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 8

KW6002 limits cisplatin accumulation in the kidney but not in tumors.

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KW6002 limits cisplatin accumulation in the kidney but not in tumors. RP...
RPTEC/hTERT1 and H1975 cells were exposed to cisplatin and/or KW6002. n = 3 independent experiments. (A and E) Platinum quantification (ng/μg proteins) in RPTEC/hTERT1 (A) and H1975 (E) cells. ***P < 0.001 versus vehicle; °°P < 0.01 versus cisplatin; 1-way ANOVA followed by Tukey’s post hoc test. Results are the mean ± SEM (n = 3–4 independent experiments). (B and F) Platinum quantification in kidney (B) and tumor (F) samples from mice of the LLC1 syngeneic model. ***P < 0.001 versus vehicle; °°°P < 0.001 versus cisplatin; 1-way ANOVA followed by Tukey’s post hoc test. Results are the mean ± SEM (n = 12–20/group). (C and G) Active efflux in RPTEC/hTERT (C) and H1975 (G) cells. *P < 0.05 versus vehicle; °P < 0.05 versus cisplatin; 1-way ANOVA followed by Tukey’s post hoc test. Results are the mean ± SEM (n = 3 independent experiments). (D and H) Relative expression from RNA-Seq of 22 genes annotated as “export across plasma membrane” (extracted from G0: 0055085 transmembrane transport) in kidney (D) and tumor (H) samples from mice of the LLC1 syngeneic model (n = 5–6/group). Inserts represent the relative expression of Mate1 and Abcc2 evaluated by quantitative PCR in kidney samples. Results are the mean ± SEM. *P < 0.05 and ***P < 0.001 versus vehicle; °P < 0.05 and °°°P < 0.001 versus cisplatin; 1-way ANOVA followed by Tukey’s post hoc test (n = 10–12/group).