Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells.
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.
Panicker
Jyoti
J
Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
Li
Zhijie
Z
McMahon
Christine
C
Sizer
Caroline
C
Steadman
Kenneth
K
Piekarz
Richard
R
Bates
Susan E
SE
Thiele
Carol J
CJ
D000107:Acetylation; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D047630:Depsipeptides / Q000627:therapeutic use*; D016193:G1 Phase; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009447:Neuroblastoma / Q000188:drug therapy*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D020800:Receptor, Nerve Growth Factor; D016159:Tumor Suppressor Protein p53; C087123:romidepsin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D006655:Histone Deacetylases
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