(R)-roscovitine (CYC202, Seliciclib) sensitizes SH-SY5Y neuroblastoma cells to nutlin-3-induced apoptosis

Exp Cell Res. 2006 Jul 15;312(12):2394-400. doi: 10.1016/j.yexcr.2006.04.021.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Imidazoles / pharmacology*
  • L-Lactate Dehydrogenase / metabolism
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Peptide Hydrolases / metabolism
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Purines / pharmacology*
  • Roscovitine
  • Time Factors
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Enzyme Inhibitors
  • Imidazoles
  • Piperazines
  • Purines
  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • Roscovitine
  • nutlin 3
  • L-Lactate Dehydrogenase
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Peptide Hydrolases
  • Caspases
  • DEVDase