MG-132isapotent,non-specific20Sproteasomeinhibitor,withIC50of24.2nMfortheβ5chymotrypsin-likeactivesite.CustomerValidation•CancerLett.2017Dec1;410:112-123.•Oncotarget.2016May10;7(19):27176-84.•SciRep.2017Jul5;7(1):4738.•SciRep.2017Jun7;7(1):2929.•JInorgBiochem.2017Jul19;175:92-100.•BiochemBiophysResCommun.2017Sep2;490(4):1168-1175.•CanJPhysiolPharmacol.2016Nov30:1-11.•CanJPhysiolPharmacol.2016Sep19.•ActaNeuropatholCommun.2017Sep6;5(1):67.•BloodAdvances.20171:1773-1785.•HarvardMedicalSchoolLINCSLIBRARYDescriptionMG-132isapotent,non-specific20Sproteasomeinhibitor,withIC50of24.2nMfortheβ5chymotrypsin-likeactivesite.IC50&TargetIC50:24.2nM(chymotrypsin-likeactivity)[1]InVitroDose-dependentinhibitionofcellgrowthisobservedinHeLacellswithanIC50ofapproximately5μMMG132for24h.MG132inhibitsthegrowthofHeLacellsviainducingthecellcyclearrestaswellastriggeringapoptosis[2].MG-132inhibitsC6gliomacellproliferationinatime-anddose-dependentmanner(theIC50valueat24his18.5μM).MG-132(18.5μM)suppressestheproteasomeactivitybyabout70%at3h.MG-132inducesapoptosisviadown-regulationofantiapoptoticproteinsBcl-2andXIAP,up-regulationofpro-apoptoticproteinBaxandcaspase-3,andproductionofcleavedC-terminal85kDaPARP.MG-132alsocausesamorethan5-foldincreaseofreactiveoxygenspecies[3].TheIC50ofMG-132againstHeLa,CaSki,andC33AcervicalcancercellsviABIlityafter48hofincubationis2.1,3.2,and5.2μM,respectively[4].InVivoTheinvivoantitumoractivityofMG-132againstcervicalcancerisexaminedusings.c.xenograftmodels.MG-132isinjectedat1mg/kgusingthefollowingschedule:days1,4,8,12,1518,23,and26formicebearingHeLatumors.ThegrowthinhibitionratesofMG132comparedtocontrolis49%[4].MG-132(i.p.,0.1mg/kg/day)attenuatespressure-overload-inducedcardiachypertrophyandimprovescardiacfunctioninaBDominalaorticbanding(AAB)ratsthroughregulationofERK1/2andJNK1signalingpathways[5].References[1].BraunHA,etal.Tripeptidemimeticsinhibitthe20Sproteasomebycovalentbondingtotheactivethreonines.JBiolChem.2005Aug5;280(31):28394-401.[2].HanYH,etal.TheeffectofMG132,aproteasomeinhibitoronHeLacellsinrelationtocellgrowth,reactiveoxygenspeciesandGSH.OncolRep.2009Jul;22(1):215-21.[3].FanWH,etal.ProteasomeinhibitorMG-132inducesC6gliomacellapoptosisviaoxidativestress.ActaPharmacolSin.2011May;32(5):619-25.[4].MatsumotoY,etal.EnhancedefficacyagainstcervicalcarcinomasthroughpolymericmicellesphysicallyincorporatingtheproteasomeinhibitorMG132.CancerSci.2016Jun;107(6):773-81.[5].ChenB,etal.MG132,aproteasomeinhibitor,attenuatespressure-overload-inducedcardiachypertrophyinratsbymodulationofmitogen-activatedproteinkinasesignals.ActaBiochimBiophysSin(Shanghai).2010Apr;42(4):253-8.PreparingStockSolutionsConcentrationVolumeMass1mg5mg10mg1mM2.1025mL10.5126mL21.0252mL5mM0.4205mL2.1025mL4.2050mL10mM0.2103mL1.0513mL2.1025mLPleaserefertothesolubilityinformationtoselecttheappropriatesolvent.KinaseAssay[3]Aftergrowingonsix-wellplates(3×105cells/well)for24h,C6gliomacellsaretreatedwitheitherPBS(control)or18.5μMMG-132for3,6,12,or24hat37°C.CellsarethoroughlyscrapedfromtheculturedisheswithacellscraperandwashedwithcoldPBS.Aftercentrifugationfor10minat800×g,thecellpelletsaresUSPendedinice-coldbuffer(50mMTris-HCl,pH7.5,20μMATP,5mMMgCl2,1mMdithiothreitol,and20%glycerol)andhomogenizedwithaPyrexglassmicrohomogenizer(20strokes).Thehomogenateiscentrifugedat15000×gfor10minat4°Ctoobtainsupernatant.Proteinconcentrationisdeterminedusingproteinassaykits.Atotalof10μL(1μg/μL)ofeachfreshlymadesupernatantisincubatedina96-wellplateat37°Cfor30minwith10μLof300μMofSuccinyl-LLVY-AMCand85μLofassaybuffer(20mMTris-HCl,pH7.5,and20%glycerol).ReleaseoffluorescentAMCismeasuredwithaspectrofluorometerat440nmwithanexcitationwavelengthof380nm[3].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.CellAssay[3]MG-132isdissolvedinPBStoastorageconcentrationof50μM[3].C6gliomacellsareseededonto96-wellmicroplates(3×104cells/well)andculturedfor24h.ThecellsaretreatedwithPBSorMG-132finalconcentrationsof10,20,30,and40μM,respectively.CellviabilityisassessedusinganMTTassayat3,6,12,and24hafterMG-132treatment.Theabsorbancevalueat570nmisreadusinganautomaticmulti-wellspectrophotometer.C6gliomacells(3×105cells/well)areallowedtogrowoncoverslipsin6-wellcultureplatesfor24h.ThecellsarethentreatedwitheitherPBS(control)or18.5μMMG-132at37°Cfor24h.Cellsgrowingonglasscoverslipsarefixedinmethanolfor5minatroomtemperature.ThefixedcellsarewashedtwicewithPBSandthenincubatedwithHoechst33342for5minatroomtemperatureandobservedunderafluorescencemicroscope.Fragmentedorcondensednucleiarescoredasapoptotic[3].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalAdmiNISTration[4][5]MG-132isdissolvedinvehicle(saline)(Mice)[4].MG-132isdissolvedinvehicle(0.1%DMSO)(Rat)[5].Mice[4]C.B-17/lcr-scid/scidJclmiceareinoculateds.c.withHeLa,CaSki,orC33A(1×107cells).Tumorsareallowedtogrowfor1week.Micearekilledandtumorsareremoved.Tumorsarethencutinto2-mmdiameterpiecesands.c.transplantedinC.B-17/lcr-scid/scidJclmice(n=6pergroup).Oneweekafterinoculation,micearetreatedwithi.v.injectionofsaline(control),MG-132(1mg/kg/dose)twiceaweekfor4weeks.Thevolume(V)oftumorsismeasuredbeforeeveryinjection,asestimatedusingequationV=a×b2/2whereaandbaremajorandminoraxesofthetumormeasuredbyacaliper,respectively.Rat[5]MaleSprague-Dawleyrats(8weeksold,180-230g)areusedtoestablishpressure-overloadmodel.Allanimalsareseparatedintofourgroups(10ratspergroup):(i)vehicle-treatedshamgroup;(ii)MG-132-treatedshamgroup;(iii)vehicle-treatedabdominalaorticbanding(AAB)group;and