title: Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis.
abstract: (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.
authors.affiliation: Centre de Perharidy, ManRos Therapeutics, Roscoff, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Nelson
authors.forename: Vladimir
authors.initials: V
authors.lastname: Riazanski
authors.forename: Aida G
authors.initials: AG
authors.lastname: Gabdoulkhakova
authors.forename: Geneviève
authors.initials: G
authors.lastname: Hery-Arnaud
authors.forename: Rozenn
authors.initials: R
authors.lastname: Le Berre
authors.forename: Nadège
authors.initials: N
authors.lastname: Loaëc
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nowak
authors.forename: Laetitia
authors.initials: L
authors.lastname: Gueganton
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dorothée
authors.forename: Michaela
authors.initials: M
authors.lastname: Prochazkova
authors.forename: Bradford
authors.initials: B
authors.lastname: Hall
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gray
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.forename: Véronique
authors.initials: V
authors.lastname: Witko-Sarsat
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
authors.forename: Denis
authors.initials: D
authors.lastname: Ravel
authors.forename: Dominique
authors.initials: D
authors.lastname: Mottier
authors.forename: Gilles
authors.initials: G
authors.lastname: Rault
mesh_terms: D056704:Adaptive Immunity; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation; D009369:Neoplasms / Q000188:drug therapy; D010146:Pain / Q000188:drug therapy*; D011687:Purines / Q000627:therapeutic use*; D000077546:Roscovitine
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D011687:Purines; D000077546:Roscovitine