Volume 124, Issue 11 pp. 2728-2736

Cancer Therapy

R-roscovitine sensitizes anaplastic thyroid carcinoma cells to TRAIL-induced apoptosis via regulation of IKK/NF-κB pathway

Michela Festa,

Michela Festa

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy

The first two authors contributed equally to this work.

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Antonello Petrella,

Antonello Petrella

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy

The first two authors contributed equally to this work.

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Silvia Alfano,

Silvia Alfano

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy

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Luca Parente,

Corresponding Author

Luca Parente

[email protected]

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy

Fax: + 39089-969602.

Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, ItalySearch for more papers by this author

Michela Festa,

Michela Festa

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy

The first two authors contributed equally to this work.

Search for more papers by this author

Antonello Petrella,

Antonello Petrella

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy

The first two authors contributed equally to this work.

Search for more papers by this author

Silvia Alfano,

Silvia Alfano

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy

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Luca Parente,

Corresponding Author

Luca Parente

[email protected]

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy

Fax: + 39089-969602.

Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, ItalySearch for more papers by this author

First published: 25 March 2009

https://doi.org/10.1002/ijc.24260

Citations: 22

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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.

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Volume124, Issue11

1 June 2009

Pages 2728-2736

R-roscovitine sensitizes anaplastic thyroid carcinoma cells to TRAIL-induced apoptosis via regulation of IKK/NF-κB pathway

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R-roscovitine sensitizes anaplastic thyroid carcinoma cells to TRAIL-induced apoptosis via regulation of IKK/NF-κB pathway

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