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  current news   Press   selected story    
     
  26th November  
  R-Roscovitine simultaneously targets both the p53 and NF-κB pathways and causes potentiation of apoptosis: implications in cancer therapy
 
 


Authors
Dey Anwesha, Wong EeTsin*, Cheok Chit Fang*, Tergaonkar Vinay, Lane David.

* Cheok CF and Wong ET contributed equally to the work

Correspondence to Lane DP and Tergaonkar V.
d.p.lane@imcb.a-star.edu.sg; vinayt@imcb.a-star.edu.sg

Abstract
Seliciclib (CYC202, R-Roscovitine) is a 2, 6, 9-substituted purine analogue that is currently in phase II clinical trials as an anticancer agent. We show in this study that R-Roscovitine can downregulate NF-κB activation in response to TNFα and IL1. Activation of p53 dependent transcription is not compromised when R-Roscovitine is combined with TNFα. We characterize the molecular mechanism governing NF-κB repression and show that R-Roscovitine inhibits the IKK kinase activity which leads to defective IκBα phosphorylation, degradation and hence nuclear function of NF-κB. We further show that the downregulation of the NF-κB pathway is also at the level of p65 modification and that the phosphorylation of p65 at Ser 536 is repressed by R-Roscovitine. Consistent with repression of canonical IKK signaling pathway, the induction of NF-κB target genes MCP-1, ICAM-1, Cox-2 and IL-8 is also inhibited by R-Roscovitine. We further show that treatment of cells with TNFα and R-Roscovitine causes potentiation of cell death. Based on these results, we suggest the potential use of R-Roscovitine as a bitargeted anti-cancer drug which functions by simultaneously causing p53 activation and NF-κB suppression. This study also provides mechanistic insight into the molecular mechanism of action of R-Roscovitine thereby possibly explaining its anti-inflammatory properties.



Published in Cell Death and Differentiation, 2 Nov 2007.