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2000
Volume 21, Issue 3
  • ISSN: 1567-2026
  • E-ISSN: 1875-5739

Abstract

Background

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that is difficult to remove surgically. Research suggests that substances from saffron, namely crocetin and crocin, could be effective natural treatments, showing abilities to kill cancer cells.

Methods

Our study focused on evaluating the effects of crocetin on glioma using the U87 cell line. We specifically investigated how crocetin affects the survival, growth, and spread of glioma cells, exploring its impact at concentrations ranging from 75-150 μM. The study also included experiments combining crocetin with the chemotherapy drug Temozolomide (TMZ) to assess potential synergistic effects.

Results

Crocetin significantly reduced the viability, proliferation, and migration of glioma cells. It achieved these effects by decreasing the levels of Matrix Metallopeptidase 9 (MMP-9) and Ras homolog family member A (RhoA), proteins that are critical for cancer progression. Additionally, crocetin inhibited the formation of cellular structures necessary for tumor growth. It blocked multiple points of the Ak Strain Transforming (AKT) signaling pathway, which is vital for cancer cell survival. This treatment led to increased cell death and disrupted the cell cycle in the glioma cells. When used in combination with TMZ, crocetin not only enhanced the reduction of cancer cell growth but also promoted cell death and reduced cell replication. This combination therapy further decreased levels of high mobility group box 1 (HMGB1) and Receptor for Advanced Glycation End-products (RAGE), proteins linked to inflammation and tumor progression. It selectively inhibited certain pathways involved in the cellular stress response without affecting others.

Conclusion

Our results underscore the potential of crocetin as a treatment for glioma. It targets various mechanisms involved in tumor growth and spread, offering multiple avenues for therapy. Further studies are essential to fully understand and utilize crocetin’s benefits in treating glioma.

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2025-01-15
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References

  1. StuppR. MasonW.P. van den BentM.J. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N. Engl. J. Med.20053521098799610.1056/NEJMoa043330 15758009
    [Google Scholar]
  2. MaW. LiN. AnY. ZhouC. BoC. ZhangG. Effects of temozolomide and radiotherapy on brain metastatic tumor: A systematic review and meta-analysis.World Neurosurg.20169219720510.1016/j.wneu.2016.04.011 27072333
    [Google Scholar]
  3. HosseinzadehH. YounesiH.M. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice.BMC Pharmacol.200221710.1186/1471‑2210‑2‑7 11914135
    [Google Scholar]
  4. BolhassaniA. KhavariA. BathaieS.Z. Saffron and natural carotenoids: Biochemical activities and anti-tumor effects.Biochim. Biophys. Acta2014184512030 24269582
    [Google Scholar]
  5. SalahshoorM.R. KhashiadehM. RoshankhahS. KakabaraeiS. JaliliC. Protective effect of crocin on liver toxicity induced by morphine.Res. Pharm. Sci.2016112120129 27168751
    [Google Scholar]
  6. HosseinzadehH. SadeghniaH.R. GhaeniF.A. MotamedshariatyV.S. MohajeriS.A. Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats.Phytother. Res.201226338138610.1002/ptr.3566 21774008
    [Google Scholar]
  7. GutheilW.G. ReedG. RayA. AnantS. DharA. Crocetin: an agent derived from saffron for prevention and therapy for cancer.Curr. Pharm. Biotechnol.201213117317910.2174/138920112798868566 21466430
    [Google Scholar]
  8. NasirzadehM. RasmiY. RahbarghaziR. Crocetin promotes angiogenesis in human endothelial cells through PI3K-Akt-eNOS signaling pathway.EXCLI J.201918936949 31762720
    [Google Scholar]
  9. LiS. JiangS. JiangW. Anticancer effects of crocetin in human esophageal squamous cell carcinoma KYSE-150 cells.Oncol. Lett.2015931254126010.3892/ol.2015.2869 25663893
    [Google Scholar]
  10. BathaieS.Z. HoshyarR. MiriH. SadeghizadehM. Anticancer effects of crocetin in both human adenocarcinoma gastric cancer cells and rat model of gastric cancer.Biochem. Cell Biol.201391639740310.1139/bcb‑2013‑0014 24219281
    [Google Scholar]
  11. GaskellH. GeX. NietoN. High-mobility group box-1 and liver disease.Hepatol. Commun.2018291005102010.1002/hep4.1223 30202816
    [Google Scholar]
  12. LotzeM.T. TraceyK.J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal.Nat. Rev. Immunol.20055433134210.1038/nri1594 15803152
    [Google Scholar]
  13. ChibaS. BaghdadiM. AkibaH. Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1.Nat. Immunol.201213983284210.1038/ni.2376 22842346
    [Google Scholar]
  14. Rivera VargasT. ApetohL. Danger signals: Chemotherapy enhancers?Immunol. Rev.2017280117519310.1111/imr.12581 29027217
    [Google Scholar]
  15. ItoI. FukazawaJ. YoshidaM. Post-translational methylation of high mobility group box 1 (HMGB1) causes its cytoplasmic localization in neutrophils.J. Biol. Chem.200728222163361634410.1074/jbc.M608467200 17403684
    [Google Scholar]
  16. TaguchiA. BloodD.C. del ToroG. Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases.Nature2000405678435436010.1038/35012626 10830965
    [Google Scholar]
  17. WadaT. PenningerJ.M. Mitogen-activated protein kinases in apoptosis regulation.Oncogene200423162838284910.1038/sj.onc.1207556 15077147
    [Google Scholar]
  18. ArthurJ.S.C. LeyS.C. Mitogen-activated protein kinases in innate immunity.Nat. Rev. Immunol.201313967969210.1038/nri3495 23954936
    [Google Scholar]
  19. SchaefferH.J. WeberM.J. Mitogen-activated protein kinases: specific messages from ubiquitous messengers.Mol. Cell. Biol.19991942435244410.1128/MCB.19.4.2435 10082509
    [Google Scholar]
  20. KieferF. TibblesL.A. LassamN. ZankeB. IscoveN. WoodgettJ.R. Novel components of mammalian stress-activated protein kinase cascades.Biochem. Soc. Trans.199725249149810.1042/bst0250491 9191142
    [Google Scholar]
