Journal
MOLECULAR NEUROBIOLOGY
Volume 54, Issue 10, Pages 7610-7619Publisher
HUMANA PRESS INC
DOI: 10.1007/s12035-016-0250-3
Keywords
Retinoid; Histone deacetylase; DNA methyltransferase; Cell proliferation; Cell differentiation; Neuroblastoma
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Funding
- National Council for Scientific and Technological Development (CNPq) [484185/2012-8, 303276/2013-4]
- PRONON/Ministry of Health, Brazil [25000.162.034/2014-21]
- Rafael Koff Acordi Research Fund, Children's Cancer Institute (ICI)
- Clinical Hospital institutional research fund (FIPE/HCPA)
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Neuroblastoma (NB) is the most common extracranial solid childhood tumor accounting for around 15% of pediatric cancer deaths and most probably originates from a failure in the development of embryonic neural crest cells. Retinoids can inhibit the proliferation and stimulate differentiation of NB cells. In addition, epigenetic events involving changes in chromatin structure and DNA methylation can mediate the effects of retinoids; hence, the scope of this study is to investigate the use of retinoids and epigenetic drugs in NB cell lines. Here, we demonstrate that the combination of retinoid all trans-retinoic acid (ATRA) with inhibitors of either histone deacetylases (HDACs) or DNA methyltransferase is more effective in impairing the proliferation of human SH-SY5Y and SK-N-BE(2) NB cells than any drug given alone. Treatments also induced differential changes on the messenger RNA (mRNA) expression of retinoid receptor subtypes and reduced the protein content of c-Myc, the neuronal markers NeuN and beta-3 tubulin, and the oncoprotein Bmi1. These results suggest that the combination of retinoids with epigenetic modulators is more effective in reducing NB growth than treatment with single drugs.
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