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 4

Transcriptomic analysis detailing the protective effect of KW6002 on renal toxicity induced by subchronic cisplatin administration.

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Transcriptomic analysis detailing the protective effect of KW6002 on ren...
(A) PCA of kidney RNA-Seq (n = 5–6 per group). (B) Venn diagram representing the number of genes deregulated by cisplatin (CIS) alone (4,649 genes) or by KW6002 plus cisplatin (2,515 genes). (C) Volcano plots showing the number of renal genes significantly up- or downregulated in the different conditions. (D–F) Analysis of the 811 genes normalized by KW6002 coadministration among the 2,350 genes upregulated by cisplatin. (D) Venn diagram showing that a marked number of renal genes (n = 811) downregulated (DOWN) by KW6002 in cisplatin-treated animals overlapped with genes upregulated (UP) by cisplatin alone. (E) These 811 genes are represented according to their changes in expression due to treatment with cisplatin alone or with cisplatin plus KW6002. (F) GO enrichment analysis of the 811 genes both overexpressed following cisplatin treatment and repressed by KW6002 treatment. (G–I) Analysis of the 635 genes normalized by KW6002 coadministration among the 2,299 genes downregulated by cisplatin. (G) Venn diagram shows that a substantial number of renal genes (n = 635) upregulated by KW6002 in cisplatin-treated animals overlapped with genes downregulated by cisplatin alone. (H) These 635 genes are represented according to their changes in expression due to treatment with cisplatin alone or with cisplatin plus KW6002. (I) GO enrichment analysis of the 635 genes both overexpressed following cisplatin treatment and repressed by KW6002 treatment. VEH, vehicle.