Abstract
Among thyroid carcinomas, highly aggressive undifferentiated or anaplastic carcinomas still await effective therapeutic strategies. R‐roscovitine is a novel cyclin‐dependent kinase inhibitor in clinical trials as anti‐cancer agent. We have investigated the effects of R‐roscovitine on proliferation and apoptosis of 4 thyroid cancer cell lines with different degrees of malignancy. R‐roscovitine induced cell cycle arrest in G2/M phase in all cells analyzed possibly by inhibiting the CDK1‐cyclin B1 complex. However, the compound was unable to induce a significant cell apoptosis. R‐roscovitine has been shown to sensitize cancer cells to TRAIL‐induced apoptosis. We report that R‐roscovitine sensitized thyroid cell lines to TRAIL‐induced apoptosis with the highest degree of synergism observed in the most undifferentiated cancer cells. Apoptosis was associated with the activation of caspases. In thyroid cancers, NF‐κB is constitutively activated contributing to the proliferation of malignant cells. Accordingly, we observed that R‐roscovitine inhibited p65 expression and nuclear translocation. Moreover, IKKβ over‐expression inhibited R‐roscovitine‐ and TRAIL‐induced apoptosis. The combined treatment also caused down‐regulation of anti‐apoptotic proteins transcriptionally regulated by NF‐κB. Finally, R‐roscovitine up‐regulated expression of DR5 TRAIL receptors. These results demonstrate that undifferentiated thyroid carcinoma cells can be effectively killed by a combination treatment of subtoxic doses of R‐roscovitine and TRAIL. R‐roscovitine sensitization of TRAIL‐induced apoptosis appears to be mediated by the inhibition of the IKK/NF‐KB pathway leading to down‐regulation of anti‐apoptotic genes and up‐regulation of TRAIL death receptors. The combination of R‐roscovitine and TRAIL may represent a novel approach to the treatment of anaplastic thyroid carcinomas resistant to conventional chemotherapy. © 2009 Wiley‐Liss, Inc.