A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival

Alvi, Azra J.; Austen, Belinda; Weston, Victoria; Fegan, Christopher; MacCallum, David E.; Gianella‐Borradori, Athos; Lane, David P.; Hubank, Michael; Powell, Judith E.; Wei, Wenbin; Taylor, Alexander M.; Moss, Paul; Stankovic, Tatjana

doi:10.1182/blood-2004-07-2713

Cited by 125 publications

(116 citation statements)

References 30 publications

(48 reference statements)

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“…8,16 Consistent with their studies, we also see downregulation of total Pol II and Ser2 phosphorylation upon treatment with R-Roscovitine (Supplementary data 1). However, our data also support specific effects of R-Roscovitine on inhibiting TNFa-induced activation of the NF-kB pathway.…”

Section: R-roscovitine Inhibitssupporting

confidence: 89%

“…12 It has been reported to have antitumor activity against several cancer cell lines. 11,13,14 It can also induce apoptosis in multiple myeloma cells, 15 primary B-cell chronic lymphatic leukemia cells 16 and also maturing cerebellar granule neurons. 17 Another study demonstrated the ability of RRoscovitine to promote resolution of inflammation and inflammatory cell apoptosis associated with the loss of expression of Mcl-1.…”

mentioning

confidence: 99%

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

Dey

Wong²,

Cheok

et al. 2007

Cell Death Differ

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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-jB) activation in response to tumor necrosis factor (TNF)a and interleukin 1. Activation of p53-dependent transcription is not compromised when RRoscovitine is combined with TNFa. We characterize the molecular mechanism governing NF-jB repression and show that RRoscovitine inhibits the IjB kinase (IKK) kinase activity, which leads to defective IjBa phosphorylation, degradation and hence nuclear function of NF-jB. We further show that the downregulation of the NF-jB 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-jB 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 RRoscovitine 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-jB suppression. This study also provides mechanistic insight into the molecular mechanism of action of R-Roscovitine, thereby possibly explaining its antiinflammatory properties. The p53 and nuclear factor-kappa B (NF-kB) pathways are two critical transcriptional regulatory networks deregulated in various human ailments including cancer and there has been a lot of evidence of cross-talk between these two pathways. 1 Activation of p53 is associated with cell cycle arrest and apoptosis while NF-kB activation is associated with cell survival. Hence, the cross-talk between these pathways must be finely tuned and regulated.p53 is one of the most extensively studied tumor suppressor proteins. 2 Loss or mutation of p53 function is correlated with increased cancer susceptibility. Hence, activating p53 has been a goal of several small molecule inhibitors currently being evaluated in the clinic.NF-kB is a transcription factor critical for the control of inflammation, apoptosis and cell proliferation. 3,4 Chronic inflammation by constitutively active NF-kB has been shown to contribute to the development of many cancers. 5 It is becoming apparent that deregulated activity of NF-kB is observed and causally linked to the development of several diseases that have an inflammatory component. 6,7 Hence, identification of NF-kB inhibitors has been the focus of several academic and pharmaceutical establishments. 6,7 Since p53 promotes cell death and NF-kB prevents cell death, an anticancer agent that simultaneously activates p53 and inhibits NF-kB would offer greater potential to target two cancer targets positively.One of the ways in which the p53 pathway has been successfully targeted is by using cyclin-dependent kinase (CDK) inhibi...

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Section: R-roscovitine Inhibitssupporting

confidence: 89%

mentioning

confidence: 99%

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

Dey

Wong²,

Cheok

et al. 2007

Cell Death Differ

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“…17 Crosslinking GAH antibody (indicated as XL) (50 mg/ml) was added 30 min after the indicated mAbs. As a positive control for apoptosis induction, cells were treated with different cytotoxic drugs: fludarabine 50 mM, 25mM roscovitine, a cyclin-dependent kinase inhibitor and potent inducer of apoptosis in CLL 18,19 or bortezomib 30 nM. The pancaspase inhibitors 20 mM Q-VD and 200 mM Z-VADfmk were added 30 min before the indicated time of addition of mAbs or roscovitine.…”

Section: Induction and Analysis Of Apoptosismentioning

confidence: 99%

CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

et al. 2011

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In vitro CD40-stimulated chronic lymphocytic leukemia (CLL) cells are resistant to cytotoxic drugs. In sharp contrast, we here show that CD40 stimulation sensitizes CLL cells to rituximabmediated cell death. This increased sensitivity is specific for anti-CD20 treatment. Rituximab-mediated death in CD40-stimulated CLL cells shows rapid kinetics (within hours), and is caspase and p53 independent, but depends on extracellular Ca 2 þ and reactive oxygen species (ROS) production. By increasing basal ROS production, CD40 stimulation sensitizes CLL cells to rituximab-mediated death. Our findings provide a rationale for combination treatment of CLL with cytotoxic drugs and anti-CD20 monoclonal antibodies.

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“…Seliciclib was most active in inhibiting the proliferation of colon, non-small-cell lung, breast and prostate human cancer xenografts. It also induces caspasedependent apoptosis in primary B-cell chronic lymphatic leukaemia cells ex vivo, downregulating the antiapoptotic proteins Mcl-1 and XIAP, and increasing Bak expression and Bax cleavage (Alvi et al, 2005). In addition, seliciclib demonstrates antitumour activity in multiple myeloma cultures and cell lines, inducing apoptosis associated with downregulation of Mcl-1 and interleukin (IL)-6 transcription and protein expression Raje et al, 2005).…”

mentioning

confidence: 99%

A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

et al. 2006

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Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39 -73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2 -5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer.

show abstract

A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival

Cited by 125 publications

References 30 publications

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

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

CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

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