The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury

doi:10.1038/cddis.2014.241

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury
	Li, J-X 1; Feng, J-M 1; Wang, Y.1; Li, X-H 1; Chen, X-X 2; Su, Y.1; Shen, Y-Y 1; Chen, Y.1 ; Xiong, B.2 ; Yang, C-H 2
刊名	CELL DEATH & DISEASE
	2014-06
卷号	5
ISSN号	2041-4889
DOI	10.1038/cddis.2014.241
文献子类	Article
英文摘要	Receptor-interacting protein (RIP) 3 is a critical regulator of necroptosis and has been demonstrated to be associated with various diseases, suggesting that its inhibitors are promising in the clinic. However, there have been few RIP3 inhibitors reported as yet. B-Raf(V600E) inhibitors are an important anticancer drug class for metastatic melanoma therapy. In this study, we found that 6 B-Raf inhibitors could inhibit RIP3 enzymatic activity in vitro. Among them, dabrafenib showed the most potent inhibition on RIP3, which was achieved by its ATP-competitive binding to the enzyme. Dabrafenib displayed highly selective inhibition on RIP3 over RIP1, RIP2 and RIP5. Moreover, only dabrafenib rescued cells from RIP3-mediated necroptosis induced by the necroptosis-induced combinations, that is, tumor necrosis factor (TNF)alpha, TNF-related apoptosis-inducing ligand or Fas ligand plus Smac mimetic and the caspase inhibitor z-VAD. Dabrafenib decreased the RIP3-mediated Ser358 phosphorylation of mixed lineage kinase domain-like protein (MLKL) and disrupted the interaction between RIP3 and MLKL. Notably, RIP3 inhibition of dabrafenib appeared to be independent of its B-Raf inhibition. Dabrafenib was further revealed to prevent acetaminophen-induced necrosis in normal human hepatocytes, which is considered to be mediated by RIP3. In acetaminophen-overdosed mouse models, dabrafenib was found to apparently ease the acetaminophen-caused liver damage. The results indicate that the anticancer B-Raf(V600E) inhibitor dabrafenib is a RIP3 inhibitor, which could serve as a sharp tool for probing the RIP3 biology and as a potential preventive or therapeutic agent for RIP3-involved necroptosis-related diseases such as acetaminophen-induced liver damage.
资助项目	National Natural Science Foundation of China[81373446] ; National Natural Science Foundation of China[81025020] ; National Natural Science Foundation of China[81321092] ; National Basic Research Program of China[2012CB932502] ; National Science and Technology Major Project of China[2012ZX09301-001-002] ; 'Interdisciplinary Cooperation Team' Program for Science and Technology Innovation of the Chinese Academy of Sciences[00000000] ; State Key Laboratory of Drug Research[SIMM1203ZZ-0103]
WOS关键词	PROTEIN-KINASE 3 ; B-RAF KINASE ; CELL-DEATH ; ANTITUMOR-ACTIVITY ; TNF-ALPHA ; NECROSIS ; INFLAMMATION ; BRAF ; PROLIFERATION ; NECROSTATINS
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000338778500006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277040]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Miao, Z-H
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Li, J-X,Feng, J-M,Wang, Y.,et al. The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury[J]. CELL DEATH & DISEASE,2014,5.
APA	Li, J-X.,Feng, J-M.,Wang, Y..,Li, X-H.,Chen, X-X.,...&Miao, Z-H.(2014).The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury.CELL DEATH & DISEASE,5.
MLA	Li, J-X,et al."The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury".CELL DEATH & DISEASE 5(2014).