(iv)MG-132-treatedAABgroup.Underintraperitonealpentobarbital(50mg/kg)anesthesia,AABiscreatedusinga5-0suturetiedtwicearoundtheabdominalaortainwhicha21-gaugeneedleisinserted.Theneedleisthenretractedyieldinga70-80%constrictionwithanouteraorticdiameterof~0.8mm.Intheshamsurgeryrats,thesamesurgeryisperformedexcepttheaortaisconstricted.AtDay3afterthesurgery,MG-132-treatedratsareintraperitoneallyinjectedwith0.1mg/kg/dayofMG-132for8weeks.Allcontrolanimalsareinjectedwithacorrespondingvolumeofvehicleonly(0.1%DMSO).MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.References[1].BraunHA,etal.Tripeptidemimeticsinhibitthe20Sproteasomebycovalentbondingtotheactivethreonines.JBiolChem.2005Aug5;280(31):28394-401.[2].HanYH,etal.TheeffectofMG132,aproteasomeinhibitoronHeLacellsinrelationtocellgrowth,reactiveoxygenspeciesandGSH.OncolRep.2009Jul;22(1):215-21.[3].FanWH,etal.ProteasomeinhibitorMG-132inducesC6gliomacellapoptosisviaoxidativestress.ActaPharmacolSin.2011May;32(5):619-25.[4].MatsumotoY,etal.EnhancedefficacyagainstcervicalcarcinomasthroughpolymericmicellesphysicallyincorporatingtheproteasomeinhibitorMG132.CancerSci.2016Jun;107(6):773-81.[5].ChenB,etal.MG132,aproteasomeinhibitor,attenuatespressure-overload-inducedcardiachypertrophyinratsbymodulationofmitogen-activatedproteinkinasesignals.ActaBiochimBiophysSin(Shanghai).2010Apr;42(4):253-8.MolecularWeight475.62FormulaC₂₆H₄₁N₃O₅CASNo.133407-82-6Storage4°C,protectfromlightShippingRoomtemperatureincontinentalUS;mayvaryelsewhereSolvent&Solubility10mMinDMSO*"

托烷司琼临床评价药物相关作用适应症托烷司琼CAS号:89565-68-4英文名称:Tropisetron英文同义词:icf205-930;TROPICACID;TROPISETRON;SS-TROPISETRON;BETA-TROPISETRON;Tropisetron(ICS205930);TROPISHTRONHYDROCHLORIDE;Indole-3-carbonylchloride;3-Tropanylindole-3-carboxylate;lαH，5Αh-Tropan-3α-ylindole-3-carboxylate中文名称:托烷司琼中文同义词:托普西隆;托普西龙;曲匹西龙;托烷司琼;Β-托烷司琼;CS-348;Β-内托烷司琼;吲哚-3-甲酰氯;Β-托烷司琼(光学异构体);Β-托烷司琼,托烷司琼异构体CBNumber:CB3236404分子式:C17H20N2O2分子量:284.35MOLFile:89565-68-4.mol化学性质安全信息用途供应商112化学性质安全信息用途供应商112托烷司琼化学性质熔点:201-202°C沸点:448.5±35.0°C(Predicted)密度:1.26储存条件:2-8°C溶解度:H2O:soluble形态:solid酸度系数(pKa):15.38±0.30(Predicted)颜色:whiteCAS数据库:Chemicalbook89565-68-4(CASDataBaseReference)安全信息WGKGermany:3托烷司琼化学药品说明书托烷司琼|药物应用信息托烷司琼性质、用途与生产工艺临床评价Sorbe等报道本品对含顺铂(剂量50～89mg/m2)化疗方案引起的急性呕吐完全控制率为63%。58例恶性肿瘤化疗所致恶心、呕吐者，应用托烷司琼或昂丹司琼8mg分别在同一病人前后2个化疗周期的第1d给药前30min静脉注射，并用地塞米松10mg静脉滴注。结果两药控制急性及迟发性恶心、呕吐的疗效基本相似，均可达81%～100%。本品对强致吐化疗药物顺铂的止吐疗效突出。药物相关作用饮食可略为延长本品的吸收。本品与利福平、苯巴比妥等肝酶诱导药同时使用，可加快代谢，故快代谢型者需增加剂量，慢者则不必。西咪替丁等肝酶抑制药对本品血药浓度无明显影响。适应症托烷司琼临床用于预防和治疗癌症化疗引起的恶心和呕吐。化学性质结晶，熔点201-202℃(二氯甲烷-乙酸乙酯)。单盐酸托烷司琼(TropisetronMonohydroehloride)：C17H20N2O2?HCI。[105826-92-4]。熔点283-285℃(分解)。用途有高效性和选择性的5-HT3受体拮抗剂。用于化疗所致的呕吐。用途为5-羟色胺拮抗药生产方法托品醇(I)和酰氯(Ⅱ)反应，可得托烷司琼。托烷司琼上下游产品信息上游原料托品醇下游产品