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Journal of Cancer Research and Clinical Oncology

, Volume 145, Issue 2, pp 393–409 | Cite as

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 FestucciaEmail author
Original Article – Cancer Research

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

Glioblastoma Cancer stem cells HDACs HDACs’ inhibitor Givinostat ITF2357 

Notes

Acknowledgements

We are grateful to the Umberto Veronesi Foundation for awarding a post-doctoral fellowship to Francesco Marampon for the year 2018 and “FIVA Confcommercio” for supporting part of our work. ITF2357 was provided by Italfarmaco SpA.

Author contributions

FMa and FL planned experiments; AM, IP, SDM, SC, FMe GP, EG, and PP performed experiments; AB, PM, RM, and VT analyze data; GLG and CF wrote the paper.

Compliance with ethical standards

Conflict of interest

Giuliana Porro, Elisabetta Galbiati, Pietro Pozzi, and Paolo Mascagni are employers of ItalfarmacoSpA. The other authors declare that they have no competing interests.

Ethical approval

Studies on animal models were performed according to the guidelines established by the University of L’Aquila, Medical School and Science and Technology School Board Regulations, in compliance with the Italian government regulation no. 116 January 27, 1992 and national/international guidelines for the care and use of animals. The present study was approved by the Ethical Committee of the Medical School of the University of L’Aquila, (555/2017-PR). This article does not contain any studies with human participants performed by any of the authors.

Informed consent

This article does not contain any studies with human participants performed by any of the authors.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Francesco Marampon
    • 1
  • Flavio Leoni
    • 2
  • Andrea Mancini
    • 3
  • Ilaria Pietrantoni
    • 4
  • Silvia Codenotti
    • 5
  • Ferella Letizia
    • 3
    • 6
  • Francesca Megiorni
    • 7
  • Giuliana Porro
    • 2
  • Elisabetta Galbiati
    • 2
  • Pietro Pozzi
    • 2
  • Paolo Mascagni
    • 2
  • Alfredo Budillon
    • 8
  • Roberto Maggio
    • 4
  • Vincenzo Tombolini
    • 1
  • Alessandro Fanzani
    • 5
  • Giovanni Luca Gravina
    • 3
    • 6
  • Claudio Festuccia
    • 3
    Email author
  1. 1.Department of RadiotherapyPoliclinico Umberto I, “Sapienza” University of RomeRomeItaly
  2. 2.Research CenterItalfarmaco SpAMilanItaly
  3. 3.Radiobiology Laboratory, Department of Biotechnological and Applied Clinical SciencesUniversity of L’AquilaL’aquilaItaly
  4. 4.Laboratory of Pharmacology, Department of Biotechnological and Applied Clinical SciencesUniversity of L’AquilaL’aquilaItaly
  5. 5.Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  6. 6.Division of Radiation Oncology, Department of Biotechnological and Applied Clinical SciencesUniversity of L’AquilaL’aquilaItaly
  7. 7.Department of Experimental Medicine“Sapienza” University of RomeRomeItaly
  8. 8.Experimental Pharmacology UnitIstituto Nazionale Tumori-IRCCS-Fondazione G. PascaleNaplesItaly

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