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

J Cancer Res Clin Oncol. 2019 Feb;145(2):393-409. doi: 10.1007/s00432-018-2800-8. Epub 2018 Nov 24.


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.

Keywords: Cancer stem cells; Givinostat; Glioblastoma; HDACs; HDACs’ inhibitor; ITF2357.

MeSH terms

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


  • Carbamates
  • givinostat
  • Histone Deacetylases