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

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.