Histone deacetylase inhibitor ITF2357 (givinostat) reverts transformed phenotype and counteracts stemness in in vitro and in vivo models of human glioblastoma

Francesco Marampon, Flavio Leoni, Andrea Mancini, Ilaria Pietrantoni, Silvia Codenotti, Ferella Letizia, Francesca Megiorni, Giuliana Porro, Elisabetta Galbiati, Pietro Pozzi, Paolo Mascagni, Alfredo Budillon, Roberto Maggio, Vincenzo Tombolini, Alessandro Fanzani, Giovanni Luca Gravina, Claudio Festuccia

Research output: Contribution to journalArticle

Abstract

PURPOSE: Aberrant expression and activity of histone deacetylases (HDACs) sustain glioblastoma (GBM) onset and progression, and, therefore, HDAC inhibitors (HDACi) represent a promising class of anti-tumor agents. Here, we analyzed the effects of ITF2357 (givinostat), a pan-HDACi, in GBM models for its anti-neoplastic potential.

METHODS: A set of GBM- and patient-derived GBM stem-cell lines was used and the ITF2357 effects on GBM oncophenotype were investigated in in vitro and in vivo xenograft models.

RESULTS: ITF2357 inhibited HDAC activity and affected GBM cellular fate in a dose-dependent manner by inducing G1/S growth arrest (1-2.5 µM) or caspase-mediated cell death (≥ 2.5 µM). Chronic treatment with low doses (≤ 1 µM) induced autophagy-mediated cell death, neuronal-like phenotype, and the expression of differentiation markers, such as glial fibrillar actin protein (GFAP) and neuron-specific class III beta-tubulin (Tuj-1); this reduces neurosphere formation from patient-derived GBM stem cells. Autophagy inhibition counteracted the ITF2357-induced expression of differentiation markers in p53-expressing GBM cells. Finally, in in vivo experiments, ITF2357 efficiently passed the blood-brain barrier, so rapidly reaching high concentration in the brain tissues, and significantly affected U87MG and U251MG growth in orthotopic xenotransplanted mice.

CONCLUSIONS: The present findings provide evidence of the key role played by HDACs in sustaining transformed and stem phenotype of GBM and strongly suggest that ITF2357 may have a clinical potential for the HDACi-based therapeutic strategies against GBM.

Original languageEnglish
Pages (from-to)393-409
Number of pages17
JournalJournal of Cancer Research and Clinical Oncology
Volume145
Issue number2
DOIs
Publication statusPublished - Feb 2019

Keywords

  • Animals
  • Apoptosis
  • Carbamates/pharmacology
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic/drug effects
  • Glioblastoma/drug therapy
  • Histone Deacetylases/chemistry
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells/drug effects
  • Phenotype
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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  • Cite this

    Marampon, F., Leoni, F., Mancini, A., Pietrantoni, I., Codenotti, S., Letizia, F., Megiorni, F., Porro, G., Galbiati, E., Pozzi, P., Mascagni, P., Budillon, A., Maggio, R., Tombolini, V., Fanzani, A., Gravina, G. L., & Festuccia, C. (2019). Histone deacetylase inhibitor ITF2357 (givinostat) reverts transformed phenotype and counteracts stemness in in vitro and in vivo models of human glioblastoma. Journal of Cancer Research and Clinical Oncology, 145(2), 393-409. https://doi.org/10.1007/s00432-018-2800-8