Tumor Biology

, Volume 35, Issue 5, pp 4567–4580 | Cite as

The impact of arsenic trioxide and all-trans retinoic acid on p53 R273H-codon mutant glioblastoma

  • Michael Karsy
  • Ladislau Albert
  • Raj Murali
  • Meena Jhanwar-Uniyal
Research Article


Glioblastoma (GBM) is the most common primary brain tumor in adults and demonstrates a 1-year median survival time. Codon-specific hotspot mutations of p53 result in constitutively active mutant p53, which promotes aberrant proliferation, anti-apoptosis, and cell cycle checkpoint failure in GBM. Recently identified CD133+ cancer stem cell populations (CSC) within GBM also confer therapeutic resistance. We studied targeted therapy in a codon-specific p53 mutant (R273H) created by site-directed mutagenesis in U87MG. The effects of arsenic trioxide (ATO, 1 μM) and all-trans retinoic acid (ATRA, 10 μM), possible targeted treatments of CSCs, were investigated in U87MG neurospheres. The results showed that U87-p53R273H cells generated more rapid neurosphere growth than U87-p53wt but inhibition of neurosphere proliferation was seen with both ATO and ATRA. U87-p53R273H neurospheres showed resistance to differentiation into glial cells and neuronal cells with ATO and ATRA exposure. ATO was able to generate apoptosis at high doses and proliferation of U87-p53wt and U87-p53R273H cells was reduced with ATO and ATRA in a dose-dependent manner. Elevated pERK1/2 and p53 expression was seen in U87-p53R273H neurospheres, which could be reduced with ATO and ATRA treatment. Additionally, differential responses in pERK1/2 were seen with ATO treatment in neurospheres and non-neurosphere cells. In conclusion, codon-specific mutant p53 conferred a more aggressive phenotype to our CSC model. However, ATO and ATRA could potently suppress CSC properties in vitro and may support further clinical investigation of these agents.





This work was supported by an NYMC intramural grant, the Children’s Hospital Foundation Grant, the NYMC Departments of Pathology and Neurosurgery, and the NYMC Graduate School of Basic Medical Sciences. We would like to thank Dr. Wei Dai for his generous donation of a wild-type p53/pcDNA3.1 construct, Dr. Zeling Chau and Mr. Nicolaus Gulati for their assistance of generation and verification of the U87-p53R273H cell line, Dr. David Frick for support on amplification of the vector, and Dr. Fred Wu for assistance on U87 transfection and clone selection.

Conflicts of interest


Supplementary material

13277_2013_1601_MOESM1_ESM.jpg (166 kb)
Supplemental Figure 1 Differentiation of neurospheres into neuronal lineages and the synergistic impact of combined ATO/ATRA treatment. Immunofluorescence analysis of nestin and TUJ1 was evaluated in U87-p53wt neurospheres following ATO or ATRA treatment. Evaluation of differentiation with combined ATO and ATRA was also performed in order to evaluate synergistic/additive effects. A) Immunofluorescence images indicate predominant nestin expression in controls and lower TUJ1 expression. U87-p53wt cells staining for nestin decreased while cells cell staining for TUJ1 increased after treatment with ATO or ATRA. B) Quantitation of cells expressing nestin or TUJ1 indicate that ATO or ATRA treatment resulted in a significant decrease of nestin-expressing cells and a significant increase in TUJ1 expressing cells. C) Quantitation of the number of cells co-expressing TUJ1 and nestin showed a significant decrease after ATO or ATRA treatment. D) Combined treatment with ATO and ATRA demonstrated a significant reduction in nestin-expressing cells with a significant increase in GFAP or TUJ1 expressing cells. E) Co-expression of GFAP and nestin or TUJ1 and nestin was significantly reduced following combined ATO and ATRA treatment compared to control. *p < 0.05, t test (JPEG 166 kb)
13277_2013_1601_MOESM2_ESM.jpg (590 kb)
Supplemental Figure 2 Impact of high dose ATO and ATRA on GBM neurospheres. The role of high dose ATO and ATRA was evaluated on GBM integrity. Phase contrast photomicroscopy was used to evaluate various doses of ATO (0.5, 1, 2, 4, and 16 μM) and ATRA (2, 5, 10, 20, and 40 μM). High doses of ATO (4 and 16 μM) demonstrated loss of cell–cell contact, increased cellular debris, and neurosphere detachment suggestive of apoptosis. However, high doses of ATRA (20, 40 μM) did not yield similar features. (JPEG 589 kb)


  1. 1.
    Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, et al. Long-term survival with glioblastoma multiforme. Brain. 2007;130:2596–606.CrossRefPubMedGoogle Scholar
  2. 2.
    Louis DN, Ohgaki HH, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system. 4th ed. Albany: WHO Press; 2007.Google Scholar
  3. 3.
    Li S, Jiang T, Li G, Wang Z. Impact of p53 status to response of temozolomide in low MGMT expression glioblastomas: preliminary results. Neurol Res. 2008;30:567–70.CrossRefPubMedGoogle Scholar
  4. 4.
    Kim EH, Yoon MJ, Kim SU, Kwon TK, Sohn S, Choi KS. Arsenic trioxide sensitizes human glioma cells, but not normal astrocytes, to TRAIL-induced apoptosis via CCAAT/enhancer-binding protein homologous protein-dependent DR5 up-regulation. Cancer Res. 2008;68:266–75.CrossRefPubMedGoogle Scholar
  5. 5.
    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.CrossRefPubMedGoogle Scholar
  6. 6.
    Ohgaki H, Kleihues P. Genetic profile of astrocytic and oligodendroglial gliomas. Brain Tumor Pathol. 2011;28:177–83.CrossRefPubMedGoogle Scholar
  7. 7.
    Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE, et al. Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell. 2009;15:514–26.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen A-J, et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature. 2008;455:1129–33.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.CrossRefGoogle Scholar
  10. 10.
    England B, Huang T, Karsy M. Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumour Biol. 2013;34:2063–74.CrossRefPubMedGoogle Scholar
  11. 11.
    Sami A, Karsy M. Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding. Tumour Biol. 2013;34:1991–2002.CrossRefPubMedGoogle Scholar
  12. 12.
    Okorokov AL, Orlova EV. Structural biology of the p53 tumour suppressor. Curr Opin Struct Biol. 2009;19:197–202.CrossRefPubMedGoogle Scholar
  13. 13.
    Houillier C, Lejeune J, Benouaich-Amiel A, Laigle-Donadey F, Criniere E, Mokhtari K, et al. Prognostic impact of molecular markers in a series of 220 primary glioblastomas. Cancer. 2006;106:2218–23.CrossRefPubMedGoogle Scholar
  14. 14.
    Felsberg J, Rapp M, Loeser S, Fimmers R, Stummer W, Goeppert M, et al. Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients. Clin Cancer Res. 2009;15:6683–93.CrossRefPubMedGoogle Scholar
  15. 15.
    Guimaraes DP, Hainaut P. TP53: a key gene in human cancer. Biochimie. 2002;84:83–93.CrossRefPubMedGoogle Scholar
  16. 16.
    Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. 2009;137:413–31.CrossRefPubMedGoogle Scholar
  17. 17.
    Bullock AN, Fersht AR. Rescuing the function of mutant p53. Nat Rev Cancer. 2001;1:68–76.CrossRefPubMedGoogle Scholar
  18. 18.
    Cho Y, Gorina S, Jeffrey PD, Pavletich NP. Crystal structure of a p53 tumor suppressor–DNA complex: understanding tumorigenic mutations. Science. 1994;265:346–55.CrossRefPubMedGoogle Scholar
  19. 19.
    Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med. 2005;353:811–22.CrossRefPubMedGoogle Scholar
  20. 20.
    Nduom EK-E, Hadjipanayis CG, Van Meir EG. Glioblastoma cancer stem-like cells: implications for pathogenesis and treatment. Cancer J. 2012;18:100–6.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Rich JN, Eyler CE. Cancer stem cells in brain tumor biology. Cold Spring Harb Symp Quant Biol. 2008;73:411–20.CrossRefPubMedGoogle Scholar
  22. 22.
    Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A. 2003;100:15178–83.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.PubMedGoogle Scholar
  24. 24.
    Vescovi AL, Galli R, Reynolds BA. Brain tumour stem cells. Nat Rev Cancer. 2006;6:425–36.CrossRefPubMedGoogle Scholar
  25. 25.
    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.CrossRefPubMedGoogle Scholar
  26. 26.
    Karsy M, Albert L, Tobias ME, Murali R, Jhanwar-Uniyal M. All-trans retinoic acid modulates cancer stem cells of glioblastoma multiforme in an MAPK-dependent manner. Anticancer Res. 2010;30:4915–20.PubMedGoogle Scholar
  27. 27.
    Antman KH. Introduction: the history of arsenic trioxide in cancer therapy. Oncologist. 2001;6 Suppl 2:1–2.Google Scholar
  28. 28.
    Dilda PJ, Hogg PJ. Arsenical-based cancer drugs. Cancer Treat Rev. 2007;33:542–64.CrossRefPubMedGoogle Scholar
  29. 29.
    Ralph SJ. Arsenic-based antineoplastic drugs and their mechanisms of action. Met Based Drugs. 2008;2008:260146.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Miller WH, Schipper HM, Lee JS, Singer J, Waxman S. Mechanisms of action of arsenic trioxide. Cancer Res. 2002;62:3893–903.PubMedGoogle Scholar
  31. 31.
    Zharova TV, Vinogradov AD. Energy-linked binding of Pi is required for continuous steady-state proton-translocating ATP hydrolysis catalyzed by F0.F1 ATP synthase. Biochemistry. 2006;45:14552–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Hong SH, Yang Z, Privalsky ML. Arsenic trioxide is a potent inhibitor of the interaction of SMRT corepressor with its transcription factor partners, including the PML-retinoic acid receptor alpha oncoprotein found in human acute promyelocytic leukemia. Mol Cell Biol. 2001;21:7172–82.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Eblin KE, Bowen ME, Cromey DW, Bredfeldt TG, Mash EA, Lau SS, et al. Arsenite and monomethylarsonous acid generate oxidative stress response in human bladder cell culture. Toxicol Appl Pharmacol. 2006;217:7–14.CrossRefPubMedGoogle Scholar
  34. 34.
    Ning S, Knox SJ. Increased cure rate of glioblastoma using concurrent therapy with radiotherapy and arsenic trioxide. Int J Radiat Oncol Biol Phys. 2004;60:197–203.CrossRefPubMedGoogle Scholar
  35. 35.
    Tomuleasa C, Soritau O, Kacso G, Fischer-Fodor E, Cocis A, Ioani H, et al. Arsenic trioxide sensitizes cancer stem cells to chemoradiotherapy. A new approach in the treatment of inoperable glioblastoma multiforme. J BUON. 2010;15:758–62.PubMedGoogle Scholar
  36. 36.
    Kanzawa T, Zhang L, Xiao L, Germano IM, Kondo Y, Kondo S. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene. 2005;24:980–91.CrossRefPubMedGoogle Scholar
  37. 37.
    Zhen Y, Zhao S, Li Q, Li Y, Kawamoto K. Arsenic trioxide-mediated Notch pathway inhibition depletes the cancer stem-like cell population in gliomas. Cancer Lett. 2010;292:64–72.CrossRefPubMedGoogle Scholar
  38. 38.
    Ning S, Knox SJ. Optimization of combination therapy of arsenic trioxide and fractionated radiotherapy for malignant glioma. Int J Radiat Oncol Biol Phys. 2006;65:493–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Wu J, Ji Z, Liu H, Liu Y, Han D, Shi C, et al. Arsenic trioxide depletes cancer stem-like cells and inhibits repopulation of neurosphere derived from glioblastoma by downregulation of Notch pathway. Toxicol Lett. 2013;220:61–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Chiu H-W, Ho S-Y, Guo H-R, Wang Y-J. Combination treatment with arsenic trioxide and irradiation enhances autophagic effects in U118-MG cells through increased mitotic arrest and regulation of PI3K/Akt and ERK1/2 signaling pathways. Autophagy. 2009;5:472–83.CrossRefPubMedGoogle Scholar
  41. 41.
    Dizaji MZ, Malehmir M, Ghavamzadeh A, Alimoghaddam K, Ghaffari SH. Synergistic effects of arsenic trioxide and silibinin on apoptosis and invasion in human glioblastoma U87MG cell line. Neurochem Res. 2012;37:370–80.CrossRefPubMedGoogle Scholar
  42. 42.
    Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993;9:138–41.CrossRefPubMedGoogle Scholar
  43. 43.
    Gulati N, Karsy M, Albert L, Murali R, Jhanwar-Uniyal M. Involvement of mTORC1 and mTORC2 in regulation of glioblastoma multiforme growth and motility. Int J Oncol. 2009;35:731–40.PubMedGoogle Scholar
  44. 44.
    Albert L, Karsy M, Murali R, Jhanwar-Uniyal M. Inhibition of mTOR activates the MAPK pathway in glioblastoma multiforme. Cancer Genomics Proteomics. 2009;6:255–61.PubMedGoogle Scholar
  45. 45.
    Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–10.CrossRefPubMedGoogle Scholar
  46. 46.
    Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.CrossRefPubMedGoogle Scholar
  48. 48.
    Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, et al. Targeting of the Bmi-1 oncogene/stem cell renewal factor by MicroRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res. 2008;68:9125–30.CrossRefPubMedGoogle Scholar
  49. 49.
    Gangemi RMR, Griffero F, Marubbi D, Perera M, Capra MC, Malatesta P, et al. SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells. 2009;27:40–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Wang J, Wang H, Li Z, Wu Q, Lathia JD, McLendon RE, et al. c-Myc is required for maintenance of glioma cancer stem cells. PLoS ONE. 2008;3:e3769.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Du Z, Jia D, Liu S, Wang F, Li G, Zhang Y, et al. Oct4 is expressed in human gliomas and promotes colony formation in glioma cells. Glia. 2009;57:724–33.CrossRefPubMedGoogle Scholar
  52. 52.
    Piccirillo SGM, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006;444:761–5.CrossRefPubMedGoogle Scholar
  53. 53.
    Eyler CE, Foo W-C, LaFiura KM, McLendon RE, Hjelmeland AB, Rich JN. Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells. 2008;26:3027–36.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kanzawa T, Kondo Y, Ito H, Kondo S, Germano I. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res. 2003;63:2103–8.PubMedGoogle Scholar
  55. 55.
    Lin T-H, Kuo H-C, Chou F-P, Lu F-J. Berberine enhances inhibition of glioma tumor cell migration and invasiveness mediated by arsenic trioxide. BMC Cancer. 2008;8:58.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Grimm SA, Marymont M, Chandler JP, Muro K, Newman SB, Levy RM, et al. Phase I study of arsenic trioxide and temozolomide in combination with radiation therapy in patients with malignant gliomas. J Neurooncol. 2012;110:237–43.CrossRefPubMedGoogle Scholar
  57. 57.
    Cohen KJ, Gibbs IC, Fisher PG, Hayashi RJ, Macy ME, Gore L. A phase I trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood. Neuro-oncol. 2013;15:783–7.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Beier D, Schulz JB, Beier CP. Chemoresistance of glioblastoma cancer stem cells—much more complex than expected. Mol Cancer. 2011;10:128. BioMed Central Ltd.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CHM, Jones DL, et al. Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66:9339–44.CrossRefPubMedGoogle Scholar
  60. 60.
    Zhang M, Song T, Yang L, Chen R, Wu L, Yang Z, et al. Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients. J Exp Clin Cancer Res. 2008;27:85.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Christensen K, Schrøder HD, Kristensen BW. CD133 identifies perivascular niches in grade II–IV astrocytomas. J Neuro-Oncol. 2008;90:157–70.CrossRefGoogle Scholar
  62. 62.
    Strojnik T, Røsland GV, Sakariassen PO, Kavalar R, Lah T. Neural stem cell markers, nestin and musashi proteins, in the progression of human glioma: correlation of nestin with prognosis of patient survival. Surg Neurol. 2007;68:133–43. discussion143–4.CrossRefPubMedGoogle Scholar
  63. 63.
    Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer. 2006;5:67.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008;40:499–507.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, et al. Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res. 2008;14:123–9.CrossRefPubMedGoogle Scholar
  66. 66.
    Beier D, Wischhusen J, Dietmaier W, Hau P, Proescholdt M, Brawanski A, et al. CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol. 2008;18:370–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Melguizo C, Prados J, González B, Ortiz R, Concha A, Alvarez PJ, et al. MGMT promoter methylation status and MGMT and CD133 immunohistochemical expression as prognostic markers in glioblastoma patients treated with temozolomide plus radiotherapy. J Transl Med. 2012;10:250.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Sun H, Zhang S. Arsenic trioxide regulates the apoptosis of glioma cell and glioma stem cell via down-regulation of stem cell marker Sox2. Biochem Biophys Res Commun. 2011;410:692–7.CrossRefPubMedGoogle Scholar
  69. 69.
    Chiu H-W, Ho Y-S, Wang Y-J. Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin. J Mol Med. 2011;89:927–41.CrossRefPubMedGoogle Scholar
  70. 70.
    Song X, Chen Z, Wu C, Zhao S. Abrogating HSP response augments cell death induced by As2O3 in glioma cell lines. Can J Neurol Sci. 2010;37:504–11.CrossRefPubMedGoogle Scholar
  71. 71.
    Zhao S, Tsuchida T, Kawakami K, Shi C, Kawamoto K. Effect of As2O3 on cell cycle progression and cyclins D1 and B1 expression in two glioblastoma cell lines differing in p53 status. Int J Oncol. 2002;21:49–55.PubMedGoogle Scholar
  72. 72.
    Raju GP. Arsenic: a potentially useful poison for Hedgehog-driven cancers. J Clin Invest. 2011;121:14–6.CrossRefPubMedGoogle Scholar
  73. 73.
    Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee Y-C, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121:148–60.CrossRefPubMedGoogle Scholar
  74. 74.
    Haga N, Fujita N, Tsuruo T. Involvement of mitochondrial aggregation in arsenic trioxide (As2O3)-induced apoptosis in human glioblastoma cells. Cancer Sci. 2005;96:825–33.CrossRefPubMedGoogle Scholar
  75. 75.
    Liu Y, Liang Y, Zheng T, Yang G, Zhang X, Sun Z, et al. Inhibition of heme oxygenase-1 enhances anti-cancer effects of arsenic trioxide on glioma cells. J Neuro-Oncol. 2011;104:449–58.CrossRefGoogle Scholar
  76. 76.
    Cowley S, Paterson H, Kemp P, Marshall CJ. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994;77:841–52.CrossRefPubMedGoogle Scholar
  77. 77.
    Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998;12:3008–19.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995;80:179–85.CrossRefPubMedGoogle Scholar
  79. 79.
    Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell. 2000;103:321–30.CrossRefPubMedGoogle Scholar
  80. 80.
    Zhao S, Zhang J, Zhang X, Dong X, Sun X. Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008;35:421–9.CrossRefPubMedGoogle Scholar
  81. 81.
    Yu X, Robinson JF, Gribble E, Hong SW, Sidhu JS, Faustman EM. Gene expression profiling analysis reveals arsenic-induced cell cycle arrest and apoptosis in p53-proficient and p53-deficient cells through differential gene pathways. Toxicol Appl Pharmacol. 2008;233:389–403.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Sathornsumetee S, Rich JN. Designer therapies for glioblastoma multiforme. Ann N Y Acad Sci. 2008;1142:108–32.CrossRefPubMedGoogle Scholar
  83. 83.
    Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM, et al. A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell. 2010;17:362–75.CrossRefPubMedGoogle Scholar
  84. 84.
    Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res. 2005;65:6207–19.CrossRefPubMedGoogle Scholar
  85. 85.
    Laks DR, Masterman-Smith M, Visnyei K, Angenieux B, Orozco NM, Foran I, et al. Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells. 2009;27:980–7.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Lathia JD, Venere M, Rao MS, Rich JN. Seeing is believing: are cancer stem cells the Loch Ness monster of tumor biology? Stem Cell Rev. 2011;7:227–37.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Jhanwar-Uniyal M, Albert L, McKenna E, Karsy M, Rajdev P, Braun A, et al. Deciphering the signaling pathways of cancer stem cells of glioblastoma multiforme: role of Akt/mTOR and MAPK pathways. Adv Enzym Regul. 2011;51:164–70.CrossRefGoogle Scholar
  88. 88.
    Cordey M, Limacher M, Kobel S, Taylor V, Lutolf MP. Enhancing the reliability and throughput of neurosphere culture on hydrogel microwell arrays. Stem Cells. 2008;26:2586–94.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Michael Karsy
    • 1
  • Ladislau Albert
    • 2
  • Raj Murali
    • 2
  • Meena Jhanwar-Uniyal
    • 2
  1. 1.Department of NeurosurgeryUniversity of UtahSalt Lake CityUSA
  2. 2.Department of NeurosurgeryNew York Medical CollegeValhallaUSA

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