Pro-differentiating and radiosensitizing effects of inhibiting HDACs by PXD-101 (Belinostat) in in vitro and in vivo models of human rhabdomyosarcoma cell lines

Bianca Maria Scicchitano, Francesco Marampon, Valentina Di Nisio, Ilaria Pietrantoni, Francesco Petragnano, Irene Fasciani, Carmela Ciccarelli, Giovanni Luca Gravina, Claudio Festuccia, Andrea Del Fattore, Mario Tombolini, Francesca De Felice, Daniela Musio, Sandra Cecconi, Paolo Tini, Marta Maddalo, Silvia Codenotti, Alessandro Fanzani, Antonella Polimeni, Roberto MaggioVincenzo Tombolini

Risultato della ricerca: Contributo in rivistaArticolo in rivista

1 Citazioni (Scopus)

Abstract

This study describes the in vitro and in vivo activity of PXD-101 (Belinostat), a novel hydroxamic acid-type pan-HDACs inhibitor characterized by a larger safety and efficacy, on myogenic-derived PAX3/FOXO1 fusion protein positive (RH30) or negative (RD) expressing rhabdomyosarcoma (RMS) cell lines. PXD-101 at low doses efficiently inhibited HDACs activity and counteracted the transformed phenotype of RMS by inducing growth arrest and apoptosis, affecting cancer stem cells population and inducing differentiation in RD. Notably, PXD-101 induced oxidative stress promoting DNA damages and affected the ability of RMS to assemble mitotic spindle. PXD-101 radiosensitized by inducing G2 cell cycle growth arrest, enhancing the radiation's ability to induce ROS accumulation and compromising both the ability of RMS to detoxify from ROS and to repair DNA damage. PXD-101 transcriptionally and post-transcriptionally affected c-Myc expression, key master regulator of rhabdomyosarcomagenesis and RMS radioresistance. All in vitro data were corroborated by in vivo experiments showing the cytostatic effects of PXD-101 when used alone and at low dose and its ability to promote the RT-induced killing of RMS. Taken together, our data confirm that altered HDACs activity plays a key role in RMS genesis and suggest PXD-101 as a valid therapeutic strategy particularly in combination with RT.
Lingua originaleEnglish
pagine (da-a)90-101
Numero di pagine12
RivistaCancer Letters
Volume461
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • Belinostat
  • Differentiation therapy
  • PXD-101
  • Radioresistance
  • Rhabdomyosarcoma

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