  21. ChangL. KarinM. Mammalian MAP kinase signalling cascades.Nature20014106824374010.1038/35065000 11242034
    [Google Scholar]
  22. YagodaN. von RechenbergM. ZaganjorE. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels.Nature2007447714686586910.1038/nature05859 17568748
    [Google Scholar]
  23. LiS. QuY. ShenX.Y. Multiple signal pathways involved in crocetin-induced apoptosis in KYSE-150 cells.Pharmacology20191035-626327210.1159/000487956 30783055
    [Google Scholar]
  24. ChengW.Y. ChiaoM.T. LiangY.J. YangY.C. ShenC.C. YangC.Y. Luteolin inhibits migration of human glioblastoma U-87 MG and T98G cells through downregulation of Cdc42 expression and PI3K/AKT activity.Mol. Biol. Rep.20134095315532610.1007/s11033‑013‑2632‑1 23677714
    [Google Scholar]
  25. SlivaD. LabarrereC. SlivovaV. SedlakM. LloydF.P.Jr HoN.W.Y. Ganoderma lucidum suppresses motility of highly invasive breast and prostate cancer cells.Biochem. Biophys. Res. Commun.2002298460361210.1016/S0006‑291X(02)02496‑8 12408995
    [Google Scholar]
  26. JiangJ. SlivovaV. ValachovicovaT. HarveyK. SlivaD. Ganoderma lucidum inhibits proliferation and induces apoptosis in human prostate cancer cells PC-3.Int. J. Oncol.20042451093109910.3892/ijo.24.5.1093 15067330
    [Google Scholar]
  27. LloydF.Jr SlivovaV. ValachovicovaT. SlivaD. Aspirin inhibits highly invasive prostate cancer cells.Int. J. Oncol.20032351277128310.3892/ijo.23.5.1277 14532966
    [Google Scholar]
  28. ChouY.C. ChangM.Y. WangM.J. PEITC inhibits human brain glioblastoma GBM 8401 cell migration and invasion through the inhibition of uPA, Rho A, and Ras with inhibition of MMP-2, -7 and -9 gene expression.Oncol. Rep.20153452489249610.3892/or.2015.4260 26352173
    [Google Scholar]
  29. GuoZ.L. LiM.X. LiX.L. Crocetin: A systematic review.Front. Pharmacol.20221274568310.3389/fphar.2021.745683 35095483
    [Google Scholar]
  30. FreedmanV. ShinS.I. Cellular tumorigenicity in nude mice: Correlation with cell growth in semi-solid medium.Cell19743435535910.1016/0092‑8674(74)90050‑6 4442124
    [Google Scholar]
  31. VignjevicD. MontagnacG. Reorganisation of the dendritic actin network during cancer cell migration and invasion.Semin. Cancer Biol.2008181122210.1016/j.semcancer.2007.08.001 17928234
    [Google Scholar]
  32. PalmD. LangK. BrandtB. ZaenkerK.S. EntschladenF. In vitro and in vivo imaging of cell migration: Two interdepending methods to unravel metastasis formation.Semin. Cancer Biol.200515539640410.1016/j.semcancer.2005.06.008 16054391
    [Google Scholar]
  33. RenK. JinH. BianC. MR-1 modulates proliferation and migration of human hepatoma HepG2 cells through myosin light chains-2 (MLC2)/focal adhesion kinase (FAK)/Akt signaling pathway.J. Biol. Chem.200828351355983560510.1074/jbc.M802253200 18948272
    [Google Scholar]
  34. JonesR.G. SaibilS.D. PunJ.M. NF-kappaB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo.J. Immunol.200517563790379910.4049/jimmunol.175.6.3790 16148125
    [Google Scholar]
  35. DillonR.L. WhiteD.E. MullerW.J. The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer.Oncogene20072691338134510.1038/sj.onc.1210202 17322919
    [Google Scholar]
  36. LiuD. SiH. ReynoldsK.A. ZhenW. JiaZ. DillonJ.S. Dehydroepiandrosterone protects vascular endothelial cells against apoptosis through a Galphai protein-dependent activation of phosphatidylinositol 3-kinase/Akt and regulation of antiapoptotic Bcl-2 expression.Endocrinology200714873068307610.1210/en.2006‑1378 17395704
    [Google Scholar]
  37. VölpK. BrezniceanuM.L. BösserS. Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas.Gut200655223424210.1136/gut.2004.062729 16118352
    [Google Scholar]
