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

Francesco Marampon, Valentina Di Nisio, Ilaria Pietrantoni, Francesco Petragnano, Irene Fasciani, Bianca Maria Scicchitano, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)90-101
Number of pages12
JournalCancer Letters
Volume461
DOIs
Publication statusPublished - Oct 1 2019

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Radiation-Sensitizing Agents
Rhabdomyosarcoma
Cell Line
DNA Damage
G2 Phase Cell Cycle Checkpoints
Hydroxamic Acids
Spindle Apparatus
Histone Deacetylase Inhibitors
Neoplastic Stem Cells
Cytostatic Agents
Growth
In Vitro Techniques
belinostat
Oxidative Stress
Radiation
Apoptosis
Phenotype
Safety

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Pro-differentiating and radiosensitizing effects of inhibiting HDACs by PXD-101 (Belinostat) in in vitro and in vivo models of human rhabdomyosarcoma cell lines. / Marampon, Francesco; Di Nisio, Valentina; Pietrantoni, Ilaria; Petragnano, Francesco; Fasciani, Irene; Scicchitano, Bianca Maria; Ciccarelli, Carmela; Gravina, Giovanni Luca; Festuccia, Claudio; Del Fattore, Andrea; Tombolini, Mario; De Felice, Francesca; Musio, Daniela; Cecconi, Sandra; Tini, Paolo; Maddalo, Marta; Codenotti, Silvia; Fanzani, Alessandro; Polimeni, Antonella; Maggio, Roberto; Tombolini, Vincenzo.

In: Cancer Letters, Vol. 461, 01.10.2019, p. 90-101.

Research output: Contribution to journalArticle

Marampon, F, Di Nisio, V, Pietrantoni, I, Petragnano, F, Fasciani, I, Scicchitano, BM, Ciccarelli, C, Gravina, GL, Festuccia, C, Del Fattore, A, Tombolini, M, De Felice, F, Musio, D, Cecconi, S, Tini, P, Maddalo, M, Codenotti, S, Fanzani, A, Polimeni, A, Maggio, R & Tombolini, V 2019, 'Pro-differentiating and radiosensitizing effects of inhibiting HDACs by PXD-101 (Belinostat) in in vitro and in vivo models of human rhabdomyosarcoma cell lines', Cancer Letters, vol. 461, pp. 90-101. https://doi.org/10.1016/j.canlet.2019.07.009
Marampon, Francesco ; Di Nisio, Valentina ; Pietrantoni, Ilaria ; Petragnano, Francesco ; Fasciani, Irene ; Scicchitano, Bianca Maria ; Ciccarelli, Carmela ; Gravina, Giovanni Luca ; Festuccia, Claudio ; Del Fattore, Andrea ; Tombolini, Mario ; De Felice, Francesca ; Musio, Daniela ; Cecconi, Sandra ; Tini, Paolo ; Maddalo, Marta ; Codenotti, Silvia ; Fanzani, Alessandro ; Polimeni, Antonella ; Maggio, Roberto ; Tombolini, Vincenzo. / Pro-differentiating and radiosensitizing effects of inhibiting HDACs by PXD-101 (Belinostat) in in vitro and in vivo models of human rhabdomyosarcoma cell lines. In: Cancer Letters. 2019 ; Vol. 461. pp. 90-101.
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AU - Marampon, Francesco

AU - Di Nisio, Valentina

AU - Pietrantoni, Ilaria

AU - Petragnano, Francesco

AU - Fasciani, Irene

AU - Scicchitano, Bianca Maria

AU - Ciccarelli, Carmela

AU - Gravina, Giovanni Luca

AU - Festuccia, Claudio

AU - Del Fattore, Andrea

AU - Tombolini, Mario

AU - De Felice, Francesca

AU - Musio, Daniela

AU - Cecconi, Sandra

AU - Tini, Paolo

AU - Maddalo, Marta

AU - Codenotti, Silvia

AU - Fanzani, Alessandro

AU - Polimeni, Antonella

AU - Maggio, Roberto

AU - Tombolini, Vincenzo

N1 - Copyright © 2019 Elsevier B.V. All rights reserved.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

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DO - 10.1016/j.canlet.2019.07.009

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VL - 461

SP - 90

EP - 101

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -