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

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Abstract

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.

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Acknowledgments

This research was supported by the National Council for Scientific and Technological Development (CNPq; grant numbers 484185/2012-8 and 303276/2013-4 to R.R.); PRONON/Ministry of Health, Brazil (number 25000.162.034/2014-21 to C.B.F); the Rafael Koff Acordi Research Fund, Children’s Cancer Institute (ICI); and the Clinical Hospital institutional research fund (FIPE/HCPA).

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Authors and Affiliations

  1. Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil

    Viviane Rösner Almeida, Marienela Buendia, Caroline Brunetto de Farias & Rafael Roesler

  2. Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil

    Viviane Rösner Almeida, Marienela Buendia & Rafael Roesler

  3. Laboratory of Genomic Medicine, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil

    Igor Araujo Vieira

  4. Children’s Cancer Institute, Porto Alegre, RS, 90420-140, Brazil

    André Tesainer Brunetto, Algemir Lunardi Brunetto & Caroline Brunetto de Farias

  5. Department of Pediatrics, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil

    Lauro J. Gregianin

  6. Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil

    Lauro J. Gregianin

  7. Laboratory of Cellular Biochemistry, Department of Biochemistry, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil

    Fábio Klamt

  8. Graduate Program in Biotechnology, Univates University Center, Lajeado, RS, 95900-000, Brazil

    Ana Lucia Abujamra

  9. Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil

    Patrícia Luciana da Costa Lopez

  10. Graduate Program in Gastroenterology and Hepatology, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil

    Patrícia Luciana da Costa Lopez

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  1. Viviane Rösner Almeida
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  2. Igor Araujo Vieira
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  3. Marienela Buendia
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  4. André Tesainer Brunetto
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  8. Caroline Brunetto de Farias
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  9. Ana Lucia Abujamra
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  10. Patrícia Luciana da Costa Lopez
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  11. Rafael Roesler
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Correspondence to Rafael Roesler.

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Almeida, V.R., Vieira, I.A., Buendia, M. et al. Combined Treatments with a Retinoid Receptor Agonist and Epigenetic Modulators in Human Neuroblastoma Cells. Mol Neurobiol 54, 7610–7619 (2017). https://doi.org/10.1007/s12035-016-0250-3

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