Combined Treatments with a Retinoid Receptor Agonist and Epigenetic Modulators in Human Neuroblastoma Cells.
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.
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil.
Viviane Rösner
VR
Almeida
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
IA
Vieira
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil.
Marienela
M
Buendia
Children's Cancer Institute, Porto Alegre, RS, 90420-140, Brazil.
André Tesainer
AT
Brunetto
Department of Pediatrics, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.|Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
Lauro J
LJ
Gregianin
Children's Cancer Institute, Porto Alegre, RS, 90420-140, Brazil.
Algemir Lunardi
AL
Brunetto
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
F
Klamt
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.|Children's Cancer Institute, Porto Alegre, RS, 90420-140, Brazil.
Caroline Brunetto
CB
de Farias
Graduate Program in Biotechnology, Univates University Center, Lajeado, RS, 95900-000, Brazil.
Ana Lucia
AL
Abujamra
Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.|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
PLDC
Lopez
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil. rafael.roesler@pq.cnpq.br.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil. rafael.roesler@pq.cnpq.br.
Rafael
R
Roesler
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism*; D013256:Steroids / Q000008:administration & dosage; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives
C559105:EA-4 (ATRA steroidal analog); D056572:Histone Deacetylase Inhibitors; D018168:Receptors, Retinoic Acid; D013256:Steroids; D014212:Tretinoin
Cell differentiation; Cell proliferation; DNA methyltransferase; Histone deacetylase; Neuroblastoma; Retinoid