Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects
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
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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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 5

KW6002 alleviates the cisplatin-induced nephrotoxicity associated with apoptosis, lipid metabolism, and oxidative stress.

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KW6002 alleviates the cisplatin-induced nephrotoxicity associated with a...
(A and B) RPTEC/hTERT1 cells were coexposed to cisplatin (50 μM) and increasing concentrations of KW6002. Cell viability (A) and caspase 3/-7 activity (B) were determined 72 hours after treatment. ***P < 0.001 versus the respective cisplatin condition; °P < 0.01 and °°°P < 0.001 versus cisplatin, not treated with KW6002; 1-way ANOVA followed by Tukey’s post hoc test (n = 3–4/condition). (C–I and N–P) RPTEC/hTERT1 cells were exposed to cisplatin (50 μM) and/or KW6002 (25 μM). n = 3 independent experiments. (C–E) Representative Western blots (C) and quantification showing the cleavage of PARP and caspase 3 proteins (D and E). (F) Bax/Bcl2 mRNA ratio. ***P < 0.001 versus vehicle; °°P < 0.01 versus cisplatin; 1-way ANOVA followed by Tukey’s post hoc test (n = 3 independent experiments). (G) Tail moment assessed by comet assay; 50 cells/condition were analyzed. (H–K) KW6002 attenuates cisplatin-induced renal lipid accumulation, assessed by Red Oil staining. Red color indicates lipid deposition. (H and I) Representative images of RPTEC/hTERT1 cells (scale bar: 20 μm) (H) and quantification (n = 5 randomly chosen fields/staining) (I). ***P < 0.001 versus vehicle; °°P < 0.01 versus cisplatin; 1-way ANOVA followed by Tukey’s post hoc test (n = 3 independent experiments). (J and K) Representative images of the subchronic cisplatin mouse model (scale bar: 200 μm) and (K) quantification (n = 8 randomly chosen fields/section) Results are the mean ± SEM. *P < 0.05 versus vehicle; °P < 0.05 versus cisplatin; 1-way ANOVA followed by Tukey’s post hoc test (n = 3 mice/group). (L and M) KW6002 attenuated cisplatin-induced oxidative stress in the subchronic cisplatin mouse model. Gene expression of Nrf2 (L) and HO1 (M). **P < 0.01 and ***P < 0.001 versus vehicle; °P < 0.05 and °°P < 0.01 versus cisplatin; 1-way ANOVA followed by Tukey’s post hoc test. Results are the mean ± SEM (n = 6–9 mice/group). (N–P) KW6002 attenuated cisplatin-induced oxidative stress in RPTEC/hTERT1 cells. (N and O) Gene expression of Nrf2 (N) and HO1 (O). (P) Catalase activity. *P < 0.05 and **P < 0.01 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).