Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

Meijer, Laurent; Nelson, Deborah J.; Riazanski, Vladimir; Gabdoulkhakova, Aida G.; Hery-Arnaud, Geneviève; Le Berre, Rozenn; Loaëc, Nadège; Oumata, Nassima; Galons, Hervé; Nowak, Emmanuel; Gueganton, Laetitia; Dorothée, Guillaume; Prochazkova, Michaela; Hall, Bradford; Kulkarni, Ashok B.; Gray, Robert D.; Rossi, Adriano G.; Witko-Sarsat, Véronique; Norez, Caroline; Becq, Frédéric; Ravel, Denis; Mottier, Dominique; Rault, Gilles

doi:10.1159/000444256

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Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

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Meijer, Laurent, Nelson, Deborah J., Riazanski, Vladimir, Gabdoulkhakova, Aida G., Hery-Arnaud, Geneviève, Le Berre, Rozenn, Loaëc, Nadège, Oumata, Nassima, Galons, Hervé, Nowak, Emmanuel, Gueganton, Laetitia, Dorothée, Guillaume, Prochazkova, Michaela, Hall, Bradford, Kulkarni, Ashok B., Gray, Robert D., Rossi, Adriano G., Witko-Sarsat, Véronique, Norez, Caroline, Becq, Frédéric, Ravel, Denis, Mottier, Dominique, Rault, Gilles·2016·Journal of Innate Immunity

DOI 10.1159/000444256

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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.

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Authors: Meijer, L., Nelson, D. J., Riazanski, V., Gabdoulkhakova, A. G., Hery-Arnaud, G., Le Berre, R., Loaëc, N., Oumata, N., Galons, H., Nowak, E., Gueganton, L., Dorothée, G., Prochazkova, M., Hall, B., Kulkarni, A. B., Gray, R. D., Rossi, A. G., Witko-Sarsat, V., Norez, C., Becq, F., Ravel, D., Mottier, D., & Rault, G.
Venue: Journal of Innate Immunity
Publisher: S. Karger AG
Published: 2016
Volume: 8
Issue: 4
Pages: 330-349
ISSN: 1662-811X (ISSN-L)
1662-8128
DOI: 10.1159/000444256
OpenAlex: W2301131921
Cited by: 4,992
References: 8
FWCI: 438.81
Type: journal article
Language: en
Open access: gold
Licence: karger.com/pages/terms-and-conditions (vor)
karger.com/pages/terms-and-conditions (tdm)

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The paper: Meijer, L., Nelson, D. J., Riazanski, V., Gabdoulkhakova, A. G., Hery-Arnaud, G., Le Berre, R., Loaëc, N., Oumata, N., Galons, H., Nowak, E., Gueganton, L., Dorothée, G., Prochazkova, M., Hall, B., Kulkarni, A. B., Gray, R. D., Rossi, A. G., Witko-Sarsat, V., Norez, C., . . . Rault, G. (2016). Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis. Journal of Innate Immunity. https://doi.org/10.1159/000444256

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Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

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