Unknown

Dataset Information

0

Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for neuroblastoma differentiation.


ABSTRACT: The discovery of new small molecules and their testing in rational combination poses an ongoing problem for rare diseases, in particular, for pediatric cancers such as neuroblastoma. Despite maximal cytotoxic therapy with double autologous stem cell transplantation, outcome remains poor for children with high-stage disease. Because differentiation is aberrant in this malignancy, compounds that modulate transcription, such as histone deacetylase (HDAC) inhibitors, are of particular interest. However, as single agents, HDAC inhibitors have had limited efficacy. In the present study, we use an HDAC inhibitor as an enhancer to screen a small-molecule library for compounds inducing neuroblastoma maturation. To quantify differentiation, we use an enabling gene expression-based screening strategy. The top hit identified in the screen was all-trans-retinoic acid. Secondary assays confirmed greater neuroblastoma differentiation with the combination of an HDAC inhibitor and a retinoid versus either alone. Furthermore, effects of combination therapy were synergistic with respect to inhibition of cellular viability and induction of apoptosis. In a xenograft model of neuroblastoma, animals treated with combination therapy had the longest survival. This work suggests that testing of an HDAC inhibitor and retinoid in combination is warranted for children with neuroblastoma and demonstrates the success of a signature-based screening approach to prioritize compound combinations for testing in rare diseases.

SUBMITTER: Hahn CK 

PROVIDER: S-EPMC2474517 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications

Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for neuroblastoma differentiation.

Hahn Cynthia K CK   Ross Kenneth N KN   Warrington Ian M IM   Mazitschek Ralph R   Kanegai Cindy M CM   Wright Renee D RD   Kung Andrew L AL   Golub Todd R TR   Stegmaier Kimberly K  

Proceedings of the National Academy of Sciences of the United States of America 20080707 28


The discovery of new small molecules and their testing in rational combination poses an ongoing problem for rare diseases, in particular, for pediatric cancers such as neuroblastoma. Despite maximal cytotoxic therapy with double autologous stem cell transplantation, outcome remains poor for children with high-stage disease. Because differentiation is aberrant in this malignancy, compounds that modulate transcription, such as histone deacetylase (HDAC) inhibitors, are of particular interest. Howe  ...[more]

Similar Datasets

| S-EPMC4089024 | biostudies-literature
| S-EPMC6858705 | biostudies-literature
| S-EPMC555706 | biostudies-literature
| S-EPMC3328162 | biostudies-other
| S-EPMC2259214 | biostudies-other
| S-EPMC3542186 | biostudies-literature
| S-EPMC4955146 | biostudies-literature
| S-EPMC3546543 | biostudies-literature
| S-EPMC3595482 | biostudies-literature
| S-EPMC3261307 | biostudies-literature