Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects
Edmone Dewaeles, … , David Blum, Christelle Cauffiez
Edmone Dewaeles, … , David Blum, Christelle Cauffiez
Published November 15, 2022
Citation Information: J Clin Invest. 2022;132(22):e152924. https://doi.org/10.1172/JCI152924.
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Research Article Nephrology

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

Abstract

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.

Authors

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

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Figure 9

KW6002 reduces the pain hypersensitivity and cytokine upregulation induced by cisplatin.

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KW6002 reduces the pain hypersensitivity and cytokine upregulation induc...
(A) Mechanical sensitivity measured by von Frey hairs in mice treated with cisplatin and/or KW6002 in the subchronic model described in Supplemental Figure 1D. The arrow represents cisplatin and/or PBS injection. Pain was measured 24 hours after KW6002 or vehicle injection. Data are the mean ± SEM. ***P < 0.001 versus vehicle; °°°P < 0.001 versus cisplatin; 2-way ANOVA (n = 5/group). (B and C) mRNA levels of Il1b (B) and Ccl2 (C) in DRGs 8 days after the start of cisplatin treatment. Data are the mean ± SEM. *P < 0.05 versus vehicle; °°P < 0.01 versus cisplatin; 2-way ANOVA (n = 5/group). (D–G) Time-course evaluation of mechanical sensitivity in mice measured by von Frey hairs during the first 180 minutes following KW6002 administration in response to cisplatin on day –3 (D–3) (D), day +2 (D+2) (E), day +4 (F), and day +7 (G). Data are the mean ± SEM. °P < 0.05 versus cisplatin; 1-way ANOVA followed by Tukey’s post hoc test (n = 5/group).