Combined Treatments with a Retinoid Receptor Agonist and Epigenetic Modulators in Human Neuroblastoma Cells

Mol Neurobiol. 2017 Dec;54(10):7610-7619. doi: 10.1007/s12035-016-0250-3. Epub 2016 Nov 10.


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 β-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.

Keywords: Cell differentiation; Cell proliferation; DNA methyltransferase; Histone deacetylase; Neuroblastoma; Retinoid.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Proliferation / physiology
  • Epigenesis, Genetic / drug effects*
  • Epigenesis, Genetic / physiology
  • Histone Deacetylase Inhibitors / administration & dosage
  • Humans
  • Neuroblastoma / metabolism*
  • Receptors, Retinoic Acid / agonists*
  • Receptors, Retinoic Acid / metabolism*
  • Steroids / administration & dosage
  • Tretinoin / administration & dosage
  • Tretinoin / analogs & derivatives


  • EA-4 (ATRA steroidal analog)
  • Histone Deacetylase Inhibitors
  • Receptors, Retinoic Acid
  • Steroids
  • Tretinoin