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Selective HDAC1/HDAC2 inhibitors induce neuroblastoma differentiation
Stacey M Frumm1, Zi Peng Fan, Kenneth N Ross
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Chemistry & Biology
|May 28, 2013
Summary
Researchers identified a new strategy to treat high-risk neuroblastoma by promoting tumor cell differentiation. Selective inhibition of histone deacetylase 1 and 2 (HDAC1/HDAC2) with compound BRD8430 induced neuroblastoma cell differentiation and reduced viability.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cytotoxic chemotherapy is standard for cancer but often insufficient for high-risk neuroblastoma.
- Tumor differentiation is a promising alternative therapeutic strategy.
Purpose of the Study:
- To identify small molecules that induce neuroblastoma differentiation.
- To investigate selective histone deacetylase (HDAC) inhibition as a therapeutic strategy for neuroblastoma.
Main Methods:
- Developed a gene expression signature for neuroblast maturation.
- Screened a small-molecule library using a high-throughput platform.
- Identified and characterized BRD8430 as a selective class I HDAC inhibitor (HDAC1 > 2 > 3).
Main Results:
- Selective HDAC1/HDAC2 inhibition, via compounds or RNA interference, induced differentiation and decreased viability in neuroblastoma cell lines.
- BRD8430 was identified as a selective HDAC1/HDAC2 inhibitor.
- Combination treatment with 13-cis retinoic acid enhanced differentiation and retinoic acid signaling.
Conclusions:
- Selective HDAC1/HDAC2 inhibition is a viable strategy for inducing neuroblastoma differentiation.
- Chemical genomic screening is effective for identifying novel cancer therapeutics.
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