The CDK inhibitor, R‐roscovitine, promotes eosinophil apoptosis by down‐regulation of Mcl‐1

Duffin, Rodger; Leitch, Andrew E.; Sheldrake, Tara A.; Hallett, John M.; Meyer, Colette; Fox, Sarah; Alessandri, Ana L.; Martin, Morag C.; Brady, Hugh J.M.; Teixeira, Mauro M.; Dransfield, Ian; Haslett, Christopher; Rossi, Adriano G.

doi:10.1016/j.febslet.2009.07.017

Cited by 48 publications

(63 citation statements)

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“…At a concentration of 250µM, cell viability was significantly (p=0.015) reduced to 70%, compared to control mice, while significant effect was observed at lower concentrations. These results were in agreement with the findings that roscovitine induced apoptosis of mature neutrophils [141], eosinophils [142]. and proliferating T-cells [143] in a concentration and exposure-time dependent manner.…”

Section: Pharmacokineticssupporting

confidence: 93%

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

Zhelev

Trifonov²,

Wang³

et al. 2013

Biodiscovery

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This monograph reviews the discovery and development of the cyclindependent kinase inhibitor roscovitine (R-roscovitine, CYC202, Seliciclib). The authors summarise the in vitro and in vivo data that have formed the basis for clinical investigation of Seliciclib as an anti-cancer drug. Kinase selectivity, cellular effects and the pharmacological properties of the drug are discussed in addition to the clinical results of Seliciclib being reviewed. Novel results on the effect of the drug in cardiac hypertrophy are summarized and potential applications of Seliciclib in other therapeutic areas, including, inflammation, virology, glomerulonephritis and polycystic kidney disease, are discussed. Finally the authors argue that optimisation of the therapeutic effect of kinase inhibitors such as Seliciclib can be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division. Seliciclib -discovery and developmentBioDiscovery 2 December 2013 | Issue 10 | 1

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Section: Pharmacokineticssupporting

confidence: 93%

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

Zhelev

Trifonov²,

Wang³

et al. 2013

Biodiscovery

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“…Although initially identified as key components of the cell cycle machinery, CDKs have played a role in cell differentiation, transcription (CDK-7 and -9), neural function and apoptosis, especially in PMNs (20,21). Our data indicate that R-roscovitine exerts profound antiinflammatory effects in lung inflammation elicited by either LTA or viable pneumococci.…”

Section: Discussionmentioning

confidence: 73%

“…Moreover, phagocytosis of apoptotic PMNs by macrophages elicits release of antiinflammatory mediators, aiding resolution of (harmful) inflammation (15,16). The exact mechanism by which CDK inhibition contributes to apoptosis is elusive, although this property is attributed to destabilization of MCL-1, a prosurvival factor, which may play a role (21,37,39). It should be noted that CDK inhibition may also induce senescence (40).…”

Section: Discussionmentioning

confidence: 99%

“…R-roscovitine's apoptosisinducing potential in PMNs has previously been established in several in vivo models of inflammation and infection, resulting in improved resolution of inflammation (20)(21)(22). Besides inducing beneficial PMN apoptosis, R-roscovitine possibly has direct antiinflammatory properties by inhibiting the transcription of proinflammatory cytokines in macrophages (19).…”

Section: Introductionmentioning

confidence: 99%

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R-roscovitine Reduces Lung Inflammation Induced by Lipoteichoic Acid and Streptococcus pneumoniae

Hoogendijk

Roelofs

Duitman

et al. 2012

Mol Med

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Bacterial pneumonia remains associated with high morbidity and mortality. The gram-positive pathogen Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. Lipoteichoic acid (LTA) is an important proinflammatory component of the gram-positive bacterial cell wall. R-roscovitine, a purine analog, is a potent cyclin-dependent kinase (CDK)-1, -2, -5 and -7 inhibitor that has the ability to inhibit the cell cycle and to induce polymorphonuclear cell (PMN) apoptosis. We sought to investigate the effect of R-roscovitine on LTA-induced activation of cell lines with relevance for lung inflammation in vitro and on lung inflammation elicited by either LTA or viable S. pneumoniae in vivo. In vitro R-roscovitine enhanced apoptosis in PMNs and reduced tumor necrosis factor (TNF)-α and keratinocyte chemoattractant (KC) production in MH-S (alveolar macrophage) and MLE-12/ MLE-15 (respiratory epithelial) cell lines. In vivo R-roscovitine treatment reduced PMN numbers in bronchoalveolar lavage fluid during LTA-induced lung inflammation; this effect was reversed by inhibiting apoptosis. Postponed treatment with R-roscovitine (24 and 72 h) diminished PMN numbers in lung tissue during gram-positive pneumonia; this step was associated with a transient increase in pulmonary bacterial loads. R-roscovitine inhibits proinflammatory responses induced by the gram-positive stimuli LTA and S. pneumoniae. R-roscovitine reduces PMN numbers in lungs upon LTA administration by enhancing apoptosis. The reduction in PMN numbers caused by R-roscovitine during S. pneumoniae pneumonia may hamper antibacterial defense.

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“…Larger sample sizes will be needed to fully characterize the genetic architecture of gene expression in airway epithelium. Chromosome 17q21 is one of the most consistent loci associated with asthma (9,10,(58)(59)(60)(61)(62)(63)(64)(65)(66)(67). Based on an eQTL study performed in lymphoblastoid cell lines and lung tissue, ORMD3L, GSDMB, and GSDMA have been suggested to be prime candidates driving the GWAS signal (9, 10, 21, 61).…”

Section: Discussionmentioning

confidence: 99%

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Luo

Obeidat

Narzo

et al. 2016

Am J Respir Cell Mol Biol

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Genome-wide association studies (GWASs) have identified loci that are robustly associated with asthma and related phenotypes; however, the molecular mechanisms underlying these associations need to be explored. The most relevant tissues to study the functional consequences of asthma are the airways. We used publically available data to derive expression quantitative trait loci (eQTLs) for human epithelial cells from small and large airways and applied the eQTLs in the interpretation of GWAS results of asthma and related phenotypes. For the small airways (n = 105), we discovered 660 eQTLs at a 10% false discovery rate (FDR), among which 315 eQTLs were not previously reported in a large-scale eQTL study of whole lung tissue. A large fraction of the identified eQTLs is supported by data from Encyclopedia of DNA Elements (ENCODE) showing that the eQTLs reside in regulatory elements (57.5 and 67.6% of cis-and trans-eQTLs, respectively). Published pulmonary GWAS hits were enriched as airway epithelial eQTLs (9.2-fold). Further, genes regulated by asthma GWAS loci in epithelium are significantly enriched in immune response pathways, such as IL-4 signaling (FDR, 5.2 3 10 24 ). The airway epithelial eQTLs described in this study are complementary to previously reported lung eQTLs and represent a powerful resource to link GWAS-associated variants to their regulatory function and thus elucidate the molecular mechanisms underlying asthma and airway-related conditions.

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The CDK inhibitor, R‐roscovitine, promotes eosinophil apoptosis by down‐regulation of Mcl‐1

Cited by 48 publications

References 50 publications

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

R-roscovitine Reduces Lung Inflammation Induced by Lipoteichoic Acid and Streptococcus pneumoniae

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

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