作用于MAPK信号转导系统的抗肿瘤药物研究

MAPK,3(,100083):(MAPK),,,,MAPK,,RasRafC:;;c2Jun;p38;:R962.1:A:167420440(2008)0320178207AntineoplasticagentstargetingonMAPKsignaltransductionsystemYANGYa2ping,LIMin(StateKeyLaboratoryofNaturalandBiomimeticdrugs,HealthScienceCenter,PekingUniversity,Beijing100083,China)Abstract:Mitogen2activatedproteinkinases(MAPKs)areimportantsignaltransductionsystemthatcon2trolawiderangeofcellularprocesses,suchasgrowth,proliferation,differentiation,apoptosis,adhesionandmigration,andthenrelatedtothedevelopmentoftumorsanddrugresistance.Therefore,MAPKscouldberecognizedasoneoftargetsforanticancerdrugs.Inrecentyears,ahugenumberofanticancerdrugstargetingonMAPKsignaltransductionsystemhavebeenreported,inwhichmanymoleculesin2volved,includingepidermalgrowthfactorreceptor,Ras,Raf,proteinkinaseC,glutathionetransferaseandsoon.Keywords:mitogen2activatedproteinkinases;extracellularsignal2regulatedkinases;c2JunN2terminalkinase;p38mitogen2activatedproteinkinase;antineoplasticagents:2007211216:,,,:,E2mail:[e-mail]3:,,,:,Tel:[phone],E2mail:[e-mail],,WHO,20201500[1],(MAPK),,,,,,1MAPKMAPK/,(),MAPK:(ERK1/2),c2Jun(JNK)/(SAPK),p38(p38MAPK)ERK5/(BMK1)ERK3,4,6,7,8[2,3]MAPK,:MAPK(MAPKKK),MAPK(MAPKK),MAPKMAPK,2,871JournalofInternationalPharmaceuticalResearch2008Jun;35(3)©1994-2009ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.[4,5](1),MAPK,MAPK[69],(1)1MAPK1MAPKEGFR,HER1/neu[10]tipifarnibRas,[11]Raf,VEGFR,PDGFR[12]PD184352MEK1/2[13]TLK286GSTp2JNK,[14,15]2MAPK211ERK1/2ERK,ERK,,ERK1/2Ras2Raf2MEK1/2(EGFR)Ras,ERK1/2EGFR22(Grb2)2(Sos)2Ras2Raf2MEK1/22ERK1/2,,21111EGFR,EGFR(HER1/ErbB21),HER2/neu(ErbB22),HER3(ErbB23)HER4(ErbB24),,EGFR2:(1)EGFR:EGFR,EGFR(cetuximab,MC2C225)(tras2tuzumab,Herceptin)EGFRHER2/neuEGFR,EGFRHER2,[16],(2)EGFR:EGFR,PD21530351EGFREGFR,(gefitinib,Iressa,ZD1839),,20035FDA,,12005,,FDA,;,[17](erlotinib,Tarceva,OSI2744),2004FDA,,EGFR,EGFR2EGFR,EKB2569CI21033(vandetanib,Zactima,ZD26474),EGFR,EGFR,,1EGFR(lapatinib,Tykerb,97120086353©1994-2009ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.)EGFRHER2,HER2HER2,,,HER228%[10],,8%,20073FDA21112RasrasRasGTP,GTPGDP,30%rasrasRasGTP,GTP,Ras,,,Ras,,[6],Ras3:(1)(farnesyltransferaseinhibitor,FTI)Ras,,RasRas,RasMAPKFTI,[18](manumycin)FTI,IL26,Ras,,FTItipifarnib(R115777),,[11]lonafarnib(SCH66336),[19],BMS214662[20](2)2=(geranylgera2nyltransferaseinhibitor,GGTI)L778123=,K2Ras(3)32232A(HMG2CoA)HMG2CoA,,Ras,,Ras21113RafRaf/,RafRaf,,Raf,RafRaf,Raf2:(1)RafRaf,(sorafenib,BAY4329006),Raf,Ras,Ras,Raf,VEGFRPDGFR[7,12]Raf,FDA200512,(2)RafRaf,Raf,(geldanamycin)Raf142323,17AAGHsp90Raf21Hsp90,Raf,,raf,RafISIS513220RafmRNA3,RafmRNA,,,081JournalofInternationalPharmaceuticalResearch2008Jun;35(3)©1994-2009ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.