期刊
BIOCHEMICAL PHARMACOLOGY
卷 188, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114542
关键词
KW-2449; Cisplatin; Necroptosis; Nephrotoxicity; RIPK1
资金
- National Natural Science Foundation of China [81773075]
- Shanghai International Cooperation and Exchange Project [18410720600]
- Fundamental Research Funds for the Central Universities
This study identified that the multitargeted kinase inhibitor KW-2449 inhibits cisplatin-induced necroptosis by directly inhibiting RIPK1 kinase activity, while enhancing cisplatin-induced apoptosis in cancer cells. Oral administration of KW-2449 alleviated renal cell necrosis and reduced pro-inflammatory responses in mouse models of cisplatin-induced nephrotoxicity, showing its potential for treating cisplatin-induced nephrotoxicity.
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.
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