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Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation

文献类型：期刊论文

作者Yang, Ying4,5,6; Suo, Na3,6; Cui, Shi-hao5,6; Wu, Xuan2; Ren, Xin-yue5,6; Liu, Yin2; Guo, Ren1,6; Xie, Xin1,2,3,4,5,6
刊名ACTA PHARMACOLOGICA SINICA
出版日期2024-06-13
页码13
关键词oligodendrocyte differentiation oligodendrocyte progenitor cell remyelination trametinib MEK inhibitor MEK/ERK pathway
ISSN号1671-4083
DOI10.1038/s41401-024-01313-9
通讯作者Xie, Xin(xxie@simm.ac.cn)
英文摘要Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays the best effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.
WOS关键词SIGNAL-REGULATED KINASE ; EMBRYONIC STEM-CELLS ; PROGENITOR CELLS ; ERYTHROID-DIFFERENTIATION ; INDUCED DEMYELINATION ; LIVER-REGENERATION ; GROUND-STATE ; PATHWAY ; INHIBITION ; MAPK
资助项目Ministry of Science and Technology of China[2022ZD0204700] ; Ministry of Science and Technology of China[2022YFA1104700] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82003723] ; National Natural Science Foundation of China[82330113] ; National Natural Science Foundation of China[32000504] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2023295] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2022280] ; Taishan Scholars Program
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001247216000002
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/311428]  
专题新药研究国家重点实验室
通讯作者Xie, Xin
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Ying,Suo, Na,Cui, Shi-hao,et al. Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation[J]. ACTA PHARMACOLOGICA SINICA,2024:13.
APA Yang, Ying.,Suo, Na.,Cui, Shi-hao.,Wu, Xuan.,Ren, Xin-yue.,...&Xie, Xin.(2024).Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation.ACTA PHARMACOLOGICA SINICA,13.
MLA Yang, Ying,et al."Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation".ACTA PHARMACOLOGICA SINICA (2024):13.

入库方式： OAI收割

来源：上海药物研究所

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