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Histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of neuroblastoma cells

Item Type:Article
Title:Histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of neuroblastoma cells
Creators Name:Deubzer, H.E. and Ehemann, V. and Westermann, F. and Heinrich, R. and Mechtersheimer, G. and Kulozik, A.E. and Schwab, M. and Witt, O.
Abstract:The survival rate of children with advanced neuroblastoma (NB) is dismal despite intensive multimodal therapy. The limited efficacy and the frequent and serious side effects of currently used therapeutic regimens necessitate the development of new, less toxic treatment strategies. This study shows that the histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of both established NB cell lines and primary NB cells with and without amplified MYCN at dosages lower than 20 nM. HC-toxin induces cell cycle arrest and apoptosis as well as neuronal differentiation and diminishes both colony formation and invasive growth. These cellular changes are accompanied by the transcriptional repression of cell cycle regulators of the retinoblastoma (RB) tumor suppressor network found at high levels in NBs with poor prognosis, like E2F-1 and its targets Skp2, N-myc, Mad2 and survivin. The levels of the hypophosphorylated active form of RB, and of cyclin-dependent kinase inhibitors including p15(INK4b), p16(INK4a), p21(cip1/waf-1) and p27(kip1) are increased. In conclusion, nanomolar doses of the HDACI HC-toxin cause a shift to a differentiated and benign phenotype of NB cells that is associated with an activation of the RB tumor suppressor network.
Keywords:Epigenetic Therapy, Cell Cycle Arrest, Differentiation, E2F-1 Regulated Genes, RB Tumor Suppressor Network
Source:International Journal of Cancer
ISSN:0020-7136
Publisher:Wiley (Switzerland)
Volume:122
Number:8
Page Range:1891-900
Date:15 April 2008
Official Publication:https://doi.org/10.1002/ijc.23295
PubMed:View item in PubMed

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