Skip to content
2000
Volume 25, Issue 18
  • ISSN: 1871-5206
  • E-ISSN: 1875-5992

Abstract

Glioma epitomizes exclusively primary brain cancer of glial cell or neuroepithelial derivation and irradiation (IR) is one of the key and standard treatment modalities for all kinds of gliomas. Patients with glioma often undergo IR, such as whole-brain radiotherapy, stereotactic radiosurgery, as well as intensity modulated radiation therapy. However, IR therapy for malignant glioma is still facing severe hindrances because gliomas have high resistance to the IR. Autophagy is a type II programmed cell death which has been implicated in IR to gliomas. Autophagy was able to protect cells under sublethal damage circumstances, and it differentially triggered cell death after lethal damage in glioma. Furthermore, IR induced cerebral vascular damage was associated with progressive endothelial cells loss. IR triggered the acceleration of autophagic flux in cerebral endothelial cells which was characterized with robust upregulation of autophagy genes. Thus, autophagy plays a pivotal role in modulating the sensitivity and resistance of glioma cells to IR therapy. However, the exact autophagic mechanisms underlying radiosensitivity and/or radioresistance is still a matter of debate, and the development of effective radiosensitizers are lacking. Specific conditions pointing to the capabilities of IR-induced autophagy augmentation or inhibition of IR-induced cell death mostly contribute to radiosensitivity or radioresistance. Thus, IR-induced autophagy mechanisms in gliomas therapy are multiplex and they either induce radiosensitivity or inhibit radioresistance leading to potential effective treatment strategies for glioma. The aim of this review is to elucidate the autophagic mechanisms associated with radiosensitivity and/or radioresistance in glioma at the bench level, and accordingly highlight the development of potentially effective and efficient radiosensitizers to argument the treatment of glioma.

Loading

Article metrics loading...

/content/journals/acamc/10.2174/0118715206371143250402175030
2025-04-10
2025-09-14
Loading full text...

Full text loading...

References

  1. ZhuangW. QinZ. LiangZ. The role of autophagy in sensitizing malignant glioma cells to radiation therapy.Acta Biochim. Biophys. Sin. (Shanghai)200941534135110.1093/abbs/gmp028 19430698
    [Google Scholar]
  2. LiuM. DaiB. KangS.H. BanK. HuangF.J. LangF.F. AldapeK.D. XieT. PelloskiC.E. XieK. SawayaR. HuangS. FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells.Cancer Res.20066673593360210.1158/0008‑5472.CAN‑05‑2912 16585184
    [Google Scholar]
  3. SurawiczT.S. DavisF. FreelsS. LawsE.R.Jr MenckH.R. Brain tumor survival: Results from the National cancer data base.J. Neurooncol.199840215116010.1023/A:1006091608586 9892097
    [Google Scholar]
  4. SiegelR. NaishadhamD. JemalA. Cancer statistics, 2013.CA Cancer J. Clin.2013631113010.3322/caac.21166 23335087
    [Google Scholar]
  5. RichardA.S. Novel pathogenic, biomarker and therapeutic potentials of Foxm1 in Glioma.Neuroquantology201917610.14704/nq.2019.17.6.2227
    [Google Scholar]
  6. GoodenbergerM.L. JenkinsR.B. Genetics of adult glioma.Cancer Genet.20122051261362110.1016/j.cancergen.2012.10.009 23238284
    [Google Scholar]
  7. RichardS.A. EugeneK.D. The pivotal immunomodulatory and anti-inflammatory effect of histone-lysine N-Methyltransferase in the glioma microenvironment: Its biomarker and therapy potentials.Anal. Cell. Pathol. (Amst.)20212021490716710.1155/2021/4907167
    [Google Scholar]
  8. RichardS.A. EPAC2: A new and promising protein for glioma pathogenesis and therapy.Oncol. Rev.202014144610.4081/oncol.2020.446 32395202
    [Google Scholar]
  9. RichardS.A. The pivotal immunoregulatory functions of microglia and macrophages in glioma pathogenesis and therapy.J. Oncol.2022202211910.1155/2022/8903482 35419058
    [Google Scholar]
  10. RichardS.A. SackeyM. KorteiN.K. Exploring the pivotal neurophysiologic and therapeutic potentials of vitamin C in glioma.J. Oncol.202120216141591
    [Google Scholar]
  11. YaoK.C. KomataT. KondoY. KanzawaT. KondoS. GermanoI.M. Molecular response of human glioblastoma multiforme cells to ionizing radiation: Cell cycle arrest, modulation of cyclin-dependent kinase inhibitors, and autophagy.J. Neurosurg.200398237838410.3171/jns.2003.98.2.0378 12593626
    [Google Scholar]
  12. MehtaM.P. ToméW.A. OliveraG.H. Radiotherapy for brain tumors.Curr. Oncol. Rep.20002543844410.1007/s11912‑000‑0064‑2 11122876
    [Google Scholar]
  13. GongL. ZhangY. LiuC. ZhangM. HanS. Application of radiosensitizers in cancer radiotherapy.Int. J. Nanomedicine2021161083110210.2147/IJN.S290438 33603370
    [Google Scholar]
  14. AiX. YeZ. YaoY. XiaoJ. YouC. XuJ. HuangX. ZhongJ. FanM. SongX. ShiH. ZhangD. ZhaoC. Endothelial autophagy: An effective target for radiation-induced cerebral capillary damage.Sci. Rep.202010161410.1038/s41598‑019‑57234‑9 31953486
    [Google Scholar]
  15. Greene-SchloesserD. MooreE. RobbinsM.E. Molecular pathways: Radiation-induced cognitive impairment.Clin. Cancer Res.20131992294230010.1158/1078‑0432.CCR‑11‑2903 23388505
    [Google Scholar]
  16. WuH. LinJ. LiuP. HuangZ. ZhaoP. JinH. MaJ. WenL. GuN. Reactive oxygen species acts as executor in radiation enhancement and autophagy inducing by AgNPs.Biomaterials20161011910.1016/j.biomaterials.2016.05.031 27254247
    [Google Scholar]
  17. ZhouW. GuoY. ZhangX. JiangZ. Lys05 induces lysosomal membrane permeabilization and increases radiosensitivity in glioblastoma.J. Cell. Biochem.202012122027203710.1002/jcb.29437 31642111
    [Google Scholar]
  18. PalumboS. CominciniS. Autophagy and ionizing radiation in tumors: The “survive or not survive” dilemma.J. Cell. Physiol.201322811810.1002/jcp.24118 22585676
    [Google Scholar]
  19. KazaN. KohliL. RothK.A. Autophagy in brain tumors: A new target for therapeutic intervention.Brain Pathol.2012221899810.1111/j.1750‑3639.2011.00544.x 22150924
    [Google Scholar]
  20. RichardS.A. The pivotal role of autophagy in the pathogenesis and therapy of medulloblastoma.Future Oncol.202420393313332410.1080/14796694.2024.2420629 39513232
    [Google Scholar]
  21. PalumboS. PirtoliL. TiniP. CeveniniG. CalderaroF. ToscanoM. MiraccoC. CominciniS. Different involvement of autophagy in human malignant glioma cell lines undergoing irradiation and temozolomide combined treatments.J. Cell. Biochem.201211372308231810.1002/jcb.24102 22345070
    [Google Scholar]
  22. KwakH.J. KimY.J. ChunK.R. WooY.M. ParkS.J. JeongJ.A. JoS.H. KimT.H. MinH.S. ChaeJ.S. ChoiE.J. KimG. ShinS.H. GwakH.S. KimS.K. HongE.K. LeeG.K. ChoiK.H. KimJ.H. YooH. ParkJ.B. LeeS.H. Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas.Oncogene201130212433244210.1038/onc.2010.620 21278789
    [Google Scholar]
  23. RichardS.A. RoyS.K. AsiamahE.A. Pivotal role of cranial irradiation-induced peripheral, intrinsic, and brain-engrafting macrophages in malignant glioma.Clin. Med. Insights Oncol.2024181179554924128209810.1177/11795549241282098 39421649
    [Google Scholar]
  24. GladsonC.L. PraysonR.A. LiuW.M. The pathobiology of glioma tumors.Annu. Rev. Pathol.201051335010.1146/annurev‑pathol‑121808‑102109 19737106
    [Google Scholar]
  25. LouisD.N. Molecular pathology of malignant gliomas.Annu. Rev. Pathol.2006119711710.1146/annurev.pathol.1.110304.100043 18039109
    [Google Scholar]
  26. SeiduR.A. WuM. SuZ. XuH. Paradoxical role of high mobility group box 1 in glioma: A suppressor or a promoter?Oncol. Rev.201711132510.4081/oncol.2017.325 28382190
    [Google Scholar]
  27. JiangM. ZhuangY. ZuW.C. JiaoL. RichardS. ZhangS. Overexpression of EPAC2 reduces the invasion of glioma cells via MMP 2.Oncol. Lett.20191765080508610.3892/ol.2019.10200 31186720
    [Google Scholar]
  28. KleihuesP. LouisD.N. ScheithauerB.W. RorkeL.B. ReifenbergerG. BurgerP.C. CaveneeW.K. The WHO classification of tumors of the nervous system.J. Neuropathol. Exp. Neurol.200261321522510.1093/jnen/61.3.215 11895036
    [Google Scholar]
  29. KleihuesP. BurgerP.C. ScheithauerB.W. The new WHO classification of brain tumours.Brain Pathol.19933325526810.1111/j.1750‑3639.1993.tb00752.x 8293185
    [Google Scholar]
  30. WenP.Y. KesariS. Malignant gliomas in adults.N. Engl. J. Med.2008359549250710.1056/NEJMra0708126 18669428
    [Google Scholar]
  31. PollackI.F. Brain tumors in children.N. Engl. J. Med.1994331221500150710.1056/NEJM199412013312207 7969301
    [Google Scholar]
  32. DaiC. CelestinoJ.C. OkadaY. LouisD.N. FullerG.N. HollandE.C. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo.Genes Dev.200115151913192510.1101/gad.903001 11485986
    [Google Scholar]
  33. KleihuesP. BurgerP.C. ScheithauerB.W. Histological typing of tumours of the central nervous system.Springer Science & Business Media201210.1007/978‑3‑642‑84988‑6
    [Google Scholar]
  34. RichardS.A. The therapeutic potential of resveratrol in gliomas.Adv. Biosci. Clin. Med.201972445910.7575/aiac.abcmed.v.7n.2p.44
    [Google Scholar]
  35. LouisD.N. PerryA. ReifenbergerG. von DeimlingA. Figarella-BrangerD. CaveneeW.K. OhgakiH. WiestlerO.D. KleihuesP. EllisonD.W. The 2016 World Health Organization classification of tumors of the central nervous system: A summary.Acta Neuropathol.2016131680382010.1007/s00401‑016‑1545‑1 27157931
    [Google Scholar]
  36. StuppR. MasonW.P. van den BentM.J. WellerM. FisherB. TaphoornM.J.B. BelangerK. BrandesA.A. MarosiC. BogdahnU. CurschmannJ. JanzerR.C. LudwinS.K. GorliaT. AllgeierA. LacombeD. CairncrossJ.G. EisenhauerE. MirimanoffR.O. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N. Engl. J. Med.20053521098799610.1056/NEJMoa043330 15758009
    [Google Scholar]
  37. SeiduA.R. YunxiaY. HaoL. MaL. ChaoY. Glioblastoma multiforme subterfuge as acute cerebral hemorrhage: A case report and literature review.Neurol. Int.201810755810.4081/ni.2018.7558
    [Google Scholar]
  38. WangQ. HuB. HuX. KimH. SquatritoM. ScarpaceL. deCarvalhoA.C. LyuS. LiP. LiY. BarthelF. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment.Cancer Cell20173214256.e610.1016/j.ccell.2017.06.003 28697342
    [Google Scholar]
  39. HuangT. WanX. AlvarezA.A. JamesC.D. SongX. YangY. SastryN. NakanoI. SulmanE.P. HuB. ChengS.Y. MIR93 (microRNA-93) regulates tumorigenicity and therapy response of glioblastoma by targeting autophagy.Autophagy20191561100111110.1080/15548627.2019.1569947 30654687
    [Google Scholar]
  40. ItoH. AokiH. KühnelF. KondoY. KubickaS. WirthT. IwadoE. IwamaruA. FujiwaraK. HessK.R. LangF.F. SawayaR. KondoS. Autophagic cell death of malignant glioma cells induced by a conditionally replicating adenovirus.J. Natl. Cancer Inst.200698962563610.1093/jnci/djj161 16670388
    [Google Scholar]
  41. SinghalN.C. SharmaN.C. UdawatJ.P. Radiosensitization of hypoxic cells by chemical drugs.Indian J. Cancer1977143269271 924510
    [Google Scholar]
  42. TangL. WeiF. WuY. HeY. ShiL. XiongF. GongZ. GuoC. LiX. Role of metabolism in cancer cell radioresistance and radiosensitization methods.J. Exp. Clin. Cancer Res.201837187
    [Google Scholar]
  43. RycajK. TangD.G. Cancer stem cells and radioresistance.Int. J. Radiat. Biol.201490861562110.3109/09553002.2014.892227 24527669
    [Google Scholar]
  44. Ogier-DenisE. CodognoP. Autophagy: A barrier or an adaptive response to cancer.Biochim. Biophys. Acta200316032113128 12618311
    [Google Scholar]
  45. CecconiF. LevineB. The role of autophagy in mammalian development: cell makeover rather than cell death.Dev. Cell200815334435710.1016/j.devcel.2008.08.012 18804433
    [Google Scholar]
  46. Scherz-ShouvalR. ShvetsE. ElazarZ. Oxidation as a post-translational modification that regulates autophagy.Autophagy20073437137310.4161/auto.4214 17438362
    [Google Scholar]
  47. ItoH. DaidoS. KanzawaT. KondoS. KondoY. Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells.Int. J. Oncol.20052651401141010.3892/ijo.26.5.1401 15809734
    [Google Scholar]
  48. GwakH.S. KimT.H. JoG.H. KimY.J. KwakH.J. KimJ.H. YinJ. YooH. LeeS.H. ParkJ.B. Silencing of microRNA-21 confers radio-sensitivity through inhibition of the PI3K/AKT pathway and enhancing autophagy in malignant glioma cell lines.PLoS One2012710e4744910.1371/journal.pone.0047449 23077620
    [Google Scholar]
  49. JoinerM.C. MarplesB. LambinP. ShortS.C. TuressonI. Low-dose hypersensitivity: Current status and possible mechanisms.Int. J. Radiat. Oncol. Biol. Phys.200149237938910.1016/S0360‑3016(00)01471‑1 11173131
    [Google Scholar]
  50. MizushimaN. YoshimoriT. OhsumiY. The role of Atg proteins in autophagosome formation.Annu. Rev. Cell Dev. Biol.201127110713210.1146/annurev‑cellbio‑092910‑154005 21801009
    [Google Scholar]
  51. WhiteE. The role for autophagy in cancer.J. Clin. Invest.20151251424610.1172/JCI73941 25654549
    [Google Scholar]
  52. HuangT. KimC.K. AlvarezA.A. PangeniR.P. WanX. SongX. ShiT. YangY. SastryN. HorbinskiC.M. LuS. StuppR. KesslerJ.A. NishikawaR. NakanoI. SulmanE.P. LuX. JamesC.D. YinX.M. HuB. ChengS.Y. MST4 phosphorylation of ATG4B regulates autophagic activity, tumorigenicity, and radioresistance in glioblastoma.Cancer Cell2017326840855.e810.1016/j.ccell.2017.11.005 29232556
    [Google Scholar]
  53. LiM. HouY. WangJ. ChenX. ShaoZ.M. YinX.M. Kinetics comparisons of mammalian Atg4 homologues indicate selective preferences toward diverse Atg8 substrates.J. Biol. Chem.201128697327733810.1074/jbc.M110.199059 21177865
    [Google Scholar]
  54. CabreraS. FernándezÁ.F. MariñoG. AguirreA. SuárezM.F. EspañolY. VegaJ.A. LauràR. FueyoA. Fernández-GarcíaM.S. FreijeJ.M.P. KroemerG. López-OtínC. ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis.Autophagy2013981188120010.4161/auto.24797 23782979
    [Google Scholar]
  55. AkinD. WangS.K. Habibzadegah-TariP. LawB. OstrovD. LiM. YinX.M. KimJ.S. HorensteinN. DunnW.A. Jr A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors.Autophagy201410112021203510.4161/auto.32229 25483883
    [Google Scholar]
  56. ShiW. LiuW. MaJ. LuJ. YangX. WangJ. CaoJ. TianY. YangH. ZhangL. The role of Atg7-mediated autophagy in ionizing radiation-induced neural stem cell damage.Gene202073814448510.1016/j.gene.2020.144485 32087272
    [Google Scholar]
  57. ThompsonB.J. SahaiE. MST kinases in development and disease.J. Cell Biol.2015210687188210.1083/jcb.201507005 26370497
    [Google Scholar]
  58. XiongW. MathesonC.J. XuM. BackosD.S. MillsT.S. Salian-MehtaS. Kiseljak-VassiliadesK. ReiganP. WiermanM.E. Structure-based screen identification of a mammalian Ste20-like kinase 4 (MST4) inhibitor with therapeutic potential for pituitary tumors.Mol. Cancer Ther.201615341242010.1158/1535‑7163.MCT‑15‑0703 26721946
    [Google Scholar]
  59. AchilleasG.M. DimitraK. AlexandraG. StamatiaP. AvgiT. RafailK. MichaelI.K. Autophagic flux response and glioblastoma sensitivity to radiation.Cancer Biol. Med.201815326027410.20892/j.issn.2095‑3941.2017.0173 30197793
    [Google Scholar]
  60. PankivS. ClausenT.H. LamarkT. BrechA. BruunJ.A. OutzenH. ØvervatnA. BjørkøyG. JohansenT. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy.J. Biol. Chem.200728233241312414510.1074/jbc.M702824200 17580304
    [Google Scholar]
  61. SettembreC. Di MaltaC. PolitoV.A. ArencibiaM.G. VetriniF. ErdinS. ErdinS.U. HuynhT. MedinaD. ColellaP. SardielloM. RubinszteinD.C. BallabioA. TFEB links autophagy to lysosomal biogenesis.Science201133260361429143310.1126/science.1204592 21617040
    [Google Scholar]
  62. TiniP. BelmonteG. ToscanoM. MiraccoC. PalumboS. PastinaP. BattagliaG. NardoneV. ButoranoM.A.G.M. MasucciA. CeraseA. PirtoliL. Combined epidermal growth factor receptor and Beclin1 autophagic protein expression analysis identifies different clinical presentations, responses to chemo- and radiotherapy, and prognosis in glioblastoma.BioMed Res. Int.2015201511310.1155/2015/208076 25821789
    [Google Scholar]
  63. HuangX. BaiH.M. ChenL. LiB. LuY.C. Reduced expression of LC3B-II and Beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors.J. Clin. Neurosci.201017121515151910.1016/j.jocn.2010.03.051 20863706
    [Google Scholar]
  64. GiatromanolakiA. SivridisE. MitrakasA. KalamidaD. ZoisC.E. HaiderS. PiperidouC. PappaA. GatterK.C. HarrisA.L. KoukourakisM.I. Autophagy and lysosomal related protein expression patterns in human glioblastoma.Cancer Biol. Ther.201415111468147810.4161/15384047.2014.955719 25482944
    [Google Scholar]
  65. WinardiD. TsaiH.P. ChaiC.Y. ChungC.L. LohJ.K. ChenY.H. HsiehC.L. Correlation of altered expression of the autophagy marker LC3B with poor prognosis in astrocytoma.BioMed Res. Int.201420141810.1155/2014/723176 24900981
    [Google Scholar]
  66. PalumboS. TiniP. ToscanoM. AllavenaG. AngelettiF. ManaiF. MiraccoC. CominciniS. PirtoliL. Combined EGFR and autophagy modulation impairs cell migration and enhances radiosensitivity in human glioblastoma cells.J. Cell. Physiol.2014229111863187310.1002/jcp.24640 24691646
    [Google Scholar]
  67. RubinszteinD.C. GestwickiJ.E. MurphyL.O. KlionskyD.J. Potential therapeutic applications of autophagy.Nat. Rev. Drug Discov.20076430431210.1038/nrd2272 17396135
    [Google Scholar]
  68. ZhuangW. LiB. LongL. ChenL. HuangQ. LiangZ. Induction of autophagy promotes differentiation of glioma‐initiating cells and their radiosensitivity.Int. J. Cancer2011129112720273110.1002/ijc.25975 21384342
    [Google Scholar]
  69. PaglinS. LeeN.Y. NakarC. FitzgeraldM. PlotkinJ. DeuelB. HackettN. McMahillM. SphicasE. LampenN. YahalomJ. Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells.Cancer Res.20056523110611107010.1158/0008‑5472.CAN‑05‑1083 16322256
    [Google Scholar]
  70. TakeuchiH. KondoY. FujiwaraK. KanzawaT. AokiH. MillsG.B. KondoS. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors.Cancer Res.20056583336334610.1158/0008‑5472.CAN‑04‑3640 15833867
    [Google Scholar]
  71. GubaM. von BreitenbuchP. SteinbauerM. KoehlG. FlegelS. HornungM. BrunsC.J. ZuelkeC. FarkasS. AnthuberM. JauchK.W. GeisslerE.K. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor.Nat. Med.20028212813510.1038/nm0202‑128 11821896
    [Google Scholar]
  72. ShinoharaE.T. CaoC. NiermannK. MuY. ZengF. HallahanD.E. LuB. Enhanced radiation damage of tumor vasculature by mTOR inhibitors.Oncogene200524355414542210.1038/sj.onc.1208715 15940265
    [Google Scholar]
  73. BaoS. WuQ. McLendonR.E. HaoY. ShiQ. HjelmelandA.B. DewhirstM.W. BignerD.D. RichJ.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.Nature2006444712075676010.1038/nature05236 17051156
    [Google Scholar]
  74. DaidoS. YamamotoA. FujiwaraK. SawayaR. KondoS. KondoY. Inhibition of the DNA-dependent protein kinase catalytic subunit radiosensitizes malignant glioma cells by inducing autophagy.Cancer Res.200565104368437510.1158/0008‑5472.CAN‑04‑4202 15899829
    [Google Scholar]
  75. FiratE. WeyerbrockA. GaedickeS. GrosuA.L. NiedermannG. Chloroquine or chloroquine-PI3K/Akt pathway inhibitor combinations strongly promote γ-irradiation-induced cell death in primary stem-like glioma cells.PLoS One2012710e4735710.1371/journal.pone.0047357 23091617
    [Google Scholar]
  76. PascoloS. Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies.Eur. J. Pharmacol.201677113914410.1016/j.ejphar.2015.12.017 26687632
    [Google Scholar]
  77. ChenT.Y. SyuJ.S. LinT.C. ChengH. LuF. WangC.Y. Chloroquine alleviates etoposide-induced centrosome amplification by inhibiting CDK2 in adrenocortical tumor cells.Oncogenesis2015412e18010.1038/oncsis.2015.37 26690546
    [Google Scholar]
  78. RosenfeldM.R. YeX. SupkoJ.G. DesideriS. GrossmanS.A. BremS. MikkelsonT. WangD. ChangY.C. HuJ. McAfeeQ. FisherJ. TroxelA.B. PiaoS. HeitjanD.F. TanK.S. PontiggiaL. O’DwyerP.J. DavisL.E. AmaravadiR.K. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.Autophagy20141081359136810.4161/auto.28984 24991840
    [Google Scholar]
  79. BriceñoE. CalderonA. SoteloJ. Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme.Surg. Neurol.200767438839110.1016/j.surneu.2006.08.080 17350410
    [Google Scholar]
  80. BulutT. Eki̇ci̇M.A. TucerB. BaşarslanS.K. KamaşakK. KurtsoyA. The effect of chloroquine treatment in malignant astrocytomas on prognosis.Turk. J. Med. Sci.201343578278910.3906/sag‑1203‑100
    [Google Scholar]
  81. CookJ.A. GiusD. WinkD.A. KrishnaM.C. RussoA. MitchellJ.B. Oxidative stress, redox, and the tumor microenvironment.Semin. Radiat. Oncol.200414325926610.1016/j.semradonc.2004.04.001 15254869
    [Google Scholar]
  82. TolerS.M. NoeD. SharmaA. Selective enhancement of cellular oxidative stress by chloroquine: Implications for the treatment of glioblastoma multiforme.Neurosurg. Focus20062161410.3171/foc.2006.21.6.1 17341043
    [Google Scholar]
  83. YeH. ChenM. CaoF. HuangH. ZhanR. ZhengX. Chloroquine, an autophagy inhibitor, potentiates the radiosensitivity of glioma initiating cells by inhibiting autophagy and activating apoptosis.BMC Neurol.201616117810.1186/s12883‑016‑0700‑6 27644442
    [Google Scholar]
  84. MautheM. OrhonI. RocchiC. ZhouX. LuhrM. HijlkemaK.J. CoppesR.P. EngedalN. MariM. ReggioriF. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.Autophagy20181481435145510.1080/15548627.2018.1474314 29940786
    [Google Scholar]
  85. CuiC.M. GaoJ.L. CuiY. SunL.Q. WangY.C. WangK.J. LiR. TianY.X. CuiJ.Z. Chloroquine exerts neuroprotection following traumatic brain injury via suppression of inflammation and neuronal autophagic death.Mol. Med. Rep.20151222323232810.3892/mmr.2015.3611 25872478
    [Google Scholar]
  86. CompterI. EekersD.B.P. HoebenA. RouschopK.M.A. ReymenB. AckermansL. BeckervordersantforthJ. BauerN.J.C. AntenM.M. WesselingP. PostmaA.A. De RuysscherD. LambinP. Chloroquine combined with concurrent radiotherapy and temozolomide for newly diagnosed glioblastoma: a phase IB trial.Autophagy20211792604261210.1080/15548627.2020.1816343 32866424
    [Google Scholar]
  87. DylgjeriE. KnudsenK.E. DNA-PKcs: A targetable protumorigenic protein kinase.Cancer Res.202282452353310.1158/0008‑5472.CAN‑21‑1756 34893509
    [Google Scholar]
  88. SmithG.C.M. JacksonS.P. The DNA-dependent protein kinase.Genes Dev.199913891693410.1101/gad.13.8.916 10215620
    [Google Scholar]
  89. IliakisG. WangY. GuanJ. WangH. DNA damage checkpoint control in cells exposed to ionizing radiation.Oncogene200322375834584710.1038/sj.onc.1206682 12947390
    [Google Scholar]
  90. GuY. JinS. GaoY. WeaverD.T. AltF.W. Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination.Proc. Natl. Acad. Sci. USA199794158076808110.1073/pnas.94.15.8076 9223317
    [Google Scholar]
  91. NussenzweigA. SokolK. BurgmanP. LiL. LiG.C. Hypersensitivity of Ku80 -deficient cell lines and mice to DNA damage: The effects of ionizing radiation on growth, survival, and development.Proc. Natl. Acad. Sci. USA19979425135881359310.1073/pnas.94.25.13588 9391070
    [Google Scholar]
  92. ZhuangW. LiB. LongL. ChenL. HuangQ. LiangZ. Knockdown of the DNA-dependent protein kinase catalytic subunit radiosensitizes glioma-initiating cells by inducing autophagy.Brain Res.2011137171510.1016/j.brainres.2010.11.044 21108935
    [Google Scholar]
  93. Lees-MillerS.P. GodboutR. ChanD.W. WeinfeldM. DayR.S.III BarronG.M. Allalunis-TurnerJ. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line.Science199526752011183118510.1126/science.7855602 7855602
    [Google Scholar]
  94. Allalunis-TurnerM.J. ZiaP.K.Y. BarronG.M. MirzayansR. DayR.S.III Radiation-induced DNA damage and repair in cells of a radiosensitive human malignant glioma cell line.Radiat. Res.1995144328829310.2307/3578948 7494872
    [Google Scholar]
  95. ZhangZ. KuoJ.C.T. YaoS. ZhangC. KhanH. LeeR.J. CpG Oligodeoxynucleotides for anticancer monotherapy from preclinical stages to clinical trials.Pharmaceutics20211417310.3390/pharmaceutics14010073 35056969
    [Google Scholar]
  96. GuptaK. CooperC. A review of the role of CpG oligodeoxynucleotides as toll-like receptor 9 agonists in prophylactic and therapeutic vaccine development in infectious diseases.Drugs R D.20089313714510.2165/00126839‑200809030‑00001 18457466
    [Google Scholar]
  97. JaboinJ.J. ShinoharaE.T. MorettiL. YangE.S. KaminskiJ.M. LuB. The role of mTOR inhibition in augmenting radiation induced autophagy.Technol. Cancer Res. Treat.20076544344710.1177/153303460700600510 17877432
    [Google Scholar]
  98. LiX. CenY. CaiY. LiuT. LiuH. CaoG. LiuD. LiB. PengW. ZouJ. PangX. ZhengJ. ZhouH. TLR9-ERK-mTOR signaling is critical for autophagic cell death induced by CpG oligodeoxynucleotide 107 combined with irradiation in glioma cells.Sci. Rep.2016612710410.1038/srep27104 27251306
    [Google Scholar]
  99. IshdorjG. LiL. GibsonS.B. Regulation of autophagy in hematological malignancies: Role of reactive oxygen species.Leuk. Lymphoma2012531263310.3109/10428194.2011.604752 21749305
    [Google Scholar]
  100. GlickD. BarthS. MacleodK.F. Autophagy: Cellular and molecular mechanisms.J. Pathol.2010221131210.1002/path.2697 20225336
    [Google Scholar]
  101. WangY. ZhangH. Regulation of autophagy by mTOR signaling pathway.Adv. Exp. Med. Biol.20191206678310.1007/978‑981‑15‑0602‑4_3 31776980
    [Google Scholar]
  102. HowlandR.H. Trifluoperazine: A sprightly old drug.J. Psychosoc. Nurs. Ment. Health Serv.2016541202210.3928/02793695‑20151223‑01 26760133
    [Google Scholar]
  103. ZhangL. YuJ. PanH. HuP. HaoY. CaiW. ZhuH. YuA.D. XieX. MaD. YuanJ. Small molecule regulators of autophagy identified by an image-based high-throughput screen.Proc. Natl. Acad. Sci. USA200710448190231902810.1073/pnas.0709695104 18024584
    [Google Scholar]
  104. ZhangX. XuR. ZhangC. XuY. HanM. HuangB. ChenA. QiuC. ThorsenF. PrestegardenL. BjerkvigR. WangJ. LiX. Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination.J. Exp. Clin. Cancer Res.201736111810.1186/s13046‑017‑0588‑z 28870216
    [Google Scholar]
  105. CannonR.O.III BrushJ.E.Jr SchenkeW.H. TracyC.M. EpsteinS.E. Beneficial and detrimental effects of lidoflazine in microvascular angina.Am. J. Cardiol.1990661374110.1016/0002‑9149(90)90732‑G 2193496
    [Google Scholar]
  106. FleischerJ.E. LanierW.L. MildeJ.H. MichenfelderJ.D. Effect of lidoflazine on cerebral blood flow and neurologic outcome when administered after complete cerebral ischemia in dogs.Anesthesiology198766330431110.1097/00000542‑198703000‑00007 3826688
    [Google Scholar]
  107. KimJ. KangH. SonB. KimM.J. KangJ. ParkK.H. JeonJ. JoS. KimH.Y. YounH. YounB. NRBF2-mediated autophagy contributes to metabolite replenishment and radioresistance in glioblastoma.Exp. Mol. Med.202254111872188510.1038/s12276‑022‑00873‑2 36333468
    [Google Scholar]
  108. LiuT.J. KoulD. LaFortuneT. TiaoN. ShenR.J. MairaS.M. Garcia-EchevrriaC. YungW.K.A. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas.Mol. Cancer Ther.2009882204221010.1158/1535‑7163.MCT‑09‑0160 19671762
    [Google Scholar]
  109. WangW. LongL. YangN. ZhangQ. JiW. ZhaoJ. QinZ. WangZ. ChenG. LiangZ. NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro.Acta Pharmacol. Sin.201334568169010.1038/aps.2013.22 23603977
    [Google Scholar]
  110. BartelD.P. MicroRNAs.Cell2004116228129710.1016/S0092‑8674(04)00045‑5 14744438
    [Google Scholar]
  111. MacfarlaneL.A. MurphyP.R. MicroRNA: Biogenesis, function and role in cancer.Curr. Genomics201011753756110.2174/138920210793175895 21532838
    [Google Scholar]
  112. RajewskyN.L. (ou)sy miRNA targets?Nat. Struct. Mol. Biol.200613975475510.1038/nsmb0906‑754 16955093
    [Google Scholar]
  113. KimH. BernardM.E. FlickingerJ.Jr EpperlyM.W. WangH. DixonT.M. ShieldsD. HoughtonF. ZhangX. GreenbergerJ.S. The autophagy-inducing drug carbamazepine is a radiation protector and mitigator.Int. J. Radiat. Biol.201187101052106010.3109/09553002.2011.587860 21728759
    [Google Scholar]
  114. JiangL. WangC. LeiF. ZhangL. ZhangX. LiuA. WuG. ZhuJ. SongL. miR-93 promotes cell proliferation in gliomas through activation of PI3K/Akt signaling pathway.Oncotarget20156108286829910.18632/oncotarget.3221 25823655
    [Google Scholar]
  115. BhatK.P.L. BalasubramaniyanV. VaillantB. EzhilarasanR. HummelinkK. HollingsworthF. WaniK. HeathcockL. JamesJ.D. GoodmanL.D. ConroyS. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma.Cancer Cell201324333134610.1016/j.ccr.2013.08.001 23993863
    [Google Scholar]
  116. SuwaT. KobayashiM. NamJ.M. HaradaH. Tumor microenvironment and radioresistance.Exp. Mol. Med.20215361029103510.1038/s12276‑021‑00640‑9 34135469
    [Google Scholar]
  117. BrantleyE.C. BenvenisteE.N. Signal transducer and activator of transcription-3: A molecular hub for signaling pathways in gliomas.Mol. Cancer Res.20086567568410.1158/1541‑7786.MCR‑07‑2180 18505913
    [Google Scholar]
  118. KimJ. PatelM. RuzevickJ. JacksonC. LimM. STAT3 activation in glioblastoma: Biochemical and therapeutic implications.Cancers 20146137639510.3390/cancers6010376 24518612
    [Google Scholar]
  119. GaoL. LiF. DongB. ZhangJ. RaoY. CongY. MaoB. ChenX. Inhibition of STAT3 and ErbB2 suppresses tumor growth, enhances radiosensitivity, and induces mitochondria-dependent apoptosis in glioma cells.Int. J. Radiat. Oncol. Biol. Phys.20107741223123110.1016/j.ijrobp.2009.12.036 20610043
    [Google Scholar]
  120. YuanX. DuJ. HuaS. ZhangH. GuC. WangJ. YangL. HuangJ. YuJ. LiuF. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells.Exp. Cell Res.2015330226727610.1016/j.yexcr.2014.09.006 25220423
    [Google Scholar]
  121. CalderaV. MellaiM. AnnovazziL. ValenteG. TessitoreL. SchifferD. Stat3 expression and its correlation with proliferation and apoptosis/autophagy in gliomas.J. Oncol.200820081910.1155/2008/219241 19421400
    [Google Scholar]
  122. LipinskiM.M. HoffmanG. NgA. ZhouW. PyB.F. HsuE. LiuX. EisenbergJ. LiuJ. BlenisJ. XavierR.J. YuanJ. A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions.Dev. Cell20101861041105210.1016/j.devcel.2010.05.005 20627085
    [Google Scholar]
  123. ChoY.H. LeeS.H. LeeS.J. KimH.N. KohJ.Y. A role of metallothionein-3 in radiation-induced autophagy in glioma cells.Sci. Rep.2020101201510.1038/s41598‑020‑58237‑7 32029749
    [Google Scholar]
  124. LeeS.J. KohJ.Y. Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes.Mol. Brain2010313010.1186/1756‑6606‑3‑30 20974010
    [Google Scholar]
  125. FalnogaI. PevecA.Z. ŠlejkovecZ. ŽnidaričM.T. ZajcI. MlakarS.J. MarcJ. Arsenic trioxide (ATO) influences the gene expression of metallothioneins in human glioblastoma cells.Biol. Trace Elem. Res.2012149333133910.1007/s12011‑012‑9431‑8 22555517
    [Google Scholar]
  126. Mehrian-ShaiR. YalonM. SimonA.J. EyalE. PismenyukT. MosheI. ConstantiniS. TorenA. High metallothionein predicts poor survival in glioblastoma multiforme.BMC Med. Genomics2015816810.1186/s12920‑015‑0137‑6 26493598
    [Google Scholar]
  127. ParkC.M. ParkM.J. KwakH.J. LeeH.C. KimM.S. LeeS.H. ParkI.C. RheeC.H. HongS.I. Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways.Cancer Res.200666178511851910.1158/0008‑5472.CAN‑05‑4340 16951163
    [Google Scholar]
  128. WuX. YangL. WangJ. HaoY. WangC. LuZ. The involvement of long non-coding RNAs in glioma: From early detection to immunotherapy.Front. Immunol.20221389775410.3389/fimmu.2022.897754 35619711
    [Google Scholar]
  129. QianX. ZhaoJ. YeungP.Y. ZhangQ.C. KwokC.K. Revealing lncRNA structures and interactions by sequencing-based approaches.Trends Biochem. Sci.2019441335210.1016/j.tibs.2018.09.012 30459069
    [Google Scholar]
  130. BuruianăA. FlorianȘ.I. FlorianA.I. TimișT.L. MihuC.M. MiclăușM. OșanS. HrapșaI. CataniciuR.C. FarcașM. ȘușmanS. The roles of miRNA in glioblastoma tumor cell communication: Diplomatic and aggressive negotiations.Int. J. Mol. Sci.2020216195010.3390/ijms21061950 32178454
    [Google Scholar]
  131. JiaP. CaiH. LiuX. ChenJ. MaJ. WangP. LiuY. ZhengJ. XueY. Long non-coding RNA H19 regulates glioma angiogenesis and the biological behavior of glioma-associated endothelial cells by inhibiting microRNA-29a.Cancer Lett.2016381235936910.1016/j.canlet.2016.08.009 27543358
    [Google Scholar]
  132. DevesonI.W. HardwickS.A. MercerT.R. MattickJ.S. The dimensions, dynamics, and relevance of the mammalian noncoding transcriptome.Trends Genet.201733746447810.1016/j.tig.2017.04.004 28535931
    [Google Scholar]
  133. JingS.Y. LuY.Y. YangJ.K. DengW.Y. ZhouQ. JiaoB.H. Expression of long non-coding RNA CRNDE in glioma and its correlation with tumor progression and patient survival.Eur. Rev. Med. Pharmacol. Sci.2016201939923996 27775801
    [Google Scholar]
  134. ZhengJ. WangB. ZhengR. ZhangJ. HuangC. ZhengR. HuangZ. QiuW. LiuM. YangK. MaoZ. JiA. YuanY. Linc-RA1 inhibits autophagy and promotes radioresistance by preventing H2Bub1/USP44 combination in glioma cells.Cell Death Dis.202011975810.1038/s41419‑020‑02977‑x 32934196
    [Google Scholar]
  135. LuanF. ChenW. ChenM. YanJ. ChenH. YuH. LiuT. MoL. An autophagy‐related long non‐coding RNA signature for glioma.FEBS Open Bio20199465366710.1002/2211‑5463.12601 30984540
    [Google Scholar]
  136. XuT. YuW. LiQ. LiX. ShiY. CaoB. ZhangY. WangS. ZhangY. WangT. HuangB. MicroRNA-524 inhibits the progress of glioma via the direct targeting of NCF2.Am. J. Transl. Res.201911316051615 30972186
    [Google Scholar]
  137. ChenX. GaoY. LiD. CaoY. HaoB. LncRNA‐TP53TG1 participated in the stress response under glucose deprivation in glioma.J. Cell. Biochem.2017118124897490410.1002/jcb.26175 28569381
    [Google Scholar]
  138. KabacikS. ManningG. RaffyC. BoufflerS. BadieC. Time, dose and ataxia telangiectasia mutated (ATM) status dependency of coding and noncoding RNA expression after ionizing radiation exposure.Radiat. Res.2015183332533710.1667/RR13876.1 25738893
    [Google Scholar]
  139. GaoW. QiaoM. LuoK. Long noncoding RNA TP53TG1 contributes to radioresistance of glioma cells via miR-524-5p/RAB5A axis.Cancer Biother. Radiopharm.202136760061210.1089/cbr.2020.3567 32762546
    [Google Scholar]
  140. FuZ. LuoW. WangJ. PengT. SunG. ShiJ. LiZ. ZhangB. Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma.Biochem. Biophys. Res. Commun.2017492348048610.1016/j.bbrc.2017.08.070 28834690
    [Google Scholar]
  141. ShenY. LiuY. SunT. YangW. LincRNA-p21 knockdown enhances radiosensitivity of hypoxic tumor cells by reducing autophagy through HIF-1/Akt/mTOR/P70S6K pathway.Exp. Cell Res.2017358218819810.1016/j.yexcr.2017.06.016 28689810
    [Google Scholar]
  142. AfratisN.A. NikitovicD. MulthauptH.A.B. TheocharisA.D. CouchmanJ.R. KaramanosN.K. Syndecans – key regulators of cell signaling and biological functions.FEBS J.20172841274110.1111/febs.13940 27790852
    [Google Scholar]
  143. ZengL. ZhengW. LiuX. ZhouY. JinX. XiaoY. BaiY. PanY. ZhangJ. ShaoC. SDC1-TGM2-FLOT1-BHMT complex determines radiosensitivity of glioblastoma by influencing the fusion of autophagosomes with lysosomes.Theranostics202313113725374310.7150/thno.81999 37441590
    [Google Scholar]
  144. CardosoA.L. FernandesA. Aguilar-PimentelJ.A. de AngelisM.H. GuedesJ.R. BritoM.A. OrtolanoS. PaniG. AthanasopoulouS. GonosE.S. SchossererM. Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.Ageing Res. Rev.20184721427710.1016/j.arr.2018.07.004 30071357
    [Google Scholar]
  145. ZhengW. ChenQ. LiuH. ZengL. ZhouY. LiuX. BaiY. ZhangJ. PanY. ShaoC. SDC1-dependent TGM2 determines radiosensitivity in glioblastoma by coordinating EPG5-mediated fusion of autophagosomes with lysosomes.Autophagy202319383985710.1080/15548627.2022.2105562 35913916
    [Google Scholar]
  146. SubramanianS.V. FitzgeraldM.L. BernfieldM. Regulated shedding of syndecan-1 and -4 ectodomains by thrombin and growth factor receptor activation.J. Biol. Chem.199727223147131472010.1074/jbc.272.23.14713 9169435
    [Google Scholar]
  147. ChenK. WilliamsK.J. Molecular mediators for raft-dependent endocytosis of syndecan-1, a highly conserved, multifunctional receptor.J. Biol. Chem.201328820139881399910.1074/jbc.M112.444737 23525115
    [Google Scholar]
  148. KobayashiJ. HasegawaT. SugenoN. YoshidaS. AkiyamaT. FujimoriK. HatakeyamaH. MikiY. TomiyamaA. KawataY. FukudaM. Extracellular α‐synuclein enters dopaminergic cells by modulating flotillin‐1–assisted dopamine transporter endocytosis.FASEB J.2019339102401025610.1096/fj.201802051R 31211923
    [Google Scholar]
  149. LiT. DongG. KangY. ZhangM. ShengX. WangZ. LiuY. KongN. SunH. Increased homocysteine regulated by androgen activates autophagy by suppressing the mammalian target of rapamycin pathway in the granulosa cells of polycystic ovary syndrome mice.Bioengineered2022134108751088810.1080/21655979.2022.2066608 35485387
    [Google Scholar]
  150. GolsonM.L. KaestnerK.H. Fox transcription factors: From development to disease.Development2016143244558457010.1242/dev.112672 27965437
    [Google Scholar]
  151. SchäferS. BehlingF. SkardellyM. KochM. OttI. PaulsenF. TabatabaiG. SchittenhelmJ. Low FoxG1 and high Olig‐2 labelling indices define a prognostically favourable subset in isocitrate dehydrogenase (IDH)‐mutant gliomas.Neuropathol. Appl. Neurobiol.201844220722310.1111/nan.12447 29053887
    [Google Scholar]
  152. XiaoN. LiC. LiaoW. YinJ. ZhangS. ZhangP. YuanL. HongM. FOXG1 mediates the radiosensitivity of glioma cells through regulation of autophagy.Int. J. Radiat. Biol.202197213914810.1080/09553002.2021.1846816 33201747
    [Google Scholar]
  153. ChenJ. WuX. XingZ. MaC. XiongW. ZhuX. HeX. FOXG1 expression is elevated in glioma and inhibits glioma cell apoptosis.J. Cancer20189577878310.7150/jca.22282 29581755
    [Google Scholar]
  154. CaoY. WangY. Abi SaabW.F. YangF. PessinJ.E. BackerJ.M. NRBF2 regulates macroautophagy as a component of Vps34 Complex I.Biochem. J.2014461231532210.1042/BJ20140515 24785657
    [Google Scholar]
  155. ZhongY. MorrisD.H. JinL. PatelM.S. KarunakaranS.K. FuY.J. MatuszakE.A. WeissH.L. ChaitB.T. WangQ.J. Nrbf2 protein suppresses autophagy by modulating Atg14L protein-containing Beclin 1-Vps34 complex architecture and reducing intracellular phosphatidylinositol-3 phosphate levels.J. Biol. Chem.201428938260212603710.1074/jbc.M114.561134 25086043
    [Google Scholar]
  156. HerbstR.S. Review of epidermal growth factor receptor biology.Int. J. Radiat. Oncol. Biol. Phys.200459Suppl. 2S21S2610.1016/j.ijrobp.2003.11.041 15142631
    [Google Scholar]
  157. KaoG.D. JiangZ. FernandesA.M. GuptaA.K. MaityA. Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation.J. Biol. Chem.200728229212062121210.1074/jbc.M703042200 17513297
    [Google Scholar]
  158. NaritaY. NaganeM. MishimaK. HuangH.J. FurnariF.B. CaveneeW.K. Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas.Cancer Res.2002622267646769 12438278
    [Google Scholar]
  159. ZhuH. AcquavivaJ. RamachandranP. BoskovitzA. WoolfendenS. PfannlR. BronsonR.T. ChenJ.W. WeisslederR. HousmanD.E. CharestA. Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis.Proc. Natl. Acad. Sci. USA200910682712271610.1073/pnas.0813314106 19196966
    [Google Scholar]
  160. ChakravartiA. DickerA. MehtaM. The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: A review of preclinical and correlative clinical data.Int. J. Radiat. Oncol. Biol. Phys.200458392793110.1016/j.ijrobp.2003.09.092 14967452
    [Google Scholar]
  161. RuijterA.J.M. GennipA.H. CaronH.N. KempS. KuilenburgA.B.P. Histone deacetylases (HDACs): Characterization of the classical HDAC family.Biochem. J.2003370373774910.1042/bj20021321 12429021
    [Google Scholar]
  162. YangX-J. SetoE. HATs and HDACs: From structure, function and regulation to novel strategies for therapy and prevention.Oncogene200726375310531810.1038/sj.onc.1210599 17694074
    [Google Scholar]
  163. WangZ. HuP. TangF. LianH. ChenX. ZhangY. HeX. LiuW. XieC. HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma.Cancer Lett.2016379113414210.1016/j.canlet.2016.06.001 27267806
    [Google Scholar]
  164. LiS. LiuX. ChenX. ZhangL. WangX. Histone deacetylase 6 promotes growth of glioblastoma through inhibition of SMAD2 signaling.Tumour Biol.201536129661966510.1007/s13277‑015‑3747‑x 26150340
    [Google Scholar]
  165. MottetD. PirotteS. LamourV. HagedornM. JaverzatS. BikfalviA. BellahcèneA. VerdinE. CastronovoV. HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism.Oncogene200928224325610.1038/onc.2008.371 18850004
    [Google Scholar]
  166. MaramponF. MegiorniF. CameroS. CrescioliC. McDowellH.P. SferraR. VetuschiA. PompiliS. VenturaL. De FeliceF. TomboliniV. DominiciC. MaggioR. FestucciaC. GravinaG.L. HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells.Cancer Lett.201739711110.1016/j.canlet.2017.03.028 28342984
    [Google Scholar]
  167. KuoL.J. YangL.X. Gamma-H2AX: A novel biomarker for DNA double-strand breaks.In Vivo2008223305309 18610740
    [Google Scholar]
  168. ErikssonD. StigbrandT. Radiation-induced cell death mechanisms.Tumour Biol.201031436337210.1007/s13277‑010‑0042‑8 20490962
    [Google Scholar]
  169. FargeasC. Prominin–1 (CD133): From progenitor cells to human diseases.Future Lipidol.20061221322510.2217/17460875.1.2.213
    [Google Scholar]
  170. BehroozB.A. SyahirA. AhmadS. CD133: Beyond a cancer stem cell biomarker.J. Drug Target.201927325726910.1080/1061186X.2018.1479756 29911902
    [Google Scholar]
  171. SinghS.K. ClarkeI.D. TerasakiM. BonnV.E. HawkinsC. SquireJ. DirksP.B. Identification of a cancer stem cell in human brain tumors.Cancer Res.2003631858215828 14522905
    [Google Scholar]
  172. BeierD. HauP. ProescholdtM. LohmeierA. WischhusenJ. OefnerP.J. AignerL. BrawanskiA. BogdahnU. BeierC.P. CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles.Cancer Res.20076794010401510.1158/0008‑5472.CAN‑06‑4180 17483311
    [Google Scholar]
  173. LomonacoS.L. FinnissS. XiangC. DeCarvalhoA. UmanskyF. KalkanisS.N. MikkelsenT. BrodieC. The induction of autophagy by γ‐radiation contributes to the radioresistance of glioma stem cells.Int. J. Cancer2009125371772210.1002/ijc.24402 19431142
    [Google Scholar]
  174. MooreM.N. Autophagy as a second level protective process in conferring resistance to environmentally-induced oxidative stress.Autophagy20084225425610.4161/auto.5528 18196967
    [Google Scholar]
  175. KovácsR. HeinemannU. SteinhäuserC. Mechanisms underlying blood–brain barrier dysfunction in brain pathology and epileptogenesis: Role of astroglia.Epilepsia201253s6Suppl. 6535910.1111/j.1528‑1167.2012.03703.x 23134496
    [Google Scholar]
  176. BelkaC. BudachW. KortmannR.D. BambergM. Radiation induced CNS toxicity – molecular and cellular mechanisms.Br. J. Cancer20018591233123910.1054/bjoc.2001.2100 11720454
    [Google Scholar]
  177. UngvariZ. PodlutskyA. SosnowskaD. TucsekZ. TothP. DeakF. GautamT. CsiszarA. SonntagW.E. Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: Role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity.J. Gerontol. A Biol. Sci. Med. Sci.201368121443145710.1093/gerona/glt057 23689827
    [Google Scholar]
  178. DimitrievichG.S. Fischer-DzogaK. GriemM.L. Radiosensitivity of vascular tissue. I. Differential radiosensitivity of capillaries: A quantitative in vivo study.Radiat. Res.198499351153510.2307/3576327 6473711
    [Google Scholar]
  179. WarringtonJ.P. CsiszarA. JohnsonD.A. HermanT.S. AhmadS. LeeY.W. SonntagW.E. Cerebral microvascular rarefaction induced by whole brain radiation is reversible by systemic hypoxia in mice.Am. J. Physiol. Heart Circ. Physiol.20113003H736H74410.1152/ajpheart.01024.2010 21186274
    [Google Scholar]
  180. LjubimovaN.V. LevitmanM.K. PlotnikovaE.D. EidusL.K. Endothelial cell population dynamics in rat brain after local irradiation.Br. J. Radiol.19916476693494010.1259/0007‑1285‑64‑766‑934 1954536
    [Google Scholar]
  181. MariñoG. Niso-SantanoM. BaehreckeE.H. KroemerG. Self-consumption: The interplay of autophagy and apoptosis.Nat. Rev. Mol. Cell Biol.2014152819410.1038/nrm3735 24401948
    [Google Scholar]
  182. RichardS.A. Advances in synthetic lethality modalities for glioblastoma multiforme.Open Med. (Wars.)20241912024098110.1515/med‑2024‑0981 38868315
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206371143250402175030
Loading
/content/journals/acamc/10.2174/0118715206371143250402175030
Loading

Data & Media loading...


  • Article Type:
    Review Article
Keyword(s): Autophagy; glioma; irradiation; radioresistance; radiosensitivity; therapy
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