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

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. LLC1 cells (Lewis Lung Cancer cells, ATCC® CRL-1642™) were cultured in DMEM with 10% foetal calf serum and penicillin-streptomycin. LLC1 cells (107) in PBS:matrigel (1:1, for a total volume of 100 µL) were subcutaneously injected in the right flank of animals. Tumors were measured twice a week with calipers and their volumes were estimated using the following equation: ½ (length x width2). When tumor volume reached 100 mm3, mice were randomly ascribed to the four experimental groups (Vehicle, KW6002, Cisplatin and Cisplatin/KW6002) as indicated in Supplementary Figure 1E.