Document Detail

Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells.
MedLine Citation:
PMID:  20404560     Owner:  NLM     Status:  MEDLINE    
As histone deacetylase inhibitors such as romidepsin (depsipeptide, FK228) complete successful Phase I clinical trials in pediatric solid tumors, it is important that their mechanisms of action are delineated in order to inform the development of subsequent clinical trials as single agents or in combination therapies. In this study, we evaluate the effect of romidepsin as a single agent on a number of different neuroblastoma (NB) cell lines. We find that the growth of 6/6 human NB tumor cell lines but not an immortalized fibroblast cell line (NIH3T3) is inhibited by romidepsin (IC(50) = 1-6.5 ng/ml) after 72 h of treatment. Romidepsin shows selective dose-dependent cytotoxicity in both single copy and N-myc amplified NB cell lines, in cell lines with wild type or mutant p53 and those containing Alk mutations. The decrease in cell proliferation is accompanied by caspase-dependent apoptosis as shown by PARP cleavage, an accumulation of cells in the sub-G(1) phase of the cell cycle and the ability of a pan-caspase inhibitor to reduce cell death. Romidepsin inhibits the growth of subcutaneous NB xenografts in a dose dependent manner in immunocompromised mice. Furthermore, romidepsin induces expression of genes such as p21 and expression of p75 and NTRK (TrkA) which are more highly expressed in the tumors from NB patients that have a good prognosis. These studies support continued investigations into the therapeutic activity of romidepsin in NB.
Jyoti Panicker; Zhijie Li; Christine McMahon; Caroline Sizer; Kenneth Steadman; Richard Piekarz; Susan E Bates; Carol J Thiele
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2010-05-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  9     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-31     Completed Date:  2010-09-03     Revised Date:  2011-06-08    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1830-8     Citation Subset:  IM    
Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
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MeSH Terms
Antibiotics, Antineoplastic / therapeutic use*
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism
Depsipeptides / therapeutic use*
G1 Phase
Histone Deacetylase Inhibitors / therapeutic use*
Histone Deacetylases / chemistry,  metabolism
NIH 3T3 Cells
Neuroblastoma / drug therapy*
Protein-Tyrosine Kinases / genetics,  metabolism
Receptor, Nerve Growth Factor / genetics,  metabolism
Receptor, trkA / genetics,  metabolism
Transplantation, Heterologous
Tumor Suppressor Protein p53 / genetics,  metabolism
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Depsipeptides; 0/Histone Deacetylase Inhibitors; 0/Receptor, Nerve Growth Factor; 0/Tumor Suppressor Protein p53; 128517-07-7/romidepsin; EC Kinases; EC, trkA; EC lymphoma kinase; EC Deacetylases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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