Targeting neuroblastoma with hydroxamic acid based HDAC1 and HDAC2 inhibitors: Insights from in vitro and in vivo studies.

Histone deacetylases (HDACs) serve a crucial function in transcription regulation, and their dysregulation is linked to numerous diseases, including cancer. Among them, HDAC1 and HDAC2 are particularly significant in neural progenitors and are frequently overexpressed in neural-derived cancers. HDAC inhibitors (HDACis) have shown promise in overcoming chemoresistance by restoring tumor suppressor function in neuroblastoma cells. However, the lack of selectivity in existing HDACis presents challenges, highlighting the need for isoform-selective inhibitors to reduce side effects. This research investigated the anticancer properties of a newly synthesized hydroxamic acid derivative, emphasizing its selective HDAC1 and HDAC2 inhibition and strong antitumor activity. Our findings demonstrated that the newly developed hydroxamic acid analogues, 3A and 3B, effectively inhibited neuroblastoma cells (SH-SY5Y) proliferation, with IC₅₀ values of 8.49 µM and 4.44 µM, respectively, comparable to suberoylanilide hydroxamic acid (SAHA) with IC₅₀ of 0.91 µM. Additionally, compounds 3A and 3B exhibited potent HDAC inhibition. Compound 3A selectively inhibited HDAC2 with an IC₅₀ value of 0.89 μM, while compound 3B showed dual inhibition of HDAC1 and HDAC2, with IC₅₀ values of 0.44 μM and 1.94 μM, respectively. Compound 3B triggered cell cycle arrest in the G2/M phase, reduced colony formation efficiency, and altered cellular architecture upon treatment, further highlighting its anticancer potential. In an in vivo xenograft model, compound 3B significantly decreased tumor growth and tumor weight, highlighting its potential as an effective anticancer agent for neuroblastoma, offering both isoform-selective HDAC inhibition and potent anticancer effects.