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

摘要: Seliciclib (CYC202, R-Roscovitine) is a 2, 6, 9-substituted purine analog that currently in phase II clinical trials as an anticancer agent. We show this study R-Roscovitine can downregulate nuclear factor-kappa B (NF-kappaB) activation response to tumor necrosis factor (TNF)alpha and interleukin 1. Activation of p53-dependent transcription not compromised when combined with TNFalpha. characterize the molecular mechanism governing NF-kappaB repression inhibits IkappaB kinase (IKK) activity, which leads defective IkappaBalpha phosphorylation, degradation hence function NF-kappaB. further downregulation pathway also at level p65 modification phosphorylation Ser 536 repressed by R-Roscovitine. Consistent canonical IKK signaling pathway, induction target genes monocyte chemoattractant protein, intercellular adhesion molecule-1, cyclooxygenase-2 IL-8 inhibited treatment cells TNFalpha causes potentiation cell death. Based on these results, we suggest potential use bitargeted drug functions simultaneously causing p53 suppression. This provides mechanistic insight into action R-Roscovitine, thereby possibly explaining its anti-inflammatory properties.