(R)-roscovitine (CYC202, Seliciclib) sensitizes SH-SY5Y neuroblastoma cells to nutlin-3-induced apoptosis.
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.
Ribas
Judit
J
CNRS, Cell Cycle Group, Station Biologique, B.P. 74, 29682 Roscoff cedex, Bretagne, France.
Boix
Jacint
J
Meijer
Laurent
L
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; D011687:Purines; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D000077546:Roscovitine; C482205:nutlin 3; D007770:L-Lactate Dehydrogenase; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D010447:Peptide Hydrolases; D020169:Caspases; C108711:DEVDase