ArticleBritish journal of pharmacology2014
Roscovitine is a proteostasis regulator that corrects the trafficking defect of F508del-CFTR by a CDK-independent mechanism.
Article in British journal of pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Molecular characterisation of the trafficking rescue of defective ABCB4 variants by roscovitine analogues.Scientific reports · 2026Article
- Impact of overexpression of wild-type CFTR and elexacaftor-tezacaftor-ivacaftor on oxylipin production by the CFBE41o- bronchial epithelial cell line.Prostaglandins & other lipid mediators · 2025Article
- Review
- One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies.Cells · 2022Review
- Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches.International journal of molecular sciences · 2021Review
- (R)-Roscovitine and CFTR modulators enhance killing of multi-drug resistant Burkholderia cenocepacia by cystic fibrosis macrophages.Scientific reports · 2020Article
- Non-Linear Pharmacokinetics of Oral Roscovitine (Seliciclib) in Cystic Fibrosis Patients Chronically Infected withPharmaceutics · 2020Article
- Article
- Structural analogues of roscovitine rescue the intracellular traffic and the function of ER-retained ABCB4 variants in cell models.Scientific reports · 2019Article
- Innovative Therapies for Cystic Fibrosis: The Road from Treatment to Cure.Molecular diagnosis & therapy · 2019Review
- Review
- Modulators of Transient Receptor Potential (TRP) Channels as Therapeutic Options in Lung Disease.Pharmaceuticals (Basel, Switzerland) · 2019Review
- Small molecules as therapeutic agents for inborn errors of metabolism.Journal of inherited metabolic disease · 2017Review
- CFTR pharmacology.Cellular and molecular life sciences : CMLS · 2017Review
- Harnessing Neutrophil Survival Mechanisms during Chronic Infection byFrontiers in cellular and infection microbiology · 2017Review
- In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.PloS one · 2017Article
- CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis.Frontiers in pharmacology · 2016Review
- Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis.Journal of innate immunity · 2016Review
- From Starfish Oocytes to Inflammation: The Unforeseeable Destiny of Roscovitine in Cystic Fibrosis.Journal of innate immunity · 2016Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeThe most common mutation in cystic fibrosis (CF), F508del, causes defects in trafficking, channel gating and endocytosis of the CF transmembrane conductance regulator (CFTR) protein. Because CF is an orphan disease, therapeutic strategies aimed at improving mutant CFTR functions are needed to target the root cause of CF. EXPERIMENTAL APPROACH: Human CF airway epithelial cells were treated with roscovitine 100 μM for 2 h before CFTR maturation, expression and activity were examined. The mechanism of action of roscovitine was explored by recording the effect of depleting endoplasmic reticulum (ER) Ca(2+) on the F508del-CFTR/calnexin interaction and by measuring proteasome activity. KEY
resultsOf the cyclin-dependent kinase (CDK) inhibitors investigated, roscovitine was found to restore the cell surface expression and defective channel function of F508del-CFTR in human CF airway epithelial cells. Neither olomoucine nor (S)-CR8, two very efficient CDK inhibitors, corrected F508del-CFTR trafficking demonstrating that the correcting effect of roscovitine was independent of CDK inhibition. Competition studies with inhibitors of the ER quality control (ERQC) indicated that roscovitine acts on the calnexin pathway and on the degradation machinery. Roscovitine was shown (i) to partially inhibit the interaction between F508del-CFTR and calnexin by depleting ER Ca(2+) and (ii) to directly inhibit the proteasome activity in a Ca(2+) -independent manner. CONCLUSIONS AND IMPLICATIONS: Roscovitine is able to correct the defective function of F508del-CFTR by preventing the ability of the ERQC to interact with and degrade F508del-CFTR via two synergistic but CDK-independent mechanisms. Roscovitine has potential as a pharmacological therapy for CF.
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