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Problems of glioblastoma multiforme drug resistance

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Abstract

Glioblastoma multiforme (GBL) is the most common and aggressive brain neoplasm. A standard therapeutic approach for GBL involves combination therapy consisting of surgery, radiotherapy, and chemotherapy. The latter is based on temozolomide (TMZ). However, even by applying such a radical treatment strategy, the mean patient survival time is only 14.6 months. Here we review the molecular mechanisms underlying the resistance of GBL cells to TMZ including genetic and epigenetic mechanisms. Present data regarding a role for genes and proteins MGMT, IDH1/2, YB-1, MELK, MVP/LRP, MDR1 (ABCB1), and genes encoding other ABC transporters as well as Akt3 kinase in developing resistance of GBL to TMZ are discussed. Some epigenetic regulators of resistance to TMZ such as microRNA and EZH2 are reviewed.

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References

  1. Jovcevska, I., Kocevar, N., and Komel, R. (2013) Glioma and glioblastoma–how much do we (not) know? Mol. Clin. Oncol., 6, 935–941.

    Google Scholar 

  2. Ajaz, M., Jefferies, S., Brazil, L., Watts, C., and Chalmers, A. (2014) Current and investigational drug strategies for glioblastoma, Clin. Oncol. (R. Coll. Radiol.), 26, 419–430.

    Article  CAS  Google Scholar 

  3. Wilson, T. A., Karajannis, M. A., and Harter, D. H. (2014) Glioblastoma multiforme: state of the art and future therapeutics, Surg. Neurol. Int., 5, 64.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Zhang, J., Stevens, M. F., and Bradshaw, T. D. (2012) Temozolomide: mechanisms of action, repair and resistance, Curr. Mol. Pharmacol., 5, 102–114.

    Article  CAS  Google Scholar 

  5. Narita, Y. (2013) Drug review: safety and efficacy of bevacizumab for glioblastoma and other brain tumors, Jpn. J. Clin. Oncol., 43, 587–595.

    Article  PubMed  Google Scholar 

  6. Abbott, N. J. (2013) Blood–brain barrier structure and function and the challenges for CNS drug delivery, J. Inherit. Metab. Dis., 36, 437–449.

    Article  PubMed  CAS  Google Scholar 

  7. Miller, D. S. (2010) Regulation of P-glycoprotein and other ABC drug transporters at the blood–brain barrier, Trends Pharmacol. Sci., 31, 246–254.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Hartz, A. M., and Bauer, B. (2011) ABC transporters in the CNS–an inventory, Curr. Pharm. Biotechnol., 12, 656–673.

    Article  PubMed  CAS  Google Scholar 

  9. Miller, D. S. (2015) Regulation of ABC transporters blood–brain barrier: the good, the bad, and the ugly, Adv. Cancer Res., 125, 43–70.

    Article  PubMed  Google Scholar 

  10. Stavrovskaya, A. A. (2000) Cellular mechanisms of multidrug resistance of tumor cells, Biochemistry (Moscow), 65, 95–106.

    CAS  Google Scholar 

  11. Stavrovskaya, A. A., and Stromskaya, T. P. (2008) Transport proteins of the ABC family and multidrug resistance of tumor cells, Biochemistry (Moscow), 5, 592–604.

    Article  CAS  Google Scholar 

  12. Gottesman, M. M., Fojo, T., and Bates, S. E. (2002) Multidrug resistance in cancer: role of ATP dependent transporters, Nat. Rev. Cancer, 2, 48–58.

    Article  PubMed  CAS  Google Scholar 

  13. Hartz, A. M., and Bauer, B. (2011) ABC transporters in the CNS–an inventory, Curr. Pharm. Biotechnol., 12, 656–673.

    Article  PubMed  CAS  Google Scholar 

  14. Minniti, G., Muni, R., Lanzetta, G., Marchetti, P., and Enrici, R. M. (2009) Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents, Anticancer Res., 12, 5171–5184.

    Google Scholar 

  15. Zhang, J., Stevens, M. F., Hummersone, M., Madhusudan, S., Laughton, C. A., and Bradshaw, T. D. (2011) Certain imidazotetrazines escape O6-methylguanine-DNA methyltransferase and mismatch repair, Oncology, 80, 195–207.

    Article  PubMed  CAS  Google Scholar 

  16. Parker, N. R., Khong, P., Parkinson, J. F., Howell, V. M., and Wheeler, H. R. (2015) Molecular heterogeneity in glioblastoma: potential clinical implications, Front. Oncol., doi: 10.3389/fonc.2015.00055.

    Google Scholar 

  17. Brennan, C. W., Verhaak, R. G., McKenna, A., Campos, B., Noushmehr, H., Salama, S. R., Zheng, S., Chakravarty, D., Sanborn, J. Z., Berman, S. H., Beroukhim, R., Bernard, B., Wu, C. J., Genovese, G., Shmulevich, I., Barnholtz-Sloan, J., Zou, L., Vegesna, R., Shukla, S. A., Ciriello, G., Yung, W. K., Zhang, W., Sougnez, C., Mikkelsen, T., Aldape, K., Bigner, D. D., Van Meir, E. G., Prados, M., Sloan, A., Black, K. L., Eschbacher, J., Finocchiaro, G., Friedman, W., Andrews, D. W., Guha, A., Iacocca, M., O’Neill, B. P., Foltz, G., Myers, J., Weisenberger, D. J., Penny, R., Kucherlapati, R., Perou, C. M., Hayes, D. N., Gibbs, R., Marra, M., Mills, G. B., Lander, E., Spellman, P., Wilson, R., Sander, C., Weinstein, J., Meyerson, M., Gabriel, S., Laird, P. W., Haussler, D., Getz, G., and Chin, L. (2013) The somatic genomic landscape of glioblastoma, Cell, 155, 462–477.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. Villalva, C., Cortes, U., Wager, M., Tourani, J. M., Rivet, P., Marquant, C., Martin, S., Turhan, A. G., and Karayan-Tapon, L. (2012) O6-methylguanine-methyltransferase (MGMT) promoter methylation status in glioma stem-like cells is correlated to temozolomide sensitivity under differentiation-promoting conditions, Int. J. Mol. Sci., 13, 6983–6994.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Karsy, M., Neil, J. A., Guan, J., Mark, M. A., Colman, H., and Jensen, R. L. (2015) A practical review of prognostic correlations of molecular biomarkers in glioblastoma, Neurosurg. Focus, 38, doi: 10.3171/2015.1.FOCUS14755.

    Google Scholar 

  20. Hartmann, C., Hentschel, B., Simon, M., Westphal, M., Schackert, G., Tonn, J. C., Loeffler, M., Reifenberger, G., Pietsch, T., Von Deimling, A., and Weller, M. (2013) Longterm survival in primary glioblastoma with versus without isocitrate dehydrogenase mutation, Clin. Cancer Res., 19, 5146–5157.

    Article  PubMed  CAS  Google Scholar 

  21. Labussiere, M., Boisselier, B., Mokhtari, K., Di Stefano, A. L., Rahimian, A., Rossetto, M., Ciccarino, P., Saulnier, O., Paterra, R., Marie, Y., Finocchiaro, G., and Sanson, M. (2014) Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes, Neurology, 83, 1200–1206.

    PubMed  CAS  Google Scholar 

  22. Eliseeva, I. A., Kim, E. R., Gur’yanov, S. G., Ovchinnikov, L. P., and Lyabin, D. N. (2011) Y-box-binding protein-1 (YB-1) and its functions, Usp. Biol. Khim., 51, 65–132.

    Google Scholar 

  23. Stavrovskaya, A. A., and Gens, G. P. (2014) Some new aspects in studies on multidrug resistance in cancer cells, Usp. Mol. Onkol., 1, 5–11.

    Google Scholar 

  24. Cybulski, M., Jarosz, B., Nowakowski, A., Jeleniewicz, W., Kutarska, E., Bednarek, W., and Stepulak, A. (2015) Cyclin A correlates with YB1, progression and resistance to chemotherapy in human epithelial ovarian cancer, Anticancer Res., 35, 1715–1721.

    PubMed  Google Scholar 

  25. Stavrovskaya, A., Stromskaya, T., Rybalkina, E., Moiseeva, N., Vaiman, A., Guryanov, S., Ovchinnikov, L., and Guens, G. (2012) YB-1 protein and multidrug resistance of tumor cells, Curr. Signal. Transduct. Ther., 7, 237–246.

