典型文献
Upregulation of wild-type p53 by small molecule-induced elevation of NQO1 in non-small cell lung cancer cells
文献摘要：
The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms,and its reactivation represents an attractive therapeutic strategy for cancers.Here,we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer(NSCLC)cells which express wild type(wt)p53,in contract to its much weaker cytotoxicity on cells with mutant p53.RYL-687 upregulated p53 in cells with wt but not mutant p53,and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound.RYL-687 induced production of reactive oxygen species(ROS)and upregulation of Nrf2,leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1(NQO1)that can protect p53 by inhibiting its degradation by 20S proteasome.RYL-687 bound NQO1,facilitating the physical interaction between NQO1 and p53.NQO1 was required for RYL-687-induced p53 accumulation,because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine,drastically suppressed RYL-687-induced p53 upregulation.Moreover,a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model.These data indicate that targeting NQO1 is a rational strategy to reactivate p53,and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53.
文献关键词：
中图分类号：
作者姓名：
Hong Yu;Hong-ying Gao;Hua Guo;Gui-zhen Wang;Yi-qing Yang;Qian Hu;Li-jun Liang;Qun Zhao;Da-wei Xie;Yu Rao;Guang-biao Zhou
作者机构：
School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 100029,China;State Key Laboratory of Molecular Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China;MOE Key Laboratory of Protein Sciences,School of Pharmaceutical Sciences,MOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology,and School of Medicine and Collaborative Innovation Center of Biotherapy,Tsinghua University,Beijing 100084,China;Hubei University of Medicine,Shiyan 442000,China
文献出处：
引用格式：
[1]Hong Yu;Hong-ying Gao;Hua Guo;Gui-zhen Wang;Yi-qing Yang;Qian Hu;Li-jun Liang;Qun Zhao;Da-wei Xie;Yu Rao;Guang-biao Zhou-.Upregulation of wild-type p53 by small molecule-induced elevation of NQO1 in non-small cell lung cancer cells)[J].中国药理学报（英文版）,2022(03):692-702
A类：
RYL,quinoneoxidoreductase,NSCLCs
B类：
Upregulation,wild,type,p53,by,small,molecule,induced,elevation,NQO1,lung,cells,tumor,suppressor,usually,inactivated,somatic,mutations,malignant,neoplasms,its,reactivation,represents,attractive,therapeutic,strategy,cancers,Here,reported,that,new,quinolone,compound,significantly,inhibited,which,contract,much,weaker,cytotoxicity,mutant,upregulated,but,not,ectopic,expression,enhanced,anti,activity,this,production,reactive,oxygen,species,ROS,upregulation,Nrf2,leading,NAD,protect,inhibiting,degradation,20S,proteasome,bound,facilitating,physical,interaction,between,was,required,accumulation,because,silencing,specific,siRNA,inhibitor,uridine,drastically,suppressed,Moreover,related,prodrug,growth,NOD,SCID,mice,inoculated,patient,derived,xenograft,mouse,model,These,data,indicate,targeting,rational,reactivate,stabilizer,bears,potentials
AB值：
0.515339
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