title: Effects of epigenetic modificators in combination with small molecule inhibitors of receptor tyrosine kinases on medulloblastoma growth.
abstract: Epigenetic alterations and aberrant expression of genes controlling epigenetic mechanisms have been identified in several cancers, including medulloblastoma, the most common brain tumor in children. Here we show that combining drugs that inhibit two of the most important epigenetic factors, gene methylation and post-translational modifications of protein histone-associated DNA, with small molecule inhibitors of receptor tyrosine kinases induces apoptosis. The histone deacetylation inhibitor, 4-phenylbutyrate (4-PB) and the demethylation agent, 5-Aza-2'deoxycytidine (5-Aza-dC) had minor effects on medulloblastoma cell cytotoxity in single agent treatment whereas a significant enhancement in cell cytotoxity was seen when these drugs were combined with Gleevec. Triple treatment of medulloblastoma cells with 4-PB, 5-Aza and Gleevec were associated with reduced DNA methyltransferase activity, reduced global methylation and induction of apoptosis. Taken together these results suggest that a combination of these drugs may be beneficial in the treatment of medulloblastoma.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. Electronic address: annamcmarino@yahoo.se.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Marino
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Frijhoff
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Raul
authors.initials: R
authors.lastname: Calero
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ninib
authors.initials: N
authors.lastname: Baryawno
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases
keywords: DNA methyltransferases; Histone deacetylases; Medulloblastoma; Receptor Tyrosine Kinases