    Article  CAS  Google Scholar 

  26. Gao, Y., Fotovati, A., Lee, C., Wang, M., Cote, G., Guns, E., Toyota, B., Faury, D., Jabado, N., and Dunn, S. E. (2009) Inhibition of Y-box binding protein-1 slows the growth of glioblastoma multiforme and sensitizes to temozolomide independent O6-methylguanine-DNA methyltransferase, Mol. Cancer Ther., 8, 3276–3284.

    Article  PubMed  CAS  Google Scholar 

  27. Bonnet, D., and Dick, J. E. (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell, Nat. Med., 3, 730–737.

    Article  PubMed  CAS  Google Scholar 

  28. Fotovati, A., Abu-Ali, S., Wang, P. S., Deleyrolle, L. P., Lee, C., Triscott, J., Chen, J. Y., Franciosi, S., Nakamura, Y., Sugita, Y., Uchiumi, T., Kuwano, M., Leavitt, B. R., Singh, S. K., Jury, A., Jones, C., Wakimoto, H., Reynolds, B. A., Pallen, C. J., and Dunn, S. E. (2011) YB-1 bridges neural stem cells and brain tumor-initiating cells via its roles in differentiation and cell growth, Cancer Res., 71, 5569–5578.

    Article  PubMed  CAS  Google Scholar 

  29. Reipas, K. M., Law, J. H., Couto, N., Islam, S., Li, Y., Li, H., Cherkasov, A., Jung, K., Cheema, A. S., Jones, S. J., Hassell, J. A., and Dunn, S. E. (2013) Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y-box binding protein-1 (YB-1), Oncotarget, 4, 329–345.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Triscott, J., Lee, C., Hu, K., Fotovati, A., Berns, R., Pambid, M., Luk, M., Kast, R. E., Kong, E., Toyota, E., Yip, S., Toyota, B., and Dunn, S. E. (2012) Disulfiram, a drug widely used to control alcoholism, suppresses the selfrenewal of glioblastoma and over-rides resistance to temozolomide, Oncotarget, 3, 1112–1123.

    Google Scholar 

  31. Nakano, I., Masterman-Smith, M., Saigusa, K., Paucar, A. A., Horvath, S., Shoemaker, L., Watanabe, M., Negro, A., Bajpai, R., Howes, A., Lelievre, V., Waschek, J. A., Lazareff, J. A., Freije, W. A., Liau, L. M., Gilbertson, R. J., Cloughesy, T. F., Geschwind, D. H., Nelson, S. F., Mischel, P. S., Terskikh, A. V., and Kornblum, H. I. (2008) Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells, J. Neurosci. Res., 86, 48–60.

    PubMed  CAS  Google Scholar 

  32. Joshi, K., Banasavadi-Siddegowda, Y., Mo, X., Kim, S. H., Mao, P., Kig, C., Nardini, D., Sobol, R. W., Chow, L. M., Kornblum, H. I., Waclaw, R., Beullens, M., and Nakano, I. (2013) MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells, Stem Cells, 31, 1051–1963.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Ganguly, R., Hong, C. S., Smith, L. G., Kornblum, H. I., and Nakano, I. (2014) Maternal embryonic leucine zipper kinase: key kinase for stem cell phenotype in glioma and other cancers, Mol. Cancer Ther., 13, 1393–1398.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Liu, G., Yuan, X., Zeng, Z., Tunici, P., Ng, H., Abdulkadir, I. R., Lu, L., Irvin, D., Black, K. L., and Yu, J. S. (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma, Mol. Cancer, 5, 67.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Berger, W., Steiner, E., Grusch, M., Elbling, L., and Micksche, M. (2009) Vaults and the major vault protein: novel roles in signal pathway regulation and immunity, Cell. Mol. Life Sci., 66, 43–61.

    Article  PubMed  CAS  Google Scholar 

  36. Gillet, J. P., and Gottesman, M. M. (2010) Mechanisms of multidrug resistance in cancer, Methods Mol. Biol., 596, 47–76.

    Article  PubMed  CAS  Google Scholar 

  37. Berger, W., Spiegl-Kreinecker, S., Buchroithner, J., Elbling, L., Pirker, C., Fischer, J., and Micksche, M. (2001) Overexpression of the human major vault protein in astrocytic brain tumor cells, Int. J. Cancer., 94, 377–382.

    Article  PubMed  CAS  Google Scholar 

  38. Lotsch, D., Steiner, E., Holzmann, K., Spiegl-Kreinecker, S., Pirker, C., Hlavaty, J., Petznek, H., Hegedus, B., Garay, T., Mohr, T., Sommergruber, W., Grusch, M., and Berger, W. (2013) Major vault protein supports glioblastoma survival and migration by upregulating the EGFR/PI3K signaling axis, Oncotarget, 4, 1904–1918.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Lara, P. C., Pruschy, M., Zimmermann, M., and Henriquez-Hernandez, L. A. (2011) MVP and vaults: a role in the radiation response, Radiat. Oncol., 6, doi: 10.1186/1748-717X-6-148.

    Google Scholar 

  40. Kedracka-Krok, S., Jankowska, U., Elas, M., Sowa, U., Swakon, J., Cierniak, A., Olko, P., Romanowska-Dixon, B., and Urbanska, K. (2014) Proteomic analysis of proton beam irradiated human melanoma cells, PLoS One, 9, doi: 10.1371/journal.pone.0084621.

    Google Scholar 

  41. Stein, U., Bergmann, S., Scheffer, G. L., Scheper, R. J., Royer, H. D., Schlag, P. M., and Walther, W. (2005) YB-1 facilitates basal and 5-fluorouracil-inducible expression of the human major vault protein (MVP) gene, Oncogene, 24, 3606–3618.

    Article  PubMed  CAS  Google Scholar 

  42. Oda, Y., Ohishi, Y., Basaki, Y., Kobayashi, H., Hirakawa, T., Wake, N., Ono, M., Nishio, K., Kuwano, M., and Tsuneyoshi, M. (2007) Prognostic implications of the nuclear localization of Y-box-binding protein-1 and CXCR4 expression in ovarian cancer: their correlation with activated Akt, LRP/MVP and P-glycoprotein expression, Cancer Sci., 98, 1020–1026.

    PubMed  CAS  Google Scholar 

  43. Hyogotani, A., Ito, K., Yoshida, K., Izumi, H., Kohno, K., and Amano, J. (2012) Association of nuclear YB-1 localization with lung resistance-related protein and epidermal growth factor receptor expression in lung cancer, Clin. Lung Cancer, 13, 375–384.

    Article  PubMed  CAS  Google Scholar 

  44. Schaich, M., Kestel, L., Pfirrmann, M., Robel, K., Illmer, T., Kramer, M., Dill, C., Ehninger, G., Schackert, G., and Krex, D. (2009) A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients, Ann. Oncol., 20, 175–181.

    Article  PubMed  CAS  Google Scholar 

  45. Lin, F., De Gooijer, M. C., Roig, E. M., Buil, L. C., Christner, S. M., Beumer, J. H., Wurdinger, T., Beijnen, J. H., and Van Tellingen, O. (2014) ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy, Clin. Cancer Res., 20, 2703–2713.

    PubMed  CAS  Google Scholar 

  46. Martin, V., Sanchez-Sanchez, A. M., Herrera, F., GomezManzano, C., Fueyo, J., Alvarez-Vega, M. A., Antolin, I., and Rodriguez, C. (2013) Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumor stem cells, Br. J. Cancer, 108, 2005–2012.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  47. Bleau, A. M., Hambardzumyan, D., Ozawa, T., Fomchenko, E. I., Huse, J. T., Brennan, C. W., and Holland, E. C. (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells, Cell Stem Cell, 4, 226–235.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  48. Liu, B., Guo, Z., Dong, H., Daofeng, T., Cai, Q., Ji, B., Zhang, S., Wu, L., Wang, J., Wang, L., Zhu, X., Liu, Y., and Chen, Q. (2015) LRIG1, human EGFR inhibitor, reverses multidrug resistance through modulation of ABCB1 and ABCG2, Brain Res., doi:10.1016/j.brainres.2015.03.023.

    Google Scholar 

  49. Oberstadt, M. C., Bien-Moller, S., Weitmann, K., Herzog, S., Hentschel, K., Rimmbach, C., Vogelgesang, S., Balz, E., Fink, M., Michael, H., Zeden, J. P., Bruckmuller, H., Werk, A. N., Cascorbi, I., Hoffmann, W., Rosskopf, D., Schroeder, H. W., and Kroemer, H. K. (2013) Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme, BMC Cancer, 13, 617.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  50. Chen, D. (2015) Tumor formation and drug resistance properties of human glioblastoma side population cells, Mol. Med. Rep., doi: 10.3892/mmr.2015.3279.

    Google Scholar 

  51. Stromskaya, T. P., Rybalkina, E. Yu., Kruglov, S. S., Zabotina, T. N., Mechetner, E. B., Turkina, A. G., and Stavrovskaya, A. A. (2008) Role of P-glycoprotein in evolution of populations of chronic myeloid leukemia cells treated with imatinib, Biochemistry (Moscow), 73, 29–37.

    Article  CAS  Google Scholar 

  52. Riganti, C., Salaroglio, I. C., Caldera, V., Campia, I., Kopecka, J., Mellai, M., Annovazzi, L., Bosia, A., Ghigo, D., and Schiffer, D. (2013) Temozolomide downregulates P-glycoprotein expression in glioblastoma stem cells by interfering with the Wnt3a/glycogen synthase-3 kinase/βcatenin pathway, Neuro Oncol., 11, 1502–1517.

    Article  CAS  Google Scholar 

  53. Verhaak, R. G., Hoadley, K. A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M. D., Miller, C. R., Ding, L., Golub, T., Mesirov, J. P., Alexe, G., Lawrence, M., O’Kelly, M., Tamayo, P., and Weir, B. A. (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1, Cancer Cell, 17, 98–110.

    Article  PubMed  CAS  Google Scholar 

  54. Bastien, J. I., McNeill, K. A., and Fine, H. A. (2015) Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date, Cancer, 121, 502–516.

    PubMed  Google Scholar 

  55. Vousden, K. H., and Prives, C. (2009) Blinded by the light: the growing complexity of p53, Cell, 137, 413–431.

    Article  PubMed  CAS  Google Scholar 

  56. Masui, K., Cloughesy, T. F., and Mischel, P. S. (2012) Review: molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies, Neuropathol. Appl. Neurobiol., 38, 271–291.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  57. Schiebe, M., Ohneseit, P., Hoffmann, W., Meyermann, R., Rodemann, H. P., and Bamberg, M. (2000) Analysis of mdm2 and p53 gene alterations in glioblastomas and its correlation with clinical factors, J. Neurooncol., 49, 197–203.

    Article  PubMed  CAS  Google Scholar 

  58. Birner, P., Piribauer, M., Fischer, I., Gatterbauer, B., Marosi, C., Ungersbock, K., Rossler, K., Budka, H., and Hainfellner, J. A. (2002) Prognostic relevance of p53 protein expression in glioblastoma, Oncol. Rep., 9, 703–707.

    PubMed  CAS  Google Scholar 

  59. Kraus, J. A., Wenghoefer, M., Glesmann, N., Mohr, S., Beck, M., Schmidt, M. C., Schroder, R., Berweiler, U., Roggendorf, W., Diete, S., Dietzmann, K., Heuser, K., Muller, B., Fimmers, R., Von Deimling, A., and Schlegel, U. (2001) TP53 gene mutations, nuclear p53 accumulation, expression of Waf/p21, Bcl-2, and CD95 (APO-1/Fas) proteins are not prognostic factors in de novo glioblastoma multiforme, J. Neurooncol., 52, 263–272.

    CAS  Google Scholar 

  60. Batchelor, T. T., Betensky, R. A., Esposito, J. M., Pham, L. D., Dorfman, M. V., Piscatelli, N., Jhung, S., Rhee, D., and Louis, D. N. (2004) Age-dependent prognostic effects of genetic alterations in glioblastoma, Clin. Cancer Res., 10, 228–233.

    Article  PubMed  CAS  Google Scholar 

  61. Rich, J. N., Hans, C., Jones, B., Iversen, E. S., McLendon, R. E., Rasheed, B. K., Dobra, A., Dressman, H. K., Bigner, D. D., Nevins, J. R., and West, M. (2005) Gene expression profiling and genetic markers in glioblastoma survival, Cancer Res., 65, 4051–4058.

    Article  PubMed  CAS  Google Scholar 

  62. Turner, K. M., Sun, Y., Ji, P., Granberg, K. J., Bernard, B., Hu, L., Cogdell, D. E., Zhou, X., Yli-Harja, O., Nykter, M., Shmulevich, I., Yung, W. K., Fuller, G. N., and Zhang, W. (2015) Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression, Proc. Natl. Acad. Sci. USA, 112, 3421–3426.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  63. Romano, G. (2013) The role of the dysfunctional Aktrelated pathway in cancer: establishment and maintenance of a malignant cell phenotype, resistance to therapy, and future strategies for drug development, Scientifica (Cairo), doi: 10.1155/2013/317186.

