Different effects of erythropoietin in cisplatin- and docetaxel-induced neurotoxicity: an in vitro study.
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a side effect limiting cisplatin (CDDP) and docetaxel (DOCE) treatment. Erythropoietin (EPO) is a hematopoietic growth factor also displaying neurotrophic properties. Evidence suggests that EPO's neuroprotective action may rely on PI3K/AKT pathway activation; however, data regarding the EPO neuroprotective mechanism are still limited. This study evaluated the effect of EPO on organotypic cultures of rat dorsal root ganglia (DRG) and in primary cultures of DRG-dissociated sensory neurons exposed to CDDP- and DOCE-induced neurotoxicity, aiming to investigate EPO's neuroprotective mechanism. Subsequently, the levels of AKT expression and activation were analyzed by Western blot in neurons exposed to CDDP or DOCE; AKT's role was further evaluated by using a chemical inhibitor of AKT activation, wortmannin. In these models EPO, was protective against both CDDP- and DOCE-induced cell death and against CDDP-induced neurite elongation reduction. A modulation of AKT activation was observed in CDDP-treated neurons, and the presence of wortmannin prevented EPO's neuroprotective action against CDDP toxicity but did not have any effect on EPO's protection against DOCE-induced toxicity, thus ruling out the PI3K-AKT pathway as the mechanism of EPO's effect in neuronal death prevention after DOCE exposure. Our results confirm in vitro the effectiveness of EPO as a neuroprotectant against both CDDP- and DOCE-induced neurotoxicity. In addition, a role of PI3K/AKT in EPO's protection against CDDP, but not against DOCE, neurotoxicity was shown, suggesting that alternative pathways could be involved in EPO's neuroprotective activity.
Maggioni
Daniele
D
Department of Neuroscience and Biomedical Technologies, University of Milan Bicocca, Monza, Italy.
Nicolini
Gabriella
G
Chiorazzi
Alessia
A
Meregalli
Cristina
C
Cavaletti
Guido
G
Tredici
Giovanni
G
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002478:Cells, Cultured; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity; D000077143:Docetaxel; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D043823:Taxoids / Q000037:antagonists & inhibitors / Q000633:toxicity
D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D043823:Taxoids; D004921:Erythropoietin; D000077143:Docetaxel; D002945:Cisplatin