姜黄素通过抑制Notch1信号通路逆转人食管癌Eca-109-VCR细胞的耐药性

姜黄素通过抑制Notch1信号通路逆转人食管癌Eca-109-VCR细胞的耐药性摘要：背景：食管癌是消化道常见的恶性肿瘤，化疗是治疗食管癌的主要手段之一。然而，由于肿瘤细胞的耐药现象，化疗效果十分有限。因此，探寻新的治疗方法显得十分重要。

方法：本研究使用MTT法检测Eca-109/VCR细胞的药物敏感性，Westernblot分析Notch1信号通路相关蛋白的表达情况，流式细胞术检测Eca-109/VCR细胞在姜黄素干预下的凋亡、增殖及周期变化情况。

结果：本研究发现姜黄素可以显著抑制Eca-109/VCR细胞的生长和增殖，增强其对化疗药物顺铂的敏感性。同时，Notch1信号通路相关蛋白的表达也被抑制。流式细胞术结果表明，Eca-109/VCR细胞在姜黄素干预下凋亡率升高，细胞周期停留在G0/G1期。

结论：姜黄素可以通过抑制Notch1信号通路来逆转Eca-109/VCR细胞的耐药性，提高其对化疗药物的敏感性。

关键词：姜黄素，Notch1信号通路，耐药性，食管癌

ABSTRACT:

Background:Esophagealcancerisacommonmalignanttumorofthedigestivetract,andchemotherapyisoneofthemaintreatmentmeasuresforesophagealcancer.However,duetodrugresistanceoftumorcells,theeffectivenessofchemotherapyislimited.Therefore,exploringnewtreatmentmethodsisveryimportant.

Methods:Inthisstudy,MTTmethodwasusedtodetectthedrugsensitivityofEca-109/VCRcells,WesternblotwasusedtoanalyzetheexpressionofNotch1signalingpathway-relatedproteins,andflowcytometrywasusedtodetecttheapoptosis,proliferation,andcyclechangesofEca-109/VCRcellsundertheinterventionofcurcumin.

Results:ThisstudyfoundthatcurcumincansignificantlyinhibitthegrowthandproliferationofEca-109/VCRcells,andenhancetheirsensitivitytothechemotherapydrugcisplatin.Atthesametime,theexpressionofNotch1signalingpathway-relatedproteinswasalsoinhibited.FlowcytometryresultsshowedthattheapoptosisrateofEca-109/VCRcellsincreasedundertheinterventionofcurcumin,andthecellcyclewasarrestedintheG0/G1phase.

Conclusion:CurcumincanreversethedrugresistanceofEca-109/VCRcellsbyinhibitingtheNotch1signalingpathwayandimprovetheirsensitivitytochemotherapydrugs.

Keywords:Curcumin,Notch1signalingpathway,drugresistance,esophagealcanceEsophagealcancerisahighlylethalmalignanttumorwithhighincidenceandmortalityrates.Chemotherapyisoneofthemaintreatmentsforesophagealcancer,butdrugresistancehasbecomeamajorobstacleinitsclinicalapplication.Therefore,theexplorationofnewdrugstoreversedrugresistanceandimprovethesensitivityofesophagealcancercellstochemotherapydrugshasbecomeahottopicincurrentresearch.

Curcumin,anaturalpolyphenoliccompoundextractedfromturmeric,hasbeenshowntohaveanticancerpropertiesandcaninhibittheproliferation,invasion,andmigrationofcancercells.Inthisstudy,weaimedtoinvestigatethepotentialtherapeuticeffectofcurcuminondrug-resistantesophagealcancercellsandexploretheunderlyingmechanisms.

OurresultsshowedthatcurcumincouldeffectivelyreversethedrugresistanceofEca-109/VCRcells,asevidencedbytheincreasedsensitivityofcellstochemotherapydrugs.Mechanistically,curcuminsuppressedtheNotch1signalingpathwayanddownregulateditsdownstreamtargetgenes,suchasHes1andHey1,whichareinvolvedindrugresistanceandcancercellsurvival.Furthermore,curcumininducedapoptosisandcellcyclearrestintheG0/G1phaseofEca-109/VCRcells,whichcontributedtoitstherapeuticeffect.

Inconclusion,ourstudysuggeststhatcurcuminhasthepotentialtoovercomedrugresistanceinesophagealcancercellsbytargetingtheNotch1signalingpathway.Therefore,curcuminmayserveasapotentadjuvanttherapyforesophagealcancerpatientswhohavedevelopeddrugresistance.FurtherstudiesareneededtoinvestigatetheinvivoefficacyandsafetyofcurcumininesophagealcancertherapyPossibledirectionsforfurtherresearchincludeexploringthemechanismsunderlyingtheinteractionbetweencurcuminandtheNotch1signalingpathway.Forexample,itwouldbeinterestingtoinvestigatewhethercurcuminbindsdirectlytoNotch1oritsupstream/downstreamcomponents,orwhetheritmodulatestheexpressionoractivityofothersignalingpathwaysthatcross-talkwithNotch1.Moreover,itwouldbevaluabletoidentifybiomarkersthatpredicttheresponseofesophagealcancercellstocurcumin,aswellastheoptimaldosinganddurationofcurcumintreatment.

Anotherareaofinterestisthecombinationofcurcuminwithotheranticanceragents,eithercytotoxicortargeted.Severalstudieshavereportedsynergisticeffectsofcurcuminwithconventionalchemotherapydrugs,suchas5-fluorouracil,cisplatin,anddoxorubicin,invariouscancertypes(Dhandapanietal.,2016).Theunderlyingmechanismsoftheseeffectsarelikelytobemultifactorial,involvinginhibitionofdrugeffluxpumps,enhancementofdruguptakeandintracellularaccumulation,reductionofdrugmetabolismandbioactivation,andmodulationofDNAdamageandrepairpathways.Hence,itwouldbeworthwhiletoinvestigatewhethersuchsynergiesexistbetweencurcuminandchemotherapeuticagentsinesophagealcancercells,andwhethertheycanovercomedrugresistance.

Furthermore,itwouldbeinterestingtocombinecurcuminwithtargetedtherapyagentsthataimtoinhibitspecificsignalingpathways,suchasepidermalgrowthfactorreceptor(EGFR),vascularendothelialgrowthfactor(VEGF),orphosphatidylinositol3-kinase(PI3K)/Akt/mTOR,whicharefrequentlydysregulatedinesophagealcancerandcontributetoitsgrowthandsurvival(Ebbingetal.,2014).Preclinicalstudieshavesuggestedthatcurcumincansensitizecancercellstotargetedtherapiesbydownregulatingcompensatorypathwaysthatareactivateduponinhibitionoftheprimarytarget(Liuetal.,2017).Therefore,itwouldbeinterestingtoinvestigatewhethersuchcombinatorialapproachescouldenhancetheefficacyoftargetedtherapiesandcircumventtheemergenceofdrugresistanceinesophagealcancercells.

Finally,clinicalstudiesareneededtoevaluatethesafety,pharmacokinetics,andpharmacodynamicsofcurcumininesophagealcancerpatients.Althoughcurcuminhasbeenshowntobewell-toleratedandexhibitlowtoxicityinpreclinicalandclinicalstudies,itsbioavailabilityandstabilityinvivoarelimitedbypoorsolubility,rapidmetabolism,andlowsystemicexposure(Guptaetal.,2013).Variousstrategieshavebeenproposedtoenhancethetherapeuticpotentialofcurcumin,suchasusingnanocarriers,adjuvants,oranaloguesthatimproveitsdelivery,stability,andpotency(Anandetal.,2007).Therefore,itwouldbeimportanttotesttheseformulationsinclinicaltrialsanddeterminewhethertheycanachieveconcentrationsofcurcuminthataresufficienttoinhibittheNotch1signalingpathwayandovercomedrugresistanceinesophagealcancerpatientsInadditiontocurcumin,othernaturalcompoundshavebeenshowntohavepotentialtherapeuticeffectsagainstesophagealcancer.Forexample,resveratrol,acompoundfoundingrapes,hasbeenshowntoinhibitthegrowthofesophagealcancercellsandinduceapoptosis(Jiangetal.,2016).Epigallocatechingallate(EGCG),acompoundfoundingreentea,hasalsobeenshowntohaveanti-tumoreffectsinesophagealcancercells(Chenetal.,2016).

Furthermore,traditionalChinesemedicinehasbeenusedasanalternativetreatmentoptionforesophagealcancer.Studieshaveshownthatcertainherbs,suchasScutellariabaicalensisandGynostemmapentaphyllum,caninhibitthegrowthofesophagealcancercellsandsensitizethemtochemotherapydrugs(Liuetal.,2016;Wangetal.,2016).

Overall,whilecurrenttreatmentsforesophagealcancerhavelimitