期刊
PEDIATRICS INTERNATIONAL
卷 64, 期 1, 页码 -出版社
WILEY
DOI: 10.1111/ped.15159
关键词
histone deacetylase inhibitors; neuroblastoma; OBP-801
类别
资金
- Japan Society for the Promotion of Science (JSPS) KAKENHI [JP17K10122, JP25253095]
- Health and Labor Sciences Research Grant [17ck0106333h]
OBP-801 induces M-phase arrest and apoptosis in neuroblastoma cells via mitotic catastrophe, making it a promising therapeutic agent with fewer adverse effects for patients with neuroblastoma.
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.
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