Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction

Roberto Pallini, Luigi Maria Larocca, Ruggero De Maria Marchiano, Giovanni Sette, Adriana Eramo, Fiorenza Lotti, Mariella Patti, Monica Bartucci, Lucia Ricci-Vitiani, Michele Signore, Giorgio Stassi, Lucio Crinò, Cesare Peschle

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Life expectancy of patients affected by glioblastoma multiforme is extremely low. The therapeutic use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed to treat this disease based on its ability to kill glioma cell lines in vitro and in vivo. Here, we show that, differently from glioma cell lines, glioblastoma multiforme tumors were resistant to TRAIL stimulation because they expressed low levels of caspase-8 and high levels of the death receptor inhibitor PED/PEA-15. Inhibition of methyltransferases by decitabine resulted in considerable up-regulation of TRAIL receptor-1 and caspase-8, down-regulation of PED/PEA-15, inhibition of cell growth, and sensitization of primary glioblastoma cells to TRAIL-induced apoptosis. Exogenous caspase-8 expression was the main event able to restore TRAIL sensitivity in primary glioblastoma cells. The antitumor activity of decitabine and TRAIL was confirmed in vivo in a mouse model of glioblastoma multiforme. Evaluation of tumor size, apoptosis, and caspase activation in nude mouse glioblastoma multiforme xenografts showed dramatic synergy of decitabine and TRAIL in the treatment of glioblastoma, whereas the single agents were scarcely effective in terms of reduction of tumor mass, apoptosis induction, and caspase activation. Thus, the combination of TRAIL and demethylating agents may provide a key tool to overcome glioblastoma resistance to therapeutic treatments. ©2005 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)11469-11477
Number of pages9
JournalCancer Research
Publication statusPublished - 2005


  • Adult
  • Aged
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Azacitidine
  • Cancer Research
  • Caspase 8
  • Caspases
  • DNA Methylation
  • DNA Modification Methylases
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma
  • Histocompatibility Antigens Class I
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mice, Nude
  • Middle Aged
  • Oncology
  • Phosphoproteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha

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