The histone deacetylase inhibitor OBP‐801 has in vitro/in vivo anti‐neuroblastoma activity

Abstract

Background Patients with high‐risk neuroblastoma have a poor prognosis; new therapeutic agents are therefore required. We investigated the antitumor effects of OBP‐801, a novel histone deacetylase inhibitor, its underlying mechanism, and its potential as a therapeutic agent for patients with neuroblastoma. Methods The study included five human neuroblastoma cell lines: IMR32, GOTO, KP‐N‐RTBM, SK‐N‐AS, and SH‐SY5Y. We investigated cell proliferation, cell cycle status, protein expression patterns, and apoptosis in neuroblastoma cells after OBP‐801 treatment in vitro. Cell survival rate and cell cycle were analyzed using the WST‐8 assay and flow cytometry, respectively. Apoptosis was detected using annexin V staining, and the expression of apoptosis‐related proteins was investigated by western blotting. The antitumor activity of OBP‐801 was examined in an in vivo xenograft mouse model. Results Dose–effect curve analysis showed that the mean half‐maximal inhibitory concentration value was 5.5 ± 5.9 nM for the MYCN‐amplified cell lines (IMR32, GOTO, and KP‐N‐RTBM) and 3.1 ± 0.7 nM for the MYCN‐nonamplified cell lines (SK‐N‐AS and SH‐SY5Y). OBP‐801 inhibited cell proliferation and growth in all the cell lines. It induced G2/M phase arrest through the p21 (CDKN1A) pathway, increasing histone H3 levels and, subsequently, apoptosis in human neuroblastoma cells. OBP‐801 suppressed the growth of neuroblastoma cells in the mouse xenograft model. Conclusions Overall, OBP‐801 induces M‐phase arrest and apoptosis in neuroblastoma cells via mitotic catastrophe. Our results indicate that OBP‐801 is a promising therapeutic agent with fewer adverse effects for patients with neuroblastoma.