    Google Scholar 

  64. Jones, P. A., and Baylin, S. B. (2007) The epigenomics of cancer, Cell, 128, 683–692.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  65. Sana, J., Hajduch, M., Michalek, J., Vyzula, R., and Slaby, O. (2011) MicroRNAs and glioblastoma: roles in core signaling pathways and potential clinical implication, J. Cell. Mol. Med., 15, 1636–1644.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. Brower, J. V., Clark, P. A., Lyon, W., and Kuo, J. S. (2014) MicroRNAs in cancer: glioblastoma and glioblastoma cancer stem cells, Neurochem. Int., 77, 68–77.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Yang, H. W., Xing, H., and Johnson, M. D. (2015) A major role for microRNAs in glioblastoma cancer stem-like cells, Arch. Pharm. Res., 38, 423–434.

    Article  PubMed  CAS  Google Scholar 

  68. Jhanwar-Uniyal, M., Labagnara, M., Friedman, M., Kwasnicki, A., and Murali, R. (2015) Glioblastoma: molecular pathways, stem cells and therapeutic targets, Cancers (Basel), 7, 538–555.

    Article  Google Scholar 

  69. Gabriely, G., Wurdinger, T., Kesari, S., Esau, C. C., Burchard, J., Linsley, P. S., and Krichevsky, A. M. (2008) MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators, Mol. Cell. Biol., 28, 5369–5380.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  70. Zhi, F., Chen, X., Wang, S., Xia, X., Shi, Y., Guan, W., Shao, N., Qu, H., Yang, C., Zhang, Y., Wang, Q., Wang, R., Zen, K., Zhang, C. Y., Zhang, J., and Yang, Y. (2010) The use of hsa-miR-21, hsa-miR-181b and hsa-miR-106a as prognostic indicators of astrocytoma, Eur. J. Cancer, 46, 1640–1649.

    PubMed  CAS  Google Scholar 

  71. Wong, S. T., Zhang, X. Q., Zhuang, J. T., Chan, H. L., Li, C. H., and Leung, G. K. (2012) MicroRNA-21 inhibition enhances in vitro chemosensitivity of temozolomide-resistant glioblastoma cells, Anticancer Res., 32, 2835–2841.

    PubMed  CAS  Google Scholar 

  72. Wang, Q., Li, P., Li, A., Jiang, W., Wang, H., Wang, J., and Xie, K. (2012) Plasma specific miRNAs as predictive biomarkers for diagnosis and prognosis of glioma, J. Exp. Clin. Cancer Res., 31, 97.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  73. Berthois, Y., Delfino, C., Metellus, P., Fina, F., NanniMetellus, I., Al Aswy, H., Pirisi, V., Ouafik, L., and Boudouresque, F. (2014) Differential expression of miR200a-3p and miR21 in grade II-III and grade IV gliomas evidence that miR200a-3p is regulated by O6methylguanine methyltransferase and promotes temozolomide responsiveness, Cancer Biol. Ther., 15, 938–950.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. Ujifuku, K., Mitsutake, N., Takakura, S., Matsuse, M., Saenko, V., Suzuki, K., Hayashi, K., Matsuo, T., Kamada, K., Nagata, I., and Yamashita, S. (2012) miR-195, miR-455-3p and miR-10a are implicated in acquired temozolomide resistance in glioblastoma multiforme cells, Cancer Lett., 296, 241–248.

    Article  CAS  Google Scholar 

  75. Shi, L., Zhang, S., Feng, K., Wu, F., Wan, Y., Wang, Z., Zhang, J., Wang, Y., Yan, W., Fu, Z., and You, Y. (2012) MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis, Int. J. Oncol., 40, 119–129.

    PubMed  Google Scholar 

  76. Zhang, W., Zhang, J., Hoadley, K., Kushwaha, D., Ramakrishnan, V., Li, S., Kang, C., You, Y., Jiang, C., Song, S. W., Jiang, T., and Chen, C. C. (2012) miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression, Neuro Oncol., 14, 712–719.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  77. Asuthkar, S., Velpula, K. K., Chetty, C., Gorantla, B., and Rao, J. S. (2012) Epigenetic regulation of miRNA-211 by MMP-9 governs glioma cell apoptosis, chemosensitivity and radiosensitivity, Oncotarget, 3, 1439–1454.

    Article  PubMed  Google Scholar 

  78. Chen, H., Li, X., Li, W, and Zheng, H. (2015) miR-130a can predict response to temozolomide in patients with glioblastoma multiforme, independently of O6-methylguanine-DNA methyltransferase, J. Transl. Med., 13, 435.

    Google Scholar 

  79. Sana, J., Hajduch, M., Michalek, J., Vyzula, R., and Slaby, O. (2011) MicroRNAs and glioblastoma: roles in core signaling pathways and potential clinical implications, J. Cell. Mol. Med., 15, 1636–1644.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  80. Yan, W., Li, R., Liu, Y., Yang, P., Wang, Z., Zhang, C., Bao, Z., Zhang, W., You, Y., and Jiang, T. (2014) MicroRNA expression patterns in the malignant progression of gliomas and a 5-microRNA signature for prognosis, Oncotarget, 5, 12908–12915.

    Article  PubMed Central  PubMed  Google Scholar 

  81. Xiong, J., Bing, Z., Su, Y., Deng, D., and Peng, X. (2014) An integrated mRNA and microRNA expression signature for glioblastoma multiforme prognosis, PLoS One, 9, doi: 10.1371/journal.pone.0098419.

    Google Scholar 

  82. Yamaguchi, H., and Hung, M. C. (2014) Regulation and role of EZH2 in cancer, Cancer Res. Treat., 46, 209–222.

    Article  PubMed Central  PubMed  Google Scholar 

  83. Zhang, J., Chen, L., Han, L., Shi, Z., Zhang, J., Pu, P., and Kang, C. (2015) EZH2 is a negative prognostic factor and exhibits pro-oncogenic activity in glioblastoma, Cancer Lett., 356, 929–936.

    Article  PubMed  CAS  Google Scholar 

  84. De Vries, N. A., Hulsman, D., Akhtar, W., De Jong, J., Miles, D. C., and Blom, M. (2015) Prolonged Ezh2 depletion in glioblastoma causes a robust switch in cell fate resulting in tumor progression, Cell Rep., doi: 10.1016/j.celrep.2014.12.028.

    Google Scholar 

  85. Cho, H. Y., Wang, W., Jhaveri, N., Lee, D. J., Sharma, N., Dubeau, L., Schonthal, A. H., Hofman, F. M., and Chen, T. C. (2014) NEO212, temozolomide conjugated to perillyl alcohol, is a novel drug for effective treatment of a broad range of temozolomide-resistant gliomas, Mol. Cancer Ther., 13, 2004–2017.

    Article  PubMed  CAS  Google Scholar 

  86. Rybalkina, E. Yu., Pavlova, G. V., and Stavrovskaya, A. A. (2014) News in investigating glioblastomas, Biol. Membr. (Moscow), 31, 379–391.

    CAS  Google Scholar 

  87. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature, 455, 1061–1068.

    Article  CAS  Google Scholar 

  88. Verhaak, R. G., Hoadley, K. A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M. D., Miller, C. R., Ding, L., Golub, T., Mesirov, J. P., Alexe, G., Lawrence, M., O’Kelly, M., Tamayo, P., Weir, B. A., Gabriel, S., Winckler, W., Gupta, S., Jakkula, L., Feiler, H. S., Hodgson, J. G., James, C. D., Sarkaria, J. N., Brennan, C., Kahn, A., Spellman, P. T., Wilson, R. K., Speed, T. P., Gray, J. W., Meyerson, M., Getz, G., Perou, C. M., and Hayes, D. N. (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1, Cancer Cell, 17, 98–110.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to E. Yu. Rybalkina.

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Original Russian Text © A. A. Stavrovskaya, S. S. Shushanov, E. Yu. Rybalkina, 2016, published in Biokhimiya, 2016, Vol. 81, No. 2, pp. 179–190.

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Stavrovskaya, A.A., Shushanov, S.S. & Rybalkina, E.Y. Problems of glioblastoma multiforme drug resistance. Biochemistry Moscow 81, 91–100 (2016). https://doi.org/10.1134/S0006297916020036

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  • DOI: https://doi.org/10.1134/S0006297916020036

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