title: R-Roscovitine simultaneously targets both the p53 and NF-kappaB pathways and causes potentiation of apoptosis: implications in cancer therapy.
abstract: 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.
authors.affiliation: Laboratory of Cell Cycle Control, Institute of Molecular and Cell Biology, Proteos, 138673, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Dey
authors.forename: E T
authors.initials: ET
authors.lastname: Wong
authors.forename: C F
authors.initials: CF
authors.lastname: Cheok
authors.forename: V
authors.initials: V
authors.lastname: Tergaonkar
authors.forename: D P
authors.initials: DP
authors.lastname: Lane
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011687:Purines; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D000077546:Roscovitine; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase