Abstract
In this study, we have analyzed the consequences, on several neuroblastoma cell lines, of combined treatments with (R)-roscovitine (CYC202, Seliciclib), a CDK inhibitory drug, and nutlin-3, a p53 activating drug. Both compounds were found to synergize, causing significant levels of apoptosis in cultured cells when combined at sublethal concentrations. In SH-SY5Y cells, Bcl-XL protein overexpression protected from apoptosis induced by either nutlin-3 alone or the (R)-roscovitine plus nutlin-3 association but failed to prevent apoptosis triggered by (R)-roscovitine alone. Moreover, Western blot studies showed that (R)-roscovitine increased nutlin-3-mediated p53 stabilization. Therefore, we conclude the contribution of (R)-roscovitine to the synergism is basically the sensitization of SH-SY5Y cells to the action of nutlin-3 on p53. The relevance of this pharmacological synergism with respect to the treatment of neuroblastoma is discussed.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Caspases / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Drug Synergism
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Enzyme Inhibitors / pharmacology
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Humans
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Imidazoles / pharmacology*
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L-Lactate Dehydrogenase / metabolism
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Neuroblastoma / genetics
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Neuroblastoma / metabolism
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Neuroblastoma / pathology
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Peptide Hydrolases / metabolism
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Piperazines / pharmacology*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Purines / pharmacology*
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Roscovitine
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Time Factors
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Transfection
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Tumor Suppressor Protein p53 / metabolism
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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Antineoplastic Agents
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Enzyme Inhibitors
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Imidazoles
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Piperazines
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Purines
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Tumor Suppressor Protein p53
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bcl-X Protein
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Roscovitine
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nutlin 3
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L-Lactate Dehydrogenase
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Peptide Hydrolases
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Caspases
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DEVDase