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

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-kappa B) 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 TNF alpha. We characterize the molecular mechanism governing NF-kappa B repression and show that R-Roscovitine inhibits the I kappa B kinase (IKK) kinase activity, which leads to defective I kappa B alpha phosphorylation, degradation and hence nuclear function of NF-kappa B. We further show that the downregulation of the NF-kappa B 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-kappa B 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 TNFa 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-kappa B suppression. This study also provides mechanistic insight into the molecular mechanism of action of R-Roscovitine, thereby possibly explaining its anti-inflammatory properties.