Identification of pimavanserin tartrate as a potent Ca^(2+)-calcineurin-NFAT pathway inhibitor for glioblastoma therapy  

作　　者：Zhen-zhen Liu Xiao-ning Liu Rui-cheng Fan Yu-ping Jia Qing-ke Zhang Xin-qing Gao Yu-qing Wang Meng-qing Yang Li-zhen Ji Yong-qing Zhou Hong-li Li Ping Li Bo Tang 

机构地区：[1]College of Chemistry,Chemical Engineering and Materials Science,Key Laboratory of Molecular and Nano Probes,Ministry of Education,Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong,Institutes of Biomedical Sciences,Shandong Normal University,Jinan 250014,China [2]Department of Histology and Embryology,College of Basic Medicine,Army Medical University,Chongqing 400038,China [3]Shandong Academy of Pharmaceutical Sciences,Jinan 250014,China [4]School of Information Science and Engineering,Shandong Normal University,Jinan 250101,China [5]College of Life Sciences,Shandong Normal University,Jinan 250014,China

出　　处：《Acta Pharmacologica Sinica》2021年第11期1860-1874,共15页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(21927811,91753111,21907061,62006144);the Key Research and Development Program of Shandong Province(2018YFJH0502);the Postdoctoral Research Foundation of China(2017M622225);Postdoctoral Innovation Foundation of Shandong Province(201703009);Jinan Innovative Team Project(2019GXRC039).

摘　　要：Glioblastoma multiforme(GBM)is the most common and malignant type of primary brain tumor,and 95%of patients die within 2 years after diagnosis.In this study,aiming to overcome chemoresistance to the first-line drug temozolomide(TMZ),we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy.To accelerate the drug’s clinical application,we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors.After screening a set of 93 FDA-approved drugs with simple structures,we identified pimavanserin tartrate(PIM),an effective 5-HT2A receptor inverse agonist used for the treatment of Parkinson’s disease-associated psychiatric symptoms,as having the most potent inhibitory activity against the NFAT signaling pathway.Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry(SOCE)and subsequent NFAT activity.In cellula,PIM significantly suppressed the proliferation,migration,division,and motility of U87 glioblastoma cells,induced G1/S phase arrest and promoted apoptosis.In vivo,the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM.Unbiased omics studies revealed the novel molecular mechanism of PIM’s antitumor activity,which included suppression of the ATR/CDK2/E2F axis,MYC,and AuroraA/B signaling.Interestingly,the genes upregulated by PIM were largely associated with cholesterol homeostasis,which may contribute to PIM’s side effects and should be given more attention.Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.

关 键 词：pimavanserin tartrate drug repurposing SOCE NFAT signaling pathway GLIOBLASTOMA 

分 类 号：R965[医药卫生—药理学]