The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis

Chunhua Rui; Shen-Nan Shi; Wenqing Ren; Xia Qin; Chunlin Zhuang; Xiaofei Chen; Gang Chen; Jianqiang Yu; Hong-Yang Wang; Zhenyu Cai

doi:10.1016/j.bcp.2021.114542

The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis

Biochem Pharmacol. 2021 Jun:188:114542. doi: 10.1016/j.bcp.2021.114542. Epub 2021 Apr 2.

Authors

Chunhua Rui¹, Shen-Nan Shi¹, Wenqing Ren², Xia Qin³, Chunlin Zhuang⁴, Xiaofei Chen⁵, Gang Chen², Jianqiang Yu⁶, Hong-Yang Wang⁷, Zhenyu Cai⁸

Affiliations

¹ Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
² Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
³ Department of General Surgery, The First Naval Hospital of Southern Theater Command, Zhanjiang 440803, China.
⁴ Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China; School of Pharmacy, Second Military Medical University, Shanghai 200433, China; College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, China.
⁵ School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
⁶ College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, China.
⁷ Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China; National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, China; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China. Electronic address: hywangk@vip.sina.com.
⁸ Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China; College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, China. Electronic address: drcaizhenyu@tongji.edu.cn.

PMID: 33819469
DOI: 10.1016/j.bcp.2021.114542

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.

Keywords: Cisplatin; KW-2449; Necroptosis; Nephrotoxicity; RIPK1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / toxicity
Cell Survival / drug effects
Cell Survival / physiology
Cells, Cultured
Cisplatin / toxicity*
Dose-Response Relationship, Drug
Drug Delivery Systems / methods*
HT29 Cells
Humans
Indazoles / administration & dosage*
Kidney Tubules, Proximal / drug effects*
Kidney Tubules, Proximal / enzymology
Kidney Tubules, Proximal / pathology
Male
Mice
Mice, Inbred C57BL
Necroptosis / drug effects*
Necroptosis / physiology
Piperazines / administration & dosage*
Protein Kinase Inhibitors / administration & dosage
Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors*
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism

Substances

Antineoplastic Agents
Indazoles
KW 2449
Piperazines
Protein Kinase Inhibitors
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk1 protein, mouse
Cisplatin