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2000
Volume 32, Issue 33
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Background

Skin melanoma is a potentially lethal cancer and ranks as the 17th most common cancer worldwide. Overcoming resistance to advanced-stage melanoma is a significant challenge in its treatment. Parthenolide (PAR) is recognized as a potent anticancer small molecule, yet its potential in treating melanoma is poorly investigated.

Objective

Our objective was to investigate the apoptotic and anti-metastatic properties of PAR against the A2058 melanoma cells .

Methods

This study employed various assays, such as cytotoxicity, apoptosis, cell cycle analysis, reactive oxygen species (ROS) production, mRNA expressions, western blotting, gelatin zymography, and scratch assay. The synergy between PAR and dacarbazine, a chemotherapy drug for treating skin cancer, was also assessed.

Results

Our study revealed that PAR significantly reduced the viability of A2058 cancer cells, demonstrating greater potency against cancer cells compared to normal L929 cells (IC: 20 µM 27 µM after 24 h). PAR increased ROS production, elevated mRNA expression of pro-apoptotic Bax and NME1 genes, and decreased expression of the MITF gene. PAR induced apoptosis and cell cycle arrest in A2058 cells, as evidenced by the increased proportion of cells in the late apoptotic phase and sub-G1 cell cycle arrest. MMP-2 and MMP-9 mRNA and protein expressions, gelatinase activity, and the migration of A2058 cells were also decreased by PAR, suggesting its potential to suppress cancer cell invasion.

Conclusion

These results, along with the synergic effect with dacarbazine, indicated that PAR may have the potential to be a therapeutic drug for melanoma by triggering apoptosis and suppressing invasion and migration.

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References

  1. KhosraviS. TamK.J. ArdekaniG.S. MartinkaM. McElweeK.J. OngC.J. eIF4E is an adverse prognostic marker of melanoma patient survival by increasing melanoma cell invasion.J. Invest. Dermatol.201513551358136710.1038/jid.2014.55225562667
     [Google Scholar]
  2. PatelM. EckburgA. GantiwalaS. HartZ. DeinJ. LamK. PuriN. Resistance to molecularly targeted therapies in melanoma.Cancers (Basel)2021135111510.3390/cancers1305111533807778
     [Google Scholar]
  3. LesiakK. KoprowskaK. ZalesnaI. NejcD. DüchlerM. CzyzM. Parthenolide, a sesquiterpene lactone from the medical herb feverfew, shows anticancer activity against human melanoma cells in vitro.Melanoma Res.2010201213410.1097/CMR.0b013e328333bbe419949351
     [Google Scholar]
  4. Gray-SchopferV. WellbrockC. MaraisR. Melanoma biology and new targeted therapy.Nature2007445713085185710.1038/nature0566117314971
     [Google Scholar]
  5. TorreL.A. BrayF. SiegelR.L. FerlayJ. Lortet-TieulentJ. JemalA. Global cancer statistics, 2012.CA Cancer J. Clin.20156528710810.3322/caac.2126225651787
     [Google Scholar]
  6. MontorW.R. SalasA.R.O.S.E. MeloF.H.M. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: The current arsenal of inhibitors.Mol. Cancer20181715510.1186/s12943‑018‑0792‑229455659
     [Google Scholar]
  7. SchrankZ. ChhabraG. LinL. IderzorigT. OsudeC. KhanN. KuckovicA. SinghS. MillerR. PuriN. Current molecular-targeted therapies in NSCLC and their mechanism of resistance.Cancers (Basel)201810722410.3390/cancers1007022429973561
     [Google Scholar]
  8. Sharifi-RadJ. OzleyenA. Boyunegmez TumerT. Oluwaseun AdetunjiC. El OmariN. BalahbibA. TaheriY. BouyahyaA. MartorellM. MartinsN. ChoW.C. Natural products and synthetic analogs as a source of antitumor drugs.Biomolecules201991167910.3390/biom911067931683894
     [Google Scholar]
  9. HuangM. LuJ.J. DingJ. Natural products in cancer therapy: Past, present and future.Nat. Prod. Bioprospect.202111151310.1007/s13659‑020‑00293‑733389713
     [Google Scholar]
  10. ZhuS. SunP. BennettS. CharlesworthO. TanR. PengX. GuQ. KujanO. XuJ. The therapeutic effect and mechanism of parthenolide in skeletal disease, cancers, and cytokine storm.Front. Pharmacol.202314111121810.3389/fphar.2023.111121837033622
     [Google Scholar]
  11. GuzmanM.L. RossiR.M. NeelakantanS. LiX. CorbettC.A. HassaneD.C. BeckerM.W. BennettJ.M. SullivanE. LachowiczJ.L. VaughanA. SweeneyC.J. MatthewsW. CarrollM. LiesveldJ.L. CrooksP.A. JordanC.T. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells.Blood2007110134427443510.1182/blood‑2007‑05‑09062117804695
     [Google Scholar]
  12. SunY. St ClairD.K. XuY. CrooksP.A. St ClairW.H. A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells.Cancer Res.20107072880289010.1158/0008‑5472.CAN‑09‑457220233868
     [Google Scholar]
  13. XuY. FangF. MiriyalaS. CrooksP.A. OberleyT.D. ChaiswingL. NoelT. HolleyA.K. ZhaoY. KininghamK.K. ClairD.K.S. ClairW.H.S. KEAP1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells.Cancer Res.201373144406441710.1158/0008‑5472.CAN‑12‑429723674500
     [Google Scholar]
  14. GuzmanM.L. RossiR.M. KarnischkyL. LiX. PetersonD.R. HowardD.S. JordanC.T. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells.Blood2005105114163416910.1182/blood‑2004‑10‑413515687234
     [Google Scholar]
  15. ZhangZ. QiaoY. SunQ. PengL. SunL. A novel SLC25A1 inhibitor, parthenolide, suppresses the growth and stemness of liver cancer stem cells with metabolic vulnerability.Cell Death Discov.20239135010.1038/s41420‑023‑01640‑637741815
     [Google Scholar]
  16. Karimian EnsafP. GoodarziM.T. Homayouni TabriziM. NeamatiA. HosseinyzadehS.S. A novel nanoformulation of parthenolide coated with polydopamine shows selective cytotoxicity and induces apoptosis in gastric cancer cells.Naunyn Schmiedebergs Arch. Pharmacol.202439764435444510.1007/s00210‑023‑02907‑638108837
     [Google Scholar]
  17. GehrenA.S. de SouzaW.F. Sousa-SquiavinatoA.C.M. RamosD.A.A. PiresB.R.B. AbdelhayE.S.F.W. Morgado-DiazJ.A. Parthenolide inhibits proliferation and invasion, promotes apoptosis, and reverts the cell–cell adhesion loss through downregulation of NF-κB pathway TNF-α-activated in colorectal cancer cells.Cell Biol. Int.20234791638164910.1002/cbin.1206037337926
     [Google Scholar]
  18. AnT. YinH. LuY. LiuF. The emerging potential of parthenolide nanoformulations in tumor therapy.Drug Des. Devel. Ther.2022161255127210.2147/DDDT.S35505935517982
     [Google Scholar]
  19. TahilianiM. KohK.P. ShenY. PastorW.A. BandukwalaH. BrudnoY. AgarwalS. IyerL.M. LiuD.R. AravindL. RaoA. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.Science2009324592993093510.1126/science.117011619372391
     [Google Scholar]
  20. SaadaneA. MastersS. DiDonatoJ. LiJ. BergerM. Parthenolide inhibits IkappaB kinase, NF-kappaB activation, and inflammatory response in cystic fibrosis cells and mice.Am. J. Respir. Cell Mol. Biol.200736672873610.1165/rcmb.2006‑0323OC17272824
     [Google Scholar]
  21. ZhangS. LinZ.N. YangC.F. ShiX. OngC.N. ShenH.M. Suppressed NF- B and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF- -induced apoptosis in human cancer cells.Carcinogenesis200425112191219910.1093/carcin/bgh23415256485
     [Google Scholar]
  22. NakshatriH. RiceS.E. Bhat-NakshatriP. Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase.Oncogene200423447330734410.1038/sj.onc.120799515286701
     [Google Scholar]
  23. SobotaR. SzwedM. KaszaA. BugnoM. KordulaT. Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family.Biochem. Biophys. Res. Commun.2000267132933310.1006/bbrc.1999.194810623619
     [Google Scholar]
  24. CarlisiD. D’AnneoA. AngileriL. LauricellaM. EmanueleS. SantulliA. VentoR. TesoriereG. Parthenolide sensitizes hepatocellular carcinoma cells to trail by inducing the expression of death receptors through inhibition of STAT3 activation.J. Cell. Physiol.201122661632164110.1002/jcp.2249421413021
     [Google Scholar]
  25. Ghorbanzadeh NeghabM. Jalili-NikM. SoltaniA. AfshariA.R. HassanianS.M. RafatpanahH. RezaeeS.A. SadeghniaH.R. Ataei AzimiS. MashkaniB. Rigosertib is more potent than wortmannin and rapamycin against adult T-cell leukemia-lymphoma.Biofactors20234961174118810.1002/biof.198537345860
     [Google Scholar]
  26. Tajvar NasabN. Jalili-NikM. AfshariA.R. Rezaei FarimaniA. SoukhtanlooM. Urolithin B inhibits proliferation and migration and promotes apoptosis and necrosis by inducing G2/M arrest and targeting MMP-2/-9 expression in osteosarcoma cells.J. Biochem. Mol. Toxicol.20233712e2348610.1002/jbt.2348637555500
     [Google Scholar]
  27. NevesJ. JorgeJ. AlvesR. GonçalvesA.C. Sarmento-RibeiroA.B. Cytotoxic effects of parthenolide on lymphoid malignancies’ cell lines.Porto Biomed. J.20172518310.1016/j.pbj.2017.07.02032258632
     [Google Scholar]
  28. Al-FatlawiA.A. Al-FatlawiA.A. IrshadM. Rahisuddin AhmadA. Effect of parthenolide on growth and apoptosis regulatory genes of human cancer cell lines.Pharm. Biol.201553110410910.3109/13880209.2014.91191925289524
     [Google Scholar]
  29. LinM. BiH. YanY. HuangW. ZhangG. ZhangG. TangS. LiuY. ZhangL. MaJ. ZhangJ. Parthenolide suppresses non-small cell lung cancer GLC-82 cells growth via B-Raf/MAPK/Erk pathway.Oncotarget2017814234362344710.18632/oncotarget.1558428423582
     [Google Scholar]
  30. GeorgeV.C. KumarD.R. KumarR.A. Relative in vitro potentials of parthenolide to induce apoptosis and cell cycle arrest in skin cancer cells.Curr. Drug Discov. Technol.2016131344010.2174/157016381366616022412402926906908
     [Google Scholar]
  31. JorgeJ. NevesJ. AlvesR. GeraldesC. GonçalvesA.C. Sarmento-RibeiroA.B. Parthenolide induces ROS-mediated apoptosis in lymphoid malignancies.Int. J. Mol. Sci.20232411916710.3390/ijms2411916737298119
     [Google Scholar]
  32. DuanD. ZhangJ. YaoJ. LiuY. FangJ. Targeting thioredoxin reductase by parthenolide contributes to inducing apoptosis of HeLa cells.J. Biol. Chem.201629119100211003110.1074/jbc.M115.70059127002142
     [Google Scholar]
  33. GrichnikJ.M. BurchJ.A. SchulteisR.D. ShanS. LiuJ. DarrowT.L. VervaertC.E. SeiglerH.F. Melanoma, a tumor based on a mutant stem cell?J. Invest. Dermatol.2006126114215310.1038/sj.jid.570001716417230
     [Google Scholar]
  34. HehnerS.P. HeinrichM. BorkP.M. VogtM. RatterF. LehmannV. Schulze-OsthoffK. DrögeW. SchmitzM.L. Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation of I kappa B-alpha and I kappa B-beta.J. Biol. Chem.199827331288129710.1074/jbc.273.3.12889430659
     [Google Scholar]
  35. babaeiG. AliarabA. AbroonS. RasmiY. AzizS.G.G. Application of sesquiterpene lactone: A new promising way for cancer therapy based on anticancer activity.Biomed. Pharmacother.201810623924610.1016/j.biopha.2018.06.13129966966
     [Google Scholar]
  36. AndersonK.N. BejcekB.E. Parthenolide induces apoptosis in glioblastomas without affecting NF-kappaB.J. Pharmacol. Sci.2008106231832010.1254/jphs.SC006016418277052
     [Google Scholar]
  37. ZhangS. OngC.N. ShenH.M. Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells.Cancer Lett.2004208214315310.1016/j.canlet.2003.11.02815142672
     [Google Scholar]
  38. CheS.T. BieL. LiX. QiH. YuP. ZuoL. Parthenolide inhibits the proliferation and induces the apoptosis of human uveal melanoma cells.Int. J. Ophthalmol.201912101531153810.18240/ijo.2019.10.0331637187
     [Google Scholar]
  39. NakagawaY. IinumaM. MatsuuraN. YiK. NaoiM. NakayamaT. NozawaY. AkaoY. A potent apoptosis-inducing activity of a sesquiterpene lactone, arucanolide, in HL60 cells: A crucial role of apoptosis-inducing factor.J. Pharmacol. Sci.200597224225210.1254/jphs.FP004045615699578
     [Google Scholar]
  40. KimS.L. KieuT.T.T. JeonB.J. KimS.H. KimI.H. LeeS.O. LeeS.T. KimS.W. Synergistic effect of parthenolide in combination with 5-fluorouracil in SW480 cells.Intest. Res.201210435736410.5217/ir.2012.10.4.35734731562
     [Google Scholar]
  41. ChengG. XieL. Parthenolide induces apoptosis and cell cycle arrest of human 5637 bladder cancer cells in vitro .Molecules20111686758676810.3390/molecules1608675821829151
     [Google Scholar]
  42. KimI.H. KimS.W. KimS.H. LeeS.O. LeeS.T. KimD.G. LeeM.J. ParkW.H. Parthenolide-induced apoptosis of hepatic stellate cells and anti-fibrotic effects in an in vivo rat model.Exp. Mol. Med.201244744845610.3858/emm.2012.44.7.05122581380
     [Google Scholar]
  43. KimS.L. LiuY.C. ParkY.R. SeoS.Y. KimS.H. KimI.H. LeeS.O. LeeS.T. KimD.G. KimS.W. Parthenolide enhances sensitivity of colorectal cancer cells to TRAIL by inducing death receptor 5 and promotes TRAIL-induced apoptosis.Int. J. Oncol.20154631121113010.3892/ijo.2014.279525502339
     [Google Scholar]
  44. Jalili-NikM. SabriH. ZamiriE. SoukhtanlooM. RoshanM.K. HosseiniA. MollazadehH. VahediM.M. AfshariA.R. MousaviS.H. Cytotoxic effects of Ferula latisecta on human glioma U87 cells.Drug Res. (Stuttg.)2019691266567010.1055/a‑0986‑654331499542
     [Google Scholar]
  45. PereiraA.M.M. Strasberg-RieberM. RieberM. Invasion-associated MMP-2 and MMP-9 are up-regulated intracellularly in concert with apoptosis linked to melanoma cell detachment.Clin. Exp. Metastasis200522428529510.1007/s10585‑005‑8672‑816170665
     [Google Scholar]
  46. CoryG. Scratch-wound assay.Methods Mol. Biol.2011769253010.1007/978‑1‑61779‑207‑6_221748666
     [Google Scholar]
  47. CzyzM. Lesiak-MieczkowskaK. KoprowskaK. Szulawska-MroczekA. WozniakM. Cell context-dependent activities of parthenolide in primary and metastatic melanoma cells.Br. J. Pharmacol.201016051144115710.1111/j.1476‑5381.2010.00749.x20590608
     [Google Scholar]
  48. LiuY.C. KimS.L. ParkY.R. LeeS.T. KimS.W. Parthenolide promotes apoptotic cell death and inhibits the migration and invasion of SW620 cells.Intest. Res.201715217418110.5217/ir.2017.15.2.17428522946
     [Google Scholar]
  49. SteegP.S. BevilacquaG. KopperL. ThorgeirssonU.P. TalmadgeJ.E. LiottaL.A. SobelM.E. Evidence for a novel gene associated with low tumor metastatic potential.J. Natl. Cancer Inst.198880320020410.1093/jnci/80.3.2003346912
     [Google Scholar]
  50. MarinoN. NakayamaJ. CollinsJ.W. SteegP.S. Insights into the biology and prevention of tumor metastasis provided by the Nm23 metastasis suppressor gene.Cancer Metastasis Rev.2012313-459360310.1007/s10555‑012‑9374‑822706779
     [Google Scholar]
  51. LeoneA. FlatowU. KingC.R. SandeenM.A. MarguliesI.M.K. LiottaL.A. SteegP.S. Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm3-transfected melanoma cells.Cell1991651253510.1016/0092‑8674(91)90404‑M2013093
     [Google Scholar]
  52. CarreiraS. GoodallJ. DenatL. RodriguezM. NuciforoP. HoekK.S. TestoriA. LarueL. GodingC.R. Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.Genes Dev.200620243426343910.1101/gad.40640617182868
     [Google Scholar]
  53. HoekK.S. SchlegelN.C. BraffordP. SuckerA. UgurelS. KumarR. WeberB.L. NathansonK.L. PhillipsD.J. HerlynM. SchadendorfD. DummerR. Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature.Pigment Cell Res.200619429030210.1111/j.1600‑0749.2006.00322.x16827748
     [Google Scholar]
  54. KoprowskaK. HartmanM.L. Sztiller-SikorskaM. CzyzM.E. Parthenolide enhances dacarbazine activity against melanoma cells.Anticancer Drugs201324883584510.1097/CAD.0b013e3283635a0423797801
     [Google Scholar]
  55. WenJ. YouK.R. LeeS.Y. SongC.H. KimD.G. Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide.J. Biol. Chem.200227741389543896410.1074/jbc.M20384220012151389
     [Google Scholar]
  56. KimH.Y. LeeH. KimS.H. JinH. BaeJ. ChoiH.K. Discovery of potential biomarkers in human melanoma cells with different metastatic potential by metabolic and lipidomic profiling.Sci. Rep.201771886410.1038/s41598‑017‑08433‑928821754
     [Google Scholar]
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Parthenolide Inhibits Tumor Cell Growth and Metastasis in Melanoma A2058 Cells
Curr. Med. Chem. 32, 7391 (2025); https://doi.org/10.2174/0109298673334309240924081449
/content/journals/cmc/10.2174/0109298673334309240924081449
/content/journals/cmc/10.2174/0109298673334309240924081449
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  • Article Type:     Research Article
Keyword(s): apoptosis; cell cycle arrest; melanoma; migration; p53; Parthenolide

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