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

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

Author information

1
Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy.
2
Research Center, Italfarmaco SpA, Cinisello Balsamo, Milan, Italy.
3
Radiobiology Laboratory, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via vetoiossnc, Coppito II, L'aquila, Italy.
4
Laboratory of Pharmacology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'aquila, Italy.
5
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
6
Division of Radiation Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'aquila, Italy.
7
Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
8
Experimental Pharmacology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.
9
Radiobiology Laboratory, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via vetoiossnc, Coppito II, L'aquila, Italy. claudio.festuccia@univaq.it.

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.

KEYWORDS:

Cancer stem cells; Givinostat; Glioblastoma; HDACs; HDACs’ inhibitor; ITF2357

PMID:
30474756
DOI:
10.1007/s00432-018-2800-8
[Indexed for MEDLINE]

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