Gefitinib Analogue V1801 Induces Apoptosis of T790M EGFR-Harboring Lung Cancer Cells by Up-Regulation of the BH-3 Only Protein Noxa 英文参考文献.docVIP

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Gefitinib Analogue V1801 Induces Apoptosis of T790M EGFR-Harboring Lung Cancer Cells by Up-Regulation of the BH-3 Only Protein Noxa 英文参考文献.doc

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Gefitinib Analogue V1801 Induces Apoptosis of T790M EGFR-Harboring Lung Cancer Cells by Up-Regulation of the BH-3 Only Protein Noxa 英文参考文献

GefitinibAnalogueV1801InducesApoptosisofT790M EGFR-HarboringLungCancerCellsbyUp-Regulationof theBH-3OnlyProteinNoxa BoZhang1,3,JiaoJiao2,YingLiu4,Liang-XiaGuo1,BoZhou1,Gang-QinLi2,Zhu-JunYao2* ,Guang- BiaoZhou1* 1Division of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, ChineseAcademyof Sciences, Beijing, China, 2State Key Laboratory ofBioorganic and Natural Products Chemistry,Shanghai Institute ofOrganic Chemistry, Chinese AcademyofSciences,Shanghai,China,3GraduateUniversityoftheChineseAcademyofSciences,Beijing,China,4TheShenzhenKeyLaboratoryofGeneandAntibody Therapy,DivisionofLifeandHealthSciences,GraduateSchoolatShenzhen,TsinghuaUniversity,Shenzhen,China Abstract Treatmentofnon-smallcelllungcancer (NSCLC)withdrugs targetingtheepidermalgrowthfactorreceptor(EGFR),e.g., gefitinib and erlotinib, will eventually fail because of the development of secondary mutations such as T790M in EGFR. Strategiestoovercomethisresistancearethereforeanurgentneed.Inthisstudy,wesynthesizedadozenofnovelgefitinib analogues and evaluated their effects on L858R/T790M-EGFR harboring NSCLC cells, and reported that one of these gefitinib mimetics, N-(2-bromo-5-(trifluoromethyl) phenyl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine (hereafter,V1801),triggeredapoptosisoftheNSCLCcellsandovercamegefitinib-resistanceinmiceinoculatedwithNCI- H1975cells.ThoughV1801onlymoderatelyinhibitedEGFRkinaseactivity,itmarkedlyinducedtheexpressionoftheBH3- onlyproteinNoxa,andNoxasilencingsignificantlyreducedV1801-inducedapoptosisofNCI-H1975cells.Itisshowedthat V1801 interfered with the expression of the transcription factor c-Myc and the extracellular signal regulated kinase (Erk) pathway.V1801 incombinationwithproteasomeinhibitor bortezomib exerted enhancedcytotoxicityin NCI-H1975cells possibly due to potentiated induction of Noxa expression. These data indicate that gefinitib analogues with w