坏死性下垂
裂谷1
顺铂
肾毒性
程序性细胞死亡
药理学
激酶
癌症研究
细胞凋亡
化学
医学
肾
化疗
内科学
生物化学
作者
Chunhua Rui,Shen-Nan Shi,Wenqing Ren,Xia Qin,Chunlin Zhuang,Xiaofei Chen,Gang Chen,Jianqiang Yu,Hongyang Wang,Zhenyu Cai
标识
DOI:10.1016/j.bcp.2021.114542
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI