The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis.
Biochem Pharmacol
; 188: 114542, 2021 06.
Article
en En
| MEDLINE
| ID: mdl-33819469
ABSTRACT
Cisplatin (cis-dichloro-diammine platinum, CDDP) is a well-known chemotherapeutic drug against a broad spectrum of human malignancies. However, the clinical utility of this effective chemotherapy agent is dose limited by its toxic side effects such as nephrotoxicity and ototoxicity. Necroptosis is a form of programmed necrotic cell death that is mediated by serine/threonine kinases, RIPK1 and RIPK3, together with MLKL. In this study, we identified that the multitargeted kinase inhibitor KW-2449 inhibited cisplatin-induced necroptosis, while potentiated cisplatin-induced apoptosis in cancer cells. Mechanistic studies indicated that KW-2449 directly inhibited RIPK1 kinase activity to block necroptosis. Oral administration of KW-2449 attenuated renal cell necrosis and reduced pro-inflammatory responses in mouse models of cisplatin-induced nephrotoxicity. Taken together, our study shows that KW-2449 is a novel necroptosis inhibitor by targeting RIPK1 kinase activity and has great clinic potential for the treatment of cisplatin-induced nephrotoxicity.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Cisplatino
/
Sistemas de Liberación de Medicamentos
/
Proteína Serina-Treonina Quinasas de Interacción con Receptores
/
Necroptosis
/
Indazoles
/
Túbulos Renales Proximales
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Año:
2021
Tipo del documento:
Article