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.
Chunhua Rui  1 ,  Shen-Nan Shi  1 ,  Wenqing Ren  2 ,  Xia Qin  3 ,  Chunlin Zhuang  4 ,  Xiaofei Chen  5 ,  Gang Chen  2 ,  Jianqiang Yu  6 ,  Hong-Yang Wang  7 ,  Zhenyu Cai  8
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: [email protected].
  • 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: [email protected].
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.
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