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Chem Biol DOI:10.1016/j.chembiol.2013.03.020

Selective HDAC1/HDAC2 inhibitors induce neuroblastoma differentiation.

Publication TypeJournal Article
Year of Publication2013
AuthorsFrumm, SM, Fan, ZPeng, Ross, KN, Duvall, JR, Gupta, S, VerPlank, L, Suh, B-C, Holson, E, Wagner, FF, Smith, WB, Paranal, RM, Bassil, CF, Qi, J, Roti, G, Kung, AL, Bradner, JE, Tolliday, N, Stegmaier, K
JournalChem Biol
Volume20
Issue5
Pages713-25
Date Published2013 May 23
ISSN1879-1301
KeywordsCell Differentiation, Cell Line, Tumor, Cell Survival, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylase Inhibitors, Humans, Lactams, Neuroblastoma, Tretinoin
Abstract

While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1074-5521(13)00128-2
DOI10.1016/j.chembiol.2013.03.020
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23706636?dopt=Abstract

Alternate JournalChem. Biol.
PubMed ID23706636
PubMed Central IDPMC3919449
Grant ListU54 RL1CA133834 / CA / NCI NIH HHS / United States
UL1DE019585 / DE / NIDCR NIH HHS / United States
RL1HG004671 / HG / NHGRI NIH HHS / United States
UL1 DE019585 / DE / NIDCR NIH HHS / United States
RL1GM084437 / GM / NIGMS NIH HHS / United States
P50 GM069721 / GM / NIGMS NIH HHS / United States
RL1 GM084437 / GM / NIGMS NIH HHS / United States
N01 CO012400 / CO / NCI NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
RL1 CA133834 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States