Istradefylline (KW6002) protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin anti-tumor effects [Kidney]

Cisplatin is a potent chemotherapeutic drug, widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, such as nephrotoxicity and chemotherapy-induced peripheral neuropathy. Therefore, there is an urgent medical need to identify novel strategies that would limit cisplatin-induced toxicity. In the present study, we provide evidence that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) significantly protects from cisplatin-induced nephrotoxicity and neuropathic pain in experimental models of acute and sub-chronic cisplatin intoxication. Importantly, we also demonstrate that the anti-tumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and even potentiated at the molecular level. Altogether, the present results support the use of istradefylline as a new valuable preventive approach for the clinical management of patients undergoing cisplatin treatment. Animal procedures were performed in 8 to 10 weeks old male C57Bl6/J mice (Janvier Labs except for pain experiments, Jackson lab). Mice were fed a laboratory standard diet with water and food ad libitum and were kept under constant environmental conditions with a 12-hour light-dark cycle. Istradefylline (KW6002; Tocris) was dissolved in a carrier solution consisting in 15% DMSO, 15% cremophor (Sigma), 70% saline solution (vehicle). Cisplatin (Accord Healthcare) was dissolved in saline solution. Toxicity of sub-chronic cisplatin was evaluated following six daily i.p. injections of cisplatin (3 mg/kg) starting at day 0 and mice were sacrificed 72h after the last injection of cisplatin. KW6002 (3 mg/kg) was tested against sub-chronic cisplatin toxicity, the drug was administered daily i.p. from day -5 to day 7 (Supplementary Figure 1D).