title: The novel histone deacetylase inhibitor BL1521 inhibits proliferation and induces apoptosis in neuroblastoma cells.
abstract: Neuroblastoma is a childhood cancer arising from the sympathetic nervous system. Disseminated neuroblastoma has a poor prognosis despite intensive multimodality treatment. Histone deacetylases (HDACs) were recently discovered as a potential target for pharmacological gene therapy in cancer. HDACs have an important function in regulating DNA packaging in chromatin, thereby affecting the transcription of genes. In this paper, we tested the efficacy of a newly developed histone deacetylase inhibitor, BL1521, on neuroblastoma in vitro by investigating the changes in: acetylation of histone H3, in situ HDAC activity, p21(WAF1/CIP1) and MYCN expression, metabolic activity, proliferation, morphology and the amount of apoptosis present. BL1521 inhibited the in situ HDAC activity of a panel of neuroblastoma cell lines by at least 85%. Western analysis showed an increase of histone H3 acetylation in neuroblastoma cells after incubation with BL1521. Northern analysis showed an increase in the expression of p21(WAF1/CIP1) and a decrease in the expression of MYCN in neuroblastoma cells after incubation with BL1521. Proliferation as well as the metabolic activity of neuroblastoma cells decreased significantly in response to treatment with BL1521, regardless of the MYCN status of the cells. BL1521 induced poly-(ADP-ribose) polymerase cleavage in a time- and dose-dependent manner, indicating the induction of apoptosis. Furthermore, when compared to the HDAC inhibitors Trichostatin A and 4-phenylbutyrate, BL1521 has an intermediate efficacy. Our results show that BL1521 is a potent inhibitor of HDAC and that HDACs are an attractive target for selective chemotherapy in neuroblastoma.
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Paediatrics/Emma Children's Hospital and Clinical Chemistry, Academic Medical Centre, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
authors.forename: Annemieke J M
authors.initials: AJ
authors.lastname: de Ruijter
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
authors.forename: Gertjan
authors.initials: G
authors.lastname: Kramer
authors.forename: Rutger J
authors.initials: RJ
authors.lastname: Meinsma
authors.forename: Judith O
authors.initials: JO
authors.lastname: Kaufmann
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009447:Neuroblastoma / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C492810:BL1521; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids