X. FuX.J. RenX. Malinzi, a traditional medicinal plants: Comprehensive review of botany, medical application, chemical composition, and pharmacology.Heliyon2024103e24986https://doi.org/https://doi.org/10.1016/j.heliyon.2024.e2498610.1016/j.heliyon.2024.e2498638333853
    [Google Scholar]
  28. Li DongyueH.L. Progress on the pharmacological activity of Irisquinone.Heilongjiang Science and Technology Information201718
    [Google Scholar]
  29. LinB. WangG. WangQ. GeC. QinM. A new belamcandaquinone from the seeds of Iris bungei Maxim.Fitoterapia20118271137113910.1016/j.fitote.2011.07.01621820495
    [Google Scholar]
  30. XuH. SunG. WangH. YueQ. TangH. WuQ. Dynamic observation of the radiosensitive effect of irisquinone on rabbit VX2 lung transplant tumors by using fluorine-18-deoxyglucose positron emission tomography/computed tomography.Nucl. Med. Commun.201334322022810.1097/MNM.0b013e32835d373023276827
    [Google Scholar]
  31. HongY. SenguptaS. HurW. SimT. Identification of novel ROS inducers: Quinone derivatives tethered to long hydrocarbon chains.J. Med. Chem.20155893739375010.1021/jm501846y25826398
    [Google Scholar]
  32. D’AutréauxB. ToledanoM.B. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis.Nat. Rev. Mol. Cell Biol.200781081382410.1038/nrm225617848967
    [Google Scholar]
  33. BedardK. KrauseK.H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.Physiol. Rev.200787124531310.1152/physrev.00044.200517237347
    [Google Scholar]
  34. GasmiA. PeanaM. ArshadM. ButnariuM. MenzelA. BjørklundG. Krebs cycle: Activators, inhibitors and their roles in the modulation of carcinogenesis.Arch. Toxicol.20219541161117810.1007/s00204‑021‑02974‑933649975
    [Google Scholar]
  35. GorriniC. HarrisI.S. MakT.W. Modulation of oxidative stress as an anticancer strategy.Nat. Rev. Drug Discov.2013121293194710.1038/nrd400224287781
    [Google Scholar]
  36. XuQ. ZhangJ. ZhaoZ. ChuY. FangJ. Revealing PACMA 31 as a new chemical type TrxR inhibitor to promote cancer cell apoptosis.Biochimica. Biophys. Acta.2022186911932310.1016/j.bbamcr.2022.119323
    [Google Scholar]
  37. ZhengK. ZhangQ. GaL. MaY. LiangG. ZhaoY. Development of an efficient synthetic process for irisquinone.Synlett202435151795179810.1055/s‑0042‑1751560
    [Google Scholar]
  38. ZhuP. QianJ. XuZ. MengC. LiuJ. ShanW. ZhuW. WangY. YangY. ZhangW. ZhangY. LingY. Piperlonguminine and Piperine Analogues as TrxR Inhibitors that Promote ROS and Autophagy and Regulate p38 and Akt/mTOR Signaling.J. Nat. Prod.202083103041304910.1021/acs.jnatprod.0c0059933026807
    [Google Scholar]
  39. CaiL. QinX. XuZ. SongY. JiangH. WuY. RuanH. ChenJ. Comparison of cytotoxicity evaluation of anticancer drugs between real-time cell analysis and CCK-8 method.ACS Omega201947120361204210.1021/acsomega.9b0114231460316
    [Google Scholar]
  40. WangX. QianJ. ZhuP. HuaR. LiuJ. HangJ. MengC. ShanW. MiaoJ. LingY. Novel phenylmethylenecyclohexenone derivatives as potent TrxR inhibitors display high antiproliferative activity and induce ROS, apoptosis, and DNA damage.ChemMedChem202116470271210.1002/cmdc.20200066033085980
    [Google Scholar]
  41. ZhouM. MaW. ZhangY. WangW. XiaoG. YeS. ChenX. ZengH. YangN. Plasma thioredoxin reductase activity, a diagnostic biomarker, is up-regulated in resectable non-small cell lung cancers.Transl. Cancer Res.20176238339210.21037/tcr.2017.03.39
    [Google Scholar]
  42. DuanD. ZhangB. YaoJ. LiuY. SunJ. GeC. PengS. FangJ. Gambogic acid induces apoptosis in hepatocellular carcinoma SMMC-7721 cells by targeting cytosolic thioredoxin reductase.Free Radic. Biol. Med.201469152510.1016/j.freeradbiomed.2013.12.02724407164
    [Google Scholar]
  43. DuanD. ZhangB. YaoJ. LiuY. FangJ. Shikonin targets cytosolic thioredoxin reductase to induce ROS-mediated apoptosis in human promyelocytic leukemia HL-60 cells.Free Radic. Biol. Med.20147018219310.1016/j.freeradbiomed.2014.02.01624583460
    [Google Scholar]
  44. ZhaoY. ZuoX. LiuS. QianW. TangX. LuJ. A fluorescent probe to detect quick disulfide reductase activity in bacteria.Antioxidants202211237710.3390/antiox1102037735204259
    [Google Scholar]
  45. LiX. ZhangB. YanC. LiJ. WangS. WeiX. JiangX. ZhouP. FangJ. A fast and specific fluorescent probe for thioredoxin reductase that works via disulphide bond cleavage.Nat. Commun.2019101274510.1038/s41467‑019‑10807‑831227705
    [Google Scholar]
  46. GuoY. ZhangQ. ZhuQ. GaoJ. ZhuX. YuH. LiY. ZhangC. Copackaging photosensitizer and PD-L1 siRNA in a nucleic acid nanogel for synergistic cancer photoimmunotherapy.Sci. Adv.2022816eabn294110.1126/sciadv.abn294135442728
    [Google Scholar]
  47. XiongJ. HeJ. ZhuJ. PanJ. LiaoW. YeH. WangH. SongY. DuY. CuiB. XueM. ZhengW. KongX. JiangK. DingK. LaiL. WangQ. Lactylation-driven METTL3-mediated RNA m(6)A modification promotes immunosuppression of tumor-infiltrating myeloid cells.Mol Cell2022821660167710.1016/j.molcel.2022.02.033
    [Google Scholar]
  48. WangZ. ChenG. LiH. LiuJ. YangY. ZhaoC. LiY. ShiJ. ChenH. ChenG. Zotarolimus alleviates post-trabeculectomy fibrosis via dual functions of anti-inflammation and regulating AMPK/mTOR axis.Int. Immunopharmacol.2024142Pt B11317610.1016/j.intimp.2024.11317639303539
    [Google Scholar]
  49. WangW. YangJ. LiaoY.Y. ChengG. ChenJ. MoS. YuanL. ChengX.D. QinJ.J. ShaoZ. AspeterreuroneA. Aspeterreurone A, a cytotoxic dihydrobenzofuran–phenyl acrylate hybrid from the deep-sea-derived fungus Aspergillus terreus CC-S06-18.J. Nat. Prod.20208361998200310.1021/acs.jnatprod.0c0018932489099
    [Google Scholar]
  50. ChenC. ChenB. LinY. HeQ. YangJ. XiaoJ. PanZ. LiS. LiM. WangF. ZhangH. WangX. ZengJ. ChiW. MengK. WangH. ChenP. Cardamonin attenuates iron overload-induced osteoblast oxidative stress through the HIF-1α/ROS pathway.Int. Immunopharmacol.2024142Pt A11289310.1016/j.intimp.2024.11289339217878
    [Google Scholar]
  51. ZhangY. JiaQ. LiJ. WangJ. LiangK. XueX. ChenT. KongL. RenH. LiuW. WangP. GeJ. Copper‐bacteriochlorin nanosheet as a specific pyroptosis inducer for robust tumor immunotherapy.Adv. Mater.20233544230507310.1002/adma.20230507337421648
    [Google Scholar]
  52. ZhuangJ. WenX. ZhangY. ShanQ. ZhangZ. ZhengG. FanS. LiM. WuD. HuB. LuJ. ZhengY. TDP-43 upregulation mediated by the NLRP3 inflammasome induces cognitive impairment in 2 2′,4,4′-tetrabromodiphenyl ether (BDE-47)-treated mice.Brain Behav. Immun.2017659911010.1016/j.bbi.2017.05.01428532818
    [Google Scholar]
  53. BianM. SunY. LiuY. XuZ. FanR. LiuZ. LiuW. GoldA. A gold(I) complex containing an oleanolic acid derivative as a potential anti‐ovarian‐cancer agent by inhibiting TrxR and activating ROS‐mediated ERS.Chemistry202026317092710810.1002/chem.20200004532037581
    [Google Scholar]
  54. Pillai-KastooriL. Schutz-GeschwenderA.R. HarfordJ.A. A systematic approach to quantitative Western blot analysis.Anal. Biochem.202059311360810.1016/j.ab.2020.11360832007473
    [Google Scholar]
  55. QianJ. XuZ. MengC. LiuJ. HsuP.L. LiY. ZhuW. YangY. Morris-NatschkeS.L. LeeK.H. ZhangY. LingY. Design and synthesis of benzylidenecyclohexenones as TrxR inhibitors displaying high anticancer activity and inducing ROS, apoptosis, and autophagy.Eur. J. Med. Chem.202020411261010.1016/j.ejmech.2020.11261032736231
    [Google Scholar]
  56. LuJ. HolmgrenA. The thioredoxin antioxidant system.Free Radic. Biol. Med.201466758710.1016/j.freeradbiomed.2013.07.03623899494
    [Google Scholar]
  57. MittlerR. ROS are good.Trends Plant Sci.2017221111910.1016/j.tplants.2016.08.00227666517
    [Google Scholar]
  58. YangS. LianG. ROS and diseases: role in metabolism and energy supply.Mol. Cell. Biochem.20204671-211210.1007/s11010‑019‑03667‑931813106
    [Google Scholar]
  59. D’ArcyM.S. Cell death: A review of the major forms of apoptosis, necrosis and autophagy.Cell Biol. Int.201943658259210.1002/cbin.1113730958602
    [Google Scholar]
  60. ElmoreS. Apoptosis: A review of programmed cell death.Toxicol. Pathol.200735449551610.1080/0192623070132033717562483
    [Google Scholar]
  61. PistrittoG. TrisciuoglioD. CeciC. GarufiA. D’OraziG. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies.Aging (Albany NY)20168460361910.18632/aging.10093427019364
    [Google Scholar]
  62. MortezaeeK. SalehiE. Mirtavoos-mahyariH. MotevaseliE. NajafiM. FarhoodB. RosengrenR.J. SahebkarA. Mechanisms of apoptosis modulation by curcumin: Implications for cancer therapy.J. Cell. Physiol.20192348125371255010.1002/jcp.2812230623450
    [Google Scholar]
  63. MoranaO. WoodW. GregoryC.D. The apoptosis paradox in cancer.Int. J. Mol. Sci.2022233132810.3390/ijms2303132835163253
    [Google Scholar]
  64. JiangH. NiuC. GuoY. LiuZ. JiangY. Wedelolactone induces apoptosis and pyroptosis in retinoblastoma through promoting ROS generation.Int. Immunopharmacol.202211110885510.1016/j.intimp.2022.10885535905560
    [Google Scholar]
  65. AlamM. AlamS. ShamsiA. AdnanM. ElasbaliA.M. Al-SoudW.A. AlreshidiM. HawsawiY.M. TippanaA. PasupuletiV.R. HassanM.I. Bax/Bcl-2 cascade is regulated by the EGFR pathway: Therapeutic targeting of non-small cell lung cancer.Front. Oncol.20221286967210.3389/fonc.2022.86967235402265
    [Google Scholar]
  66. WangY. ZhangR. HuangX. HeX. GengS. PanS. GuoW. LiuX. DangY. QuJ. MaH. ZhaoX. CD39 inhibitor (POM-1) enhances radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells by promoting apoptosis through the Bax/Bcl-2/Caspase 9/Caspase 3 pathway.Int. Immunopharmacol.2024142Pt B11324210.1016/j.intimp.2024.11324239321701
    [Google Scholar]
  67. LiD. YangC. SunL. ZhaoZ. LiuJ. ZhangC. SunD. ZhangQ. High fluoride aggravates cadmium-mediated nephrotoxicity of renal tubular epithelial cells through ROS-PINK1/Parkin pathway.Sci. Total Environ.202495317592710.1016/j.scitotenv.2024.17592739236818
    [Google Scholar]
  68. FangY. TianS. PanY. LiW. WangQ. TangY. YuT. WuX. ShiY. MaP. ShuY. Pyroptosis: A new frontier in cancer.Biomed. Pharmacother.202012110959510.1016/j.biopha.2019.10959531710896
    [Google Scholar]
  69. KovacsS.B. MiaoE.A. Gasdermins: Effectors of pyroptosis.Trends Cell Biol.201727967368410.1016/j.tcb.2017.05.00528619472
    [Google Scholar]
  70. TanY. ChenQ. LiX. ZengZ. XiongW. LiG. LiX. YangJ. XiangB. YiM. Pyroptosis: A new paradigm of cell death for fighting against cancer.J. Exp. Clin. Cancer Res.202140115310.1186/s13046‑021‑01959‑x33941231
    [Google Scholar]
  71. YangF. BettadapuraS.N. SmeltzerM.S. ZhuH. WangS. Pyroptosis and pyroptosis-inducing cancer drugs.Acta Pharmacol. Sin.202243102462247310.1038/s41401‑022‑00887‑635288674
    [Google Scholar]
  72. DuT. GaoJ. LiP. WangY. QiQ. LiuX. LiJ. WangC. DuL. Pyroptosis, metabolism, and tumor immune microenvironment.Clin. Transl. Med.2021118e49210.1002/ctm2.49234459122
    [Google Scholar]
  73. LovelessR. BloomquistR. TengY. Pyroptosis at the forefront of anticancer immunity.J. Exp. Clin. Cancer Res.202140126410.1186/s13046‑021‑02065‑834429144
    [Google Scholar]
  74. YangZ. ChenZ. WangY. WangZ. ZhangD. YueX. ZhengY. LiL. BianE. ZhaoB. A novel defined pyroptosis-related gene signature for predicting prognosis and treatment of glioma.Front. Oncol.20221271792610.3389/fonc.2022.71792635433410
    [Google Scholar]
  75. MuendleinH.I. JettonD. ConnollyW.M. EidellK.P. MagriZ. SmirnovaI. PoltorakA. cFLIP L protects macrophages from LPS-induced pyroptosis via inhibition of complex II formation.Science202036764841379138410.1126/science.aay387832193329
    [Google Scholar]
  76. WangJ. WuZ. ZhuM. ZhaoY. XieJ. ROS induced pyroptosis in inflammatory disease and cancer.Front. Immunol.202415137899010.3389/fimmu.2024.137899039011036
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206339230241202062826
Loading
/content/journals/acamc/10.2174/0118715206339230241202062826
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

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