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Targeting neuroblastoma with hydroxamic acid based HDAC1 and HDAC2 inhibitors: Insights from in vitro and in vivo
Padmini Pai1, Yashaswini Reddy1, Ipshita Das1
1Department of Biophysics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
Abstract:
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.
Insights
Newly developed hydroxamic acid derivatives, 3A and 3B, show potent anticancer effects against neuroblastoma. Compound 3B selectively inhibits HDAC1 and HDAC2, reducing tumor growth in vivo and offering a promising new therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Histone deacetylases (HDACs) regulate gene expression and are implicated in diseases like cancer.
- HDAC1 and HDAC2 are crucial in neural progenitors and often overexpressed in neural cancers.
- Existing HDAC inhibitors lack selectivity, leading to side effects and necessitating isoform-specific agents.
Purpose of the Study:
- To investigate the anticancer properties of novel hydroxamic acid derivatives.
- To evaluate the isoform-selective inhibition of HDAC1 and HDAC2 by these compounds.
- To assess their efficacy in neuroblastoma models.
Main Methods:
- Synthesis of novel hydroxamic acid analogues (3A and 3B).
- In vitro assays to determine IC50 values for cell proliferation inhibition and HDAC enzyme activity.
- Cell cycle analysis, colony formation assays, and in vivo xenograft studies.
Main Results:
- Compounds 3A and 3B inhibited neuroblastoma cell proliferation with IC50 values comparable to SAHA.
- Compound 3A selectively inhibited HDAC2, while compound 3B potently inhibited both HDAC1 and HDAC2.
- Compound 3B induced G2/M cell cycle arrest, reduced colony formation, and significantly decreased tumor growth and weight in vivo.
Conclusions:
- Novel hydroxamic acid derivatives, particularly compound 3B, demonstrate significant anticancer potential against neuroblastoma.
- Compound 3B's dual HDAC1/HDAC2 inhibition and demonstrated in vivo efficacy suggest its promise as a targeted therapeutic agent.
- These findings support the development of isoform-selective HDAC inhibitors for improved neuroblastoma treatment with reduced side effects.
