Journal
JOURNAL OF INNATE IMMUNITY
Volume 8, Issue 4, Pages 330-349Publisher
KARGER
DOI: 10.1159/000444256
Keywords
CFTR; Corrector; Cystic fibrosis; Infection; Inflammation; Innate immunity; Pseudomonas aeruginosa; Roscovitine; Seliciclib; TRPC6
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Funding
- associations Vaincre la Mucoviscidose
- ABCF Mucoviscidose
- LabEx INFLAMEX [ANR-11-IDEX-0005-02]
- Chancellerie des Universites de Paris (Legs Poix)
- National Institutes of Health Grants (USA) [RO1 GM36823, RO1 HL125076]
- Cystic Fibrosis Foundation [12 PO, 13PO]
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(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate. (C) 2016 S. Karger AG, Basel
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