Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects

Edmone Dewaeles (1, 2, 3) , Kévin Carvalho (3, 2, 4) , Sandy Fellah (2, 1) , Jaewon Sim (5) , Nihad Boukrout (2, 1) , Raphaelle Caillierez (3, 2, 4) , Hariharan Ramakrishnan (5) , Cynthia van der Hauwaert (1, 2) , Jhenkruthi Vijaya Shankara (3, 2, 4) , Nathalie Martin (1, 2) , Noura Massri (5) , Agathe Launay (3, 2, 4) , Joseph Folger (5) , Clémentine de Schutter (1, 2) , Romain Larrue (1, 2) , Ingrid Loison (1, 2) , Marine Goujon (1, 2) , Matthieu Jung (6) , Stéphanie Le Gras (6) , Victoria Gomez-Murcia (3, 2, 4) , Emilie Faivre (3, 2, 4) , Julie Lemaire (1, 2) , Anne Garat (2, 7) , Nicolas Beauval (2, 7) , Patrice Maboudou (2) , Viviane Gnemmi (1, 2) , Jean-Baptiste Gibier (1, 2) , Luc Buée (3, 2, 4) , Corinne Abbadie (1, 2) , Francois Glowacki (1, 2) , Nicolas Pottier (1, 2) , Michael Perrais (1, 2) , Rodrigo Cunha (8) , Jean-Sébastien Annicotte (9, 10, 2, 11) , Geoffroy Laumet (5) , David Blum (3, 2, 4) , Christelle Cauffiez (1, 2)

1 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
2 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
3 LilNCog - Lille Neurosciences & Cognition - U 1172
4 Excellence Laboratory LabEx DISTALZ
5 Michigan State University [East Lansing]
6 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
7 IMPECS - Impact de l'environnement chimique sur la santé humaine - ULR 4483
8 UC - University of Coimbra [Portugal]
9 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
10 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
11 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment.

Mots clés: G protein–coupled receptors; Nephrology; Pharmacology; G protein–coupled receptors

Domaines: Pharmacologie

Edmone Dewaeles, Kévin Carvalho, Sandy Fellah, Jaewon Sim, Nihad Boukrout, et al.. Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects. The Journal of clinical investigation, 2022, 132 (22), pp.e152924. ⟨10.1172/JCI152924⟩. ⟨inserm-03865945⟩