Erythropoietin reduces cisplatin-induced neurotoxicity without impairment of cytotoxic effects against tumor cells

Abstract

Cisplatin, a widely used chemotherapeutic is approved for the management of various solid tumors. Administration of cisplatin is associated with induction of significant toxicities that include neurotoxicity and nephrotoxicity, the latter leading to severe and debilitating anemia. Since erythropoietin, a hematopoietic growth factor that corrects chemotherapy-induced anemia, reduces transfusion requirements and seems to improve the patient's quality of life, has been shown to exert cytoprotective effects we decided to investigate its direct influence on cisplatin-induced neurotoxicity against primary cortical neurons isolated from rats. We observed that pre-treatment of neurons with erythropoietin significantly protects these cells from cisplatin-induced cytotoxicity. These effects correlated with amelioration of cisplatin-mediated activation of ERK1/2 kinases and decreased cleavage of caspase 3. Similarly to erythropoietin, a selective ERK1/2 inhibitor significantly reduced cisplatin-induced cytotoxicity against neuronal cells. Importantly, using the same experimental setting we did not observe any protection from cisplatin cytotoxicity against four established tumor cell lines. Altogether our studies confirm that erythropoietin might be an effective cytoprotective agent that reduces cisplatin-induced neurotoxicity.