[2123]21114MEK1/2MEK1/2ERK1/2,1MEK1/2PD98059U0126,2MEK1/2PD184352(CI21040)PD0325901PD1843521MEK,MEK1/2,ERK1/2,,,;,PD184352ERK[13]PD0325901PD184352,PD184352,,,21115ERK1/2MAPK(MAPkinasephosphatases,MKP)MAPK/,,MKP24MKP23/6[24]C(PKC)PKCRas/MAPK,ERK1/2,PKC,Balanol[25],ATPPKC,PKC,PTENERK,PTEN()PTENMAPKERK,,EGFR[26],PTENPETNERK1/2,212JNKJNK/SAPK,JNK,c2Jun,ATF2Elk1JNK,,,21211GST2JNKJNK(GST),(GSH)(),(GST/GSTp),MAPKGSTpJNK,JNK;H2O2GSTp,GSTp2JNK,JNK[27]GSTp2JNK,JNK,[14]TLK199GSH,GSTp,JNKGSTp,JNK,TLK199,,TLK199GST,[28]TLK286GSTp,JNKGSTp,TLK2864,2TLK286,,2TLK286,[15]TLK286(72nitro22,1,3,2benzoxadiazolederivatives,NBD),GST,,NBDJNK2GSTp[8]NOJS2K,CB232100PABA/NOGSTp,JNK,[29,30],PABA/NO21212JNK[31],NB4,JNK,JNKSP600125NB4,JNK,caspase,,SP600125NB4,NB4NB4JNK18120086353©1994-2009ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(bortezomib)FDA1,26S,26S,,,,(MM),p38MAPK,SCIO2469,p38MAPKHsp27MMp38MAPKp53,Bcl2XMcl21MM,p38MAPKMMp38,hsp27,MM,MM,[32,33]21312p38MAPK[9,34],p38MAPK,p38MAPKHeLa,4p38MAPKp38MAPKSB203580SB20219046%42%[35],p38MAPK,p38MAPK3MAPKMAPK,MAPK,,MEK;,[36,37]tBHQMAPK,Nrf2ARE,,,MAPKERK,JNKp38MAPKMAPK(cross2talk),,PAK1JNKp38MAPK;MAPKKK,MEKK3MEK1,MKK4;MAPKK,MKK4JNKp38MAPK;MAPK,ATF2JNKp38;,,ATF2c2Jun,,,4MAPK,,,MAPKMAPK,,,MAPK,MAPK,,MAPK,,MAPK,[1]Anonymous.TheWorldCancerReport-themajorfindings[J].CentEurJPublicHealth,2003,11(3):177-179.[2]JohnsonGL,LapadatR.Mitogen2activatedproteinkinasepath2waysmediatedbyERK,JNK,andp38proteinkinases[J].Sci2ence,2002,298(5600):1911-1912.[3]BogoyevitchMA,CourtNW.Countingonmitogenactivatedpro2teinkinases2ERKs3,4,5,6,7and8[J].CellSignal,2004,281JournalofInternationalPharmaceuticalResearch2008Jun;35(3)©1994-2009ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(12):1345-1354.[4]EngelbergD.Stress2activatedproteinkinases2tumorsuppressorsortumorinitiators?[J].SeminCancerBiol,2004,14(4):271-282.[5]DentP,YacoubA,Fisher,PB,etal.MAPKpathwaysinradia2tionresponses[J].Oncogene,2003,22(37):5885-5896.[6]AppelsNM,BeijnenJH,SchellensJH.Developmentoffarnesyltransferaseinhibitors:areview[J].Oncologist,2