M344 Suppresses Histone Deacetylase-Associated Phenotypes and Tumor Growth in Neuroblastoma.
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Neuroblastoma (NB) is an aggressive pediatric cancer, with high-risk patients facing a five-year survival rate of ~50%. Standard therapies, including surgery, chemotherapy, radiation, and immunotherapy, are associated with significant long-term toxicities and frequent relapse. Histone deacetylase (HDAC) inhibitors have emerged as promising agents for cancer therapy, given their role in modulating gene expression and tumor phenotypes. This study evaluated M344 [4-(dimethylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide], an HDAC inhibitor, for its efficacy and mechanisms of action against NB. Analysis of clinical NB Gene Expression Omnibus data revealed advanced-stage tumors exhibit higher HDAC expression relative to early-stage samples. M344 treatment effectively increased histone acetylation, induced G0/G1 cell cycle arrest, and activated caspase-mediated cell death. Relative to vorinostat, an HDAC inhibitor in clinical use for lymphoma and clinical trials for NB, M344 displayed superior cytostatic, cytotoxic, and migration-inhibitory effects. In vivo, metronomic M344 dosing suppressed tumor growth and extended survival. Combination therapy with M344 and topotecan improved topotecan tolerability, while M344 co-administration with cyclophosphamide reduced tumor rebound post-therapy. In total, M344 demonstrated strong therapeutic potential for NB, offering improved tumor suppression, reduced off-target toxicities, and enhanced control of tumor growth post-therapy. These findings support further investigation of HDAC inhibitors, such as M344, for clinical application in NB treatment.