文献类型：期刊文献

中文题名：Selective targeting p53^(WT) lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

英文题名：Selective targeting p53^(WT) lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

作者：Wei-qiang LU[1];Qian HU[1];Jian LI[1];Jin HUANG[1]

机构：[1]Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology

年份：2017

卷号：31

期号：10

起止页码：960

中文期刊名：中国药理学与毒理学杂志

外文期刊名：Chinese Journal of Pharmacology and Toxicology

收录：CSTPCD;;Scopus;北大核心:【北大核心2014】；CSCD:【CSCD2017_2018】；

基金：supported by National Natural Science Foundation of China(31371485,81402482,91313303 and 81573020);CAS Key Laboratory of Receptor Research,the Shanghai Committee of Science and Technology(15431902000)

语种：英文

中文关键词：non-small cell lung cancer;Cyclophilin A inhibitor;p53-72R polymorphsm

外文关键词：non-small cell lung cancer Cyclophilin A inhibitor p53-72R polymorphsm

摘要：OBJECTIVE To explored the potential of pharmacological stabilization and reactivation of p53 for targeted cancer therapies.METHODS The cytotoxicity of a potent Cyclophilin A(CypA)inhibitor HL001 was tasted against a panel of cancer cell lines.The genotypes and activation of p53 were compared with the cytotoxicity profile of HL001.Two-dimensional(2D)PAGE analysis was performed to investigate differentially expressed proteins that involves in the anti-proliferation effects of HL001.Pull-down and Co-IP were used to confirmed the new identified PPI between CypA and G3BP1 and orthotopic animal model of lung cancer was used to tested the anti-tumor activity of HL001 in vivo.RESULTS We identify a novel CypA small molecule inhibitor HL001 that induces non-small cell lung cancer(NSCLC)cell cycle arrest and apoptosis via restoring p53 expression.We find that HL001 stabilizes p53 through inhibiting the MDM2-mediated p53 ubiquitination.Further mechanistic studies reveal that the downregulation of G3BP1 and the induction of reactive oxygen species and DNA damage by HL001 contribute to p53 stabilization.Surprisingly,HL001 selectively suppresses tumor growth in p53wildtype NSCLC harboring Arg72 homozygous alleles(p53-72R)through disrupting interaction between MDM2 and p53-72R in a CypA dependent manner.Moreover,combining HL001 with cisplatin synergistically enhance tumor regression in orthotopic NSCLC mouse model.CONCLUSION Pharmacologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.
OBJECTIVE To explored the potential of pharmacological stabilization and reactivation of p53 for targeted cancer therapies.METHODS The cytotoxicity of a potent Cyclophilin A（CypA）inhibitor HL001 was tasted against a panel of cancer cell lines.The genotypes and activation of p53 were compared with the cytotoxicity profile of HL001.Two-dimensional（2D）PAGE analysis was performed to investigate differentially expressed proteins that involves in the anti-proliferation effects of HL001.Pull-down and Co-IP were used to confirmed the new identified PPI between CypA and G3BP1 and orthotopic animal model of lung cancer was used to tested the anti-tumor activity of HL001 in vivo.RESULTS We identify a novel CypA small molecule inhibitor HL001 that induces non-small cell lung cancer（NSCLC）cell cycle arrest and apoptosis via restoring p53 expression.We find that HL001 stabilizes p53 through inhibiting the MDM2-mediated p53 ubiquitination.Further mechanistic studies reveal that the downregulation of G3BP1 and the induction of reactive oxygen species and DNA damage by HL001 contribute to p53 stabilization.Surprisingly,HL001 selectively suppresses tumor growth in p53wildtype NSCLC harboring Arg72 homozygous alleles（p53-72R）through disrupting interaction between MDM2 and p53-72R in a CypA dependent manner.Moreover,combining HL001 with cisplatin synergistically enhance tumor regression in orthotopic NSCLC mouse model.CONCLUSION Pharmacologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.