OBP-801, a novel histone deacetylase inhibitor, induces M-phase arrest and apoptosis in rhabdomyosarcoma cells

Abstract

Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer of musculoskeletal origin. Despite multidisciplinary approaches, such as surgical resection, irradiation, and intensive chemotherapy, adopted for its treatment, the prognosis of patients with high-risk RMS remains poor. Thus, molecularly targeted therapies are required to improve patient survival and minimize side effects. Histone deacetylases (HDACs) modify transcription by deacetylation of the lysine residues in chromatin histone tails and several non-histone proteins. HDAC inhibitors, classes of compounds targeted to various HDAC proteins, are being studied for their roles in several types of cancers in a rigorous manner. This study aimed to investigate the potential of a novel HDAC inhibitor, OBP-801, as a therapeutic agent for the treatment of RMS. We used 8 RMS cell lines in this study. Protein expression patterns, cell proliferation, cell cycle status, and apoptosis in RMS cells after OBP-801 treatment in vitro were investigated. We also studied the antitumor activity of OBP-801 in an in vivo xenograft mouse model. We observed cell cycle arrest at the M-phase and apoptosis in all RMS cell lines after exposure to pharmacological levels of OBP-801 for 24 h. Immunofluorescence staining revealed that OBP-801 may induce mitotic catastrophe via chromosome misalignment and reduced survivin expression, ultimately leading to apoptosis. Our results demonstrated that the novel HDAC inhibitor OBP-801 was an effective inhibitor of RMS cell line proliferation and may be a potent therapeutic option for RMS.