Histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of neuroblastoma cells.
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.
Deubzer
Hedwig E
HE
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. h.deubzer@dkfz-heidelberg.de
Ehemann
Volker
V
Westermann
Frank
F
Heinrich
Ralf
R
Mechtersheimer
Gunhild
G
Kulozik
Andreas E
AE
Schwab
Manfred
M
Witt
Olaf
O
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006375:Helminthosporium; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009183:Mycotoxins / Q000494:pharmacology*; D053769:Nanocapsules; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009183:Mycotoxins; D053769:Nanocapsules; D025521:Tumor Suppressor Proteins