  38. RasmiY. KhajehE. KheradmandF. Crocetin suppresses the growth and migration in HCT-116 human colorectal cancer cells by activating the p-38 MAPK signaling pathway.Res. Pharm. Sci.202015659260110.4103/1735‑5362.301344 33828602
    [Google Scholar]
  39. HanifF. MuzaffarK. PerveenK. MalhiS.M. SimjeeShU. Glioblastoma Multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment.Asian Pac. J. Cancer Prev.201718139 28239999
    [Google Scholar]
  40. YangX. LvS. ZhouX. The clinical implications of transforming growth factor beta in pathological grade and prognosis of glioma patients: A meta-analysis.Mol. Neurobiol.201552127027610.1007/s12035‑014‑8872‑9 25148935
    [Google Scholar]
  41. TsaiC.F. YehW.L. HuangS.M. TanT.W. LuD.Y. Wogonin induces reactive oxygen species production and cell apoptosis in human glioma cancer cells.Int. J. Mol. Sci.20121389877989210.3390/ijms13089877 22949836
    [Google Scholar]
  42. LinS. ChenZ. WuZ. Involvement of PI3K/AKT pathway in the rapid antidepressant effects of crocetin in mice with depression-like phenotypes.Neurochem. Res.202449247749110.1007/s11064‑023‑04051‑2 37935859
    [Google Scholar]
  43. ChenS. LuoX. YangL. LuoL. HuZ. WangJ. Crocetin protects mouse brain from apoptosis in traumatic brain injury model through activation of autophagy.Brain Inj.202438752453010.1080/02699052.2024.2324022 38433503
    [Google Scholar]
  44. FanT. JiangK. WangZ. ChangY. TianH. HuangJ. Crocetin inhibits mast cell-dependent immediate-type allergic reactions through Ca2+/PLC/IP3 and TNF pathway.Int. Immunopharmacol.202412811158310.1016/j.intimp.2024.111583 38286072
    [Google Scholar]
  45. ColapietroA. ManciniA. VitaleF. Crocetin extracted from saffron shows antitumor effects in models of human glioblastoma.Int. J. Mol. Sci.202021242310.3390/ijms21020423 31936544
    [Google Scholar]
  46. LeeS.Y. Temozolomide resistance in glioblastoma multiforme.Genes Dis.20163319821010.1016/j.gendis.2016.04.007 30258889
    [Google Scholar]
  47. LiuP. XueY. ZhengB. Crocetin attenuates the oxidative stress, inflammation and apoptosis in arsenic trioxide-induced nephrotoxic rats: Implication of PI3K/AKT pathway.Int. Immunopharmacol.20208810695910.1016/j.intimp.2020.106959 32919218
    [Google Scholar]
  48. LuD.Y. ChangC.S. YehW.L. The novel phloroglucinol derivative BFP induces apoptosis of glioma cancer through reactive oxygen species and endoplasmic reticulum stress pathways.Phytomedicine201219121093110010.1016/j.phymed.2012.06.010 22819448
    [Google Scholar]
  49. KhorasanchiZ. ShafieeM. KermanshahiF. Crocus sativus a natural food coloring and flavoring has potent anti-tumor properties.Phytomedicine201843212710.1016/j.phymed.2018.03.041 29747750
    [Google Scholar]
  50. ZangM. HouJ. HuangY. Crocetin suppresses angiogenesis and metastasis through inhibiting sonic hedgehog signaling pathway in gastric cancer.Biochem. Biophys. Res. Commun.2021576869210.1016/j.bbrc.2021.08.092 34482028
    [Google Scholar]
  51. FestucciaC. ManciniA. GravinaG.L. Antitumor effects of saffron-derived carotenoids in prostate cancer cell models.BioMed Res. Int.2014201411210.1155/2014/135048 24900952
    [Google Scholar]
  52. WuQ. MaX. JinZ. NiR. PanY. YangG. Zhuidu Formula suppresses the migratory and invasive properties of triple-negative breast cancer cells via dual signaling pathways of RhoA/ROCK and CDC42/MRCK.J. Ethnopharmacol.202331511664410.1016/j.jep.2023.116644 37196814
    [Google Scholar]
  53. XueY. HeJ.T. ZhangK.K. ChenL.J. WangQ. XieX.L. Methamphetamine reduces expressions of tight junction proteins, rearranges F-actin cytoskeleton and increases the blood brain barrier permeability via the RhoA/ROCK-dependent pathway.Biochem. Biophys. Res. Commun.2019509239540110.1016/j.bbrc.2018.12.144 30594393
    [Google Scholar]
  54. XieY. ShiX. ShengK. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review).Mol. Med. Rep.2019192783791 30535469
    [Google Scholar]
  55. FuldaS. Synthetic lethality by co-targeting mitochondrial apoptosis and PI3K/Akt/mTOR signaling.Mitochondrion2014198587
    [Google Scholar]
  56. JohnstonA. CreightonN. ParkinsonJ. Ongoing improvements in postoperative survival of glioblastoma in the temozolomide era: a population-based data linkage study.Neurooncol. Pract.202071223010.1093/nop/npz021 32257281
    [Google Scholar]
  57. HegiM.E. DiserensA.C. GorliaT. MGMT gene silencing and benefit from temozolomide in glioblastoma.N. Engl. J. Med.200535210997100310.1056/NEJMoa043331 15758010
    [Google Scholar]
  58. LiZ. FuW.J. ChenX.Q. Autophagy-based unconventional secretion of HMGB1 in glioblastoma promotes chemosensitivity to temozolomide through macrophage M1-like polarization.J. Exp. Clin. Cancer Res.20224117410.1186/s13046‑022‑02291‑8 35193644
    [Google Scholar]
  59. InadaM. ShindoM. KobayashiK. Anticancer effects of a non-narcotic opium alkaloid medicine, papaverine, in human glioblastoma cells.PLoS One2019145e021635810.1371/journal.pone.0216358 31100066
    [Google Scholar]
  60. BianchiM.E. BeltrameM. PaonessaG. Specific recognition of cruciform DNA by nuclear protein HMG1.Science198924348941056105910.1126/science.2922595 2922595
    [Google Scholar]
  61. TraversA.A. Priming the nucleosome: a role for HMGB proteins?EMBO Rep.20034213113610.1038/sj.embor.embor741 12612600
    [Google Scholar]
  62. XueJ. SuarezJ.S. MinaaiM. HMGB1 as a therapeutic target in disease.J. Cell. Physiol.202123653406341910.1002/jcp.30125 33107103
    [Google Scholar]
  63. LuoY. ChiharaY. FujimotoK. High mobility group box 1 released from necrotic cells enhances regrowth and metastasis of cancer cells that have survived chemotherapy.Eur. J. Cancer201349374175110.1016/j.ejca.2012.09.016 23040637
    [Google Scholar]
  64. HuangC.Y. ChiangS.F. ChenW.T.L. HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer.Cell Death Dis.2018910100410.1038/s41419‑018‑1019‑6 30258050
    [Google Scholar]
  65. MuraoA. AzizM. WangH. BrennerM. WangP. Release mechanisms of major DAMPs.Apoptosis2021263-415216210.1007/s10495‑021‑01663‑3 33713214
    [Google Scholar]
  66. GaoX.Y. ZangJ. ZhengM.H. Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma.Front. Cell Dev. Biol.2021962088310.3389/fcell.2021.620883 33614649
    [Google Scholar]
  67. SimsG.P. RoweD.C. RietdijkS.T. HerbstR. CoyleA.J. HMGB1 and RAGE in inflammation and cancer.Annu. Rev. Immunol.201028136738810.1146/annurev.immunol.021908.132603 20192808
    [Google Scholar]
  68. WolfP. SchoenigerA. EdlichF. Pro-apoptotic complexes of BAX and BAK on the outer mitochondrial membrane.Biochim. Biophys. Acta Mol. Cell Res.202218691011931710.1016/j.bbamcr.2022.119317 35752202
    [Google Scholar]
  69. RenaultT.T. DejeanL.M. ManonS. A brewing understanding of the regulation of Bax function by Bcl-xL and Bcl-2.Mech. Ageing Dev.201716120121010.1016/j.mad.2016.04.007
    [Google Scholar]
  70. MoradzadehM. SadeghniaH.R. TabarraeiA. SahebkarA. Anti‐tumor effects of crocetin and related molecular targets.J. Cell. Physiol.201823332170218210.1002/jcp.25953 28407293
    [Google Scholar]
  71. Rubio-MoragaA. TraperoA. AhrazemO. Gómez-GómezL. Crocins transport in Crocus sativus: The long road from a senescent stigma to a newborn corm.Phytochemistry201071131506151310.1016/j.phytochem.2010.05.026 20573363
    [Google Scholar]
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  • Article Type:
    Research Article
Keyword(s): AKT signaling; cell migration; Crocetin; glioblastoma; temozolomide; tumor growth
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