R-Roscovitine simultaneously targets both the p53 and NF- B pathways and causes potentiation of apoptosis: implications in cancer therapy

• Published in: Cell death and differentiation Vol. 15; no. 2; pp. 263 - 273
• Main Authors: Dey, A, Wong, E T, Cheok, C F, Tergaonkar, V, Lane, D P
• Format: Journal Article
• Language: English
• Published: Rome Nature Publishing Group 01.02.2008
• Subjects: Apoptosis; Cancer therapies; Cell cycle; Cell death; Clinical trials; Cyclin-dependent kinases; Cytokines; Kidney diseases; Kinases; Phosphorylation; Proteins; RNA polymerase; Tumor necrosis factor-TNF; Singapore
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/sj.cdd.4402257

Seliciclib (CYC202, R-Roscovitine) is a 2, 6, 9-substituted purine analog that is currently in phase II clinical trials as an anticancer agent. We show in this study that R-Roscovitine can downregulate nuclear factor-kappa B (NF-kappaB) activation in response to tumor necrosis factor (TNF)alpha and interleukin 1. Activation of p53-dependent transcription is not compromised when R-Roscovitine is combined with TNFalpha. We characterize the molecular mechanism governing NF-kappaB repression and show that R-Roscovitine inhibits the IkappaB kinase (IKK) kinase activity, which leads to defective IkappaBalpha phosphorylation, degradation and hence nuclear function of NF-kappaB. We further show that the downregulation of the NF-kappaB 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-kappaB target genes monocyte chemoattractant protein, intercellular adhesion molecule-1, cyclooxygenase-2 and IL-8 is also inhibited by R-Roscovitine. We further show that treatment of cells with TNFalpha and R-Roscovitine causes potentiation of cell death. Based on these results, we suggest the potential use of R-Roscovitine as a bitargeted anticancer drug that functions by simultaneously causing p53 activation and NF-kappaB suppression. This study also provides mechanistic insight into the molecular mechanism of action of R-Roscovitine, thereby possibly explaining its anti-inflammatory properties.