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.
- Cell Movement
- Cell Proliferation
- Cell Transformation, Neoplastic/drug effects
- Glioblastoma/drug therapy
- Histone Deacetylases/chemistry
- In Vitro Techniques
- Mice, Nude
- Neoplastic Stem Cells/drug effects
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays