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VOLUME 3 , ISSUE 4 ( October-December, 2020 ) > List of Articles


Insights into Molecular Mediators of Oxidative Stress and Inflammation in Glioblastoma Multiforme

Indrani Biswas, Shreyas S Kuduvalli, Mariappan Vignesh, Natarajan Mangaiyarkarasi, Thirugnanasambandhar S Anitha

Citation Information : Biswas I, Kuduvalli SS, Vignesh M, Mangaiyarkarasi N, Anitha T S. Insights into Molecular Mediators of Oxidative Stress and Inflammation in Glioblastoma Multiforme. 2020; 3 (4):137-143.

DOI: 10.5005/jp-journals-10082-02274

License: CC BY-NC 4.0

Published Online: 01-05-2021

Copyright Statement:  Copyright © 2020; The Author(s).


Glioblastoma multiforme (GBM) is one of the most common aggressive and fatal forms of adult brain tumors. According to WHO classification, GBM is usually classified as a grade IV form of a brain tumor. Glioblastoma multiforme exhibits high intra- and inter-tumoral heterogeneity. Free radical generation in GBM plays a robust role in promoting and inducing inflammatory processes mediated by various signaling pathways mainly focusing on Janus-kinases (JAK). Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) stimulates signal transducer activating transcription factor 3 (STAT3) and JNK to induce proinflammatory cytokines, such as, interleukin (IL)-2, IL-6, and IL-8 to aggravate the inflammatory process. This review summarizes the convergence of inflammation and oxidative stress and examines the potential therapeutic targets aimed at the molecular markers in GBM.

  1. Pathological and molecular features of glioblastoma and its peritumoral tissue. Cancers 2019;11(4):469. DOI: 10.3390/cancers11040469.
  2. Glioblastoma multiforme: an overview of emerging therapeutic targets. Front Oncol 2019;9:963. DOI: 10.3389/fonc.2019.00963.
  3. Drug delivery to brain tumors. Curr Neurol Neurosci Rep 2008;8(3):235–241. DOI: 10.1007/s11910-008-0036-8.
  4. Role of redox status in development of glioblastoma. Front Immunol 2016;7:1–15. DOI: 10.3389/fimmu.2016.00156.
  5. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutr J 2015;15(1):71. DOI: 10.1186/s12937-016-0186-5.
  6. Role of ROS and RNS sources in physiological and pathological conditions. Oxid Med Cell Longev 2016;2016:1–44. DOI: 10.1155/2016/1245049.
  7. Antioxidant and oxidative stress: a mutual interplay in age-related diseases. Front Pharmacol 2018;9:1162. DOI: 10.3389/fphar.2018.01162.
  8. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007;170(5):144553. DOI: 10.2353/ajpath.2007.070011.
  9. Molecular alterations in glioblastoma: potential targets for immunotherapy. Prog Mol Biol Transl Sci 2011;98:187–234. DOI: 10.1016/B978-0-12-385506-0.00005-3.
  10. The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genomics 2007;8(5):271–306. DOI: 10.2174/138920207782446160.
  11. Molecular heterogeneity in glioblastoma: potential clinical implications. Front Oncol 2015;5(55):1–10. DOI: 10.3389/fonc.2015.00055.
  12. Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol 2010;2(10):a003236. DOI: 10.1101/cshperspect.a003236.
  13. Epidermal growth factor receptor (EGFR) and EGFRvIII in glioblastoma (GBM): signaling pathways and targeted therapies. Oncogene 2018;37(12):1561–1575. DOI: 10.1038/s41388-017-0045-7.
  14. IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep 2013;13(5):345. DOI: 10.1007/s11910-013-0345-4.
  15. IDH1 mutation and world health organization 2016 diagnostic criteria for adult diffuse gliomas: advances in surgical strategy. Neurosurgery 2017;64(CN Suppl 1):134–138. DOI: 10.1093/neuros/nyx247.
  16. Towards personalized therapy for patients with glioblastoma. Expert Rev Anti Cancer Ther 2011;11(12):1935–1944. DOI: 10.1586/era.11.103.
  17. The role of ATRX in glioma biology. Front Oncol 2017;7:236. DOI: 10.3389/fonc.2017.00236.
  18. The role of ATRX in the alternative lengthening of telomeres (ALT) phenotype. Genes 2016;7(9):66. DOI: 10.3390/genes7090066.
  19. Telomerase reverse transcriptase promoter alterations across cancer types as detected by next-generation sequencing: a clinical and molecular analysis of 423 patients. Cancer 2018;124(6):1288–1296. DOI: 10.1002/cncr.31175.
  20. The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas. Acta Neuropathol Commun 2017;5(1):62. DOI: 10.1186/s40478-017-0465-1.
  21. IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas. Oncotarget 2015;6(30):30295–30305. DOI: 10.18632/oncotarget.4497.
  22. Diffuse gliomas classified by 1p/19q co-deletion, TERT promoter and IDH mutation status are associated with specific genetic risk loci. Acta Neuropathol 2018;135(5):743–755. DOI: 10.1007/s00401-018-1825-z.
  23. O6-methylguanine-DNA methyltransferase in glioma therapy: promise and problems. Biochim Biophys Acta 2012;1826(1):71–82. DOI: 10.1016/j.bbcan.2011.12.004.
  24. A multifaceted review of temozolomide resistance mechanisms in glioblastoma beyond O-6-methylguanine-DNA methyltransferase. Glioma 2019;2(2):68. DOI: 10.4103/glioma.glioma_3_19.
  25. Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis 2017;6(8):e371. DOI: 10.1038/oncsis.2017.65.
  26. Cysteine, glutathione, and thiol redox balance in astrocytes. Antioxidants 2017;6(3):62. DOI: 10.3390/antiox6030062.
  27. Glutamate transporters in the biology of malignant gliomas. Cell Mol Life Sci 2014;71(10):1839–1854. DOI: 10.1007/s00018-013-1521-z.
  28. The transcription factor NF-E2-related factor 2 (Nrf2): a protooncogene? FASEB J 2013;27(2):414–423. DOI: 10.1096/fj.12-217257.
  29. Effects of Nrf2 deficiency on mitochondrial oxidative stress in aged skeletal muscle. Physiol Rep 2019;7(3):e13998. DOI: 10.14814/phy2.13998.
  30. The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules 2010;15(10):7266–7291. DOI: 10.3390/molecules15107266.
  31. The Nrf2/Keap1/ARE pathway and oxidative stress as a therapeutic target in type II diabetes mellitus. J Diabetes Res 2017;2017:1–15. DOI: 10.1155/2017/4826724.
  32. Potential applications of NRF2 inhibitors in cancer therapy. Oxid Med Cell Longev 2019;2019:1–34. DOI: 10.1155/2019/8592348.
  33. Redox-related epigenetic mechanisms in glioblastoma: nuclear factor (erythroid-derived 2)-like 2, cobalamin, and dopamine receptor subtype 4. Front Oncol 2017;7(46):1–14. DOI: 10.3389/fonc.2017.00046.
  34. The anti-inflammatory and anti-oxidant mechanisms of the Keap1/Nrf2/ARE signaling pathway in chronic diseases. Aging Dis 2019;10(3):637–651. DOI: 10.14336/AD.2018.0513.
  35. mTOR signaling in glioblastoma: lessons learned from bench to bedside. Neuro-Oncol 2010;12(8):882–889. DOI: 10.1093/neuonc/noq052.
  36. The role of mammalian target of rapamycin (mTOR) in insulin signaling. Nutrients 2017;9(11):1–17. DOI: 10.3390/nu9111176.
  37. Nrf2 transcription factor can directly regulate mTOR: linking cytoprotective gene expression to a major metabolic regulator that generates redox activity. J Biol Chem 2016;291(49):25476–25488. DOI: 10.1074/jbc.M116.760249.
  38. mTOR-mediated antioxidant activation in solid tumor radio resistance. J Oncol 2019;2019:1–11. DOI: 10.1155/2019/5956867.
  39. The NRF2/KEAP1 axis in the regulation of tumor metabolism: mechanisms and therapeutic perspectives. Biomolecules 2020;10(5):791. DOI: 10.3390/biom10050791.
  40. Regulation of the Keap1–Nrf2 pathway by p62/SQSTM1. Curr Opin Toxicol 2016;1:54–61. DOI: 10.1128/MCB.00642-17.
  41. KEAP1-NRF2 signaling and autophagy in protection against oxidative and reductive proteotoxicity. Biochem J 2015;469(3):347–355. DOI: 10.1042/BJ20150568.
  42. Antioxidant and adaptative response mediated by Nrf2 during physical exercise. Antioxidants 2019;8(6):196. DOI: 10.3390/antiox8060196.
  43. The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis. J Cancer Metastasis Treat 2016;2(3):80–89. DOI: 10.20517/2394-4722.2015.72.
  44. Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol Cancer Res 2008;6(5):675–684. DOI: 10.1158/1541-7786.
  45. PI3K/AKT and HIF-1 signaling pathway in hypoxia-ischemia (review). Mol Med Rep 2018;18(4):3547–3554. DOI: 10.3892/mmr.2018.9375.
  46. STAT3 activation in glioblastoma: biochemical and therapeutic implications. Cancers (Basel) 2014;6(1):376–395. DOI: 10.3390/cancers6010376.
  47. NF-κB and STAT3 in glioblastoma: therapeutic targets coming of age. Expert Rev Neurother 2014;14(11):1293–1306. DOI: 10.1586/14737175.2014.964211.
  48. Inflammation and gliomagenesis: bi-directional communication at early and late stages of tumor progression. Curr Pathobiol Rep 2013;1(1):19–28. DOI: 10.1007/s40139-012-0006-3.
  49. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med 2015;3(10):136. DOI: 10.3978/j.issn.2305-5839.2015.03.49.
  50. The process and regulatory components of inflammation in brain oncogenesis. Biomolecules 2017;7(2):34. DOI: 10.3390/biom7020034.
  51. Targeting the JAK/STAT signaling pathway using phytocompounds for cancer prevention and therapy. Cells 2020;9(6):1451. DOI: 10.3390/cells9061451.
  52. A STAT3-based gene signature stratifies glioma patients for targeted therapy. Nat Commun 2019;10(1):3601. DOI: 10.1038/s41467-019-11614-x.
  53. Apoptotic signaling pathways in glioblastoma and therapeutic implications. Biomed Res Int 2017;2017:7403747. DOI: 10.1155/2017/7403747.
  54. Inhibition of PI3K-AKT-mTOR signaling in glioblastoma by mTORC1/2 inhibitors. Methods Mol Biol 2012;821:349–359. DOI: 10.1007/978-1-61779-430-8_22.
  55. PI3K/AKT/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget 2016;7(22):33440–33450. DOI: 10.18632/oncotarget.7961.
  56. Trimebutine promotes glioma cell apoptosis as a potential anti-tumor agent. Front Pharmacol 2018;9:664. DOI: 10.3389/fphar.2018.00664.
  57. Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells. J Exp Clin Cancer Res CR 2019;38(1):184. DOI: 10.1186/s13046-019-1173-4.
  58. TNFα promotes glioblastoma A172 cell mitochondrial apoptosis via augmenting mitochondrial fission and repression of MAPK–ERK–YAP signaling pathways. OncoTargets Ther 2018;11:7213–7227. DOI: 10.2147/OTT.S184337.
  59. Raddeanin a suppresses glioblastoma growth by inducing ROS generation and subsequent JNK activation to promote cell apoptosis. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 2018;47(3):1108–1121. DOI: 10.1159/000490187.
  60. Tanshinone IIA inhibits the growth, attenuates the stemness and induces the apoptosis of human glioma stem cells. Oncol Rep 2014;32(3):1303–1311. DOI: 10.3892/or.2014.3293.
  61. Brevilin A promotes oxidative stress and induces mitochondrial apoptosis in U87 glioblastoma cells. OncoTargets Ther 2018;11:7031–7040. DOI: 10.2147/OTT.S179730.
  62. Shikonin inhibits proliferation and induces apoptosis in glioma cells via down regulation of CD147. Mol Med Rep 2019;19(5):4335–4343. DOI: 10.3892/mmr.2019.10101.
  63. Phytochemical evaluation, antimicrobial activity, and determination of bioactive components from leaves of Aegle marmelos. Biomed Res Int 2014;2014:497606. DOI: 10.1155/2014/497606.
  64. Baicalein induces the apoptosis of U251 glioblastoma cell lines via the NF-kB-p65-mediated mechanism. Anim Cells Syst 2016;20(5):296–302. DOI:
  65. Kukoamine A inhibits human glioblastoma cell growth and migration through apoptosis induction and epithelial-mesenchymal transition attenuation. Sci Rep 2016;6(1):36543. DOI: 10.1038/srep36543.
  66. A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer. Proc Natl Acad Sci U S A 2019;116(13):6435–6440. DOI:
  67. Natural bioactive compounds: alternative approach to the treatment of glioblastoma multiforme. Biomed Res Int 2017;2017:9363040. DOI: 10.1155/2017/9363040.
  68. Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer 2011;129(3):659–670. DOI: 10.1002/ijc.26083.
  69. Global DNA methylation patterns in human gliomas and their interplay with other epigenetic modifications. Int J Mol Sci 2019;20(14):3478. DOI: 10.3390/ijms20143478.
  70. The role of tumor protein 53 mutations in common human cancers and targeting the murine double minute 2–P53 interaction for cancer therapy. Iran J Med Sci 2012;37(1):3–8.
  71. PTEN tumor suppressor network in PI3K-AKT pathway control. Genes Cancer 2010;1(12):1170–1177. DOI: 10.1177/1947601911407325.
  72. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol 2012;226(1):7–16. DOI: 10.1002/path.2995.
  73. The interplay between Src and integrins in normal and tumor biology. Oncogene 2004;23(48):7928–7946. DOI: 10.1038/sj.onc.1208080.
  74. mTOR signaling in protein translation regulation: implications in cancer genesis and therapeutic interventions. Mol Biol Int 2014;2014:686984. DOI: 10.1155/2014/686984.
  75. Drug repurposing in oncology: compounds, pathways, phenotypes and computational approaches for colorectal cancer. Biochim Biophys Acta Rev Cancer 2019;1871(2):434–454. DOI: 10.1016/j.bbcan.2019.04.005.
  76. Disulfiram, a drug widely used to control alcoholism, suppresses self-renewal of glioblastoma and overrides resistance to temozolomide. Oncotarget 2012;3(10):1112–1123. DOI: 10.18632/oncotarget.604.
  77. Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev 2012;64(3):520–539. DOI: 10.1124/pr.111.005538.
  78. Drug repurposing for the treatment of glioblastoma multiforme. J Exp Clin Cancer Res 2017;36(1):169. DOI: 10.1186/s13046-017-0642-x.
  79. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell Metab 2016;23(6):990–1003. DOI: 10.1016/j.cmet.2016.05.009.
  80. Cancer cell metabolism: implications for therapeutic targets. Exp Mol Med 2013;45(10):e45. DOI: 10.1038/emm.2013.85.
  81. Metformin as potential therapy for high-grade glioma. Cancers 2020;12(1):210. DOI: 10.3390/cancers12010210.
  82. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res 2019;11:3295–3313. DOI: 10.2147/CMAR.S200059.
  83. Drug repositioning in glioblastoma: a pathway perspective. Front Pharmacol 2018;9:218. DOI: 10.3389/fphar.2018.00218.
  84. Therapeutics targeting the fibrinolytic system. Exp Mol Med 2020;52(3):367–379. DOI: 10.1038/s12276-020-0397-x.
  85. Anti-inflammatory agents for cancer therapy. Mol Cell Pharmacol 2009;1(1):29–43. DOI: 10.4255/mcpharmacol.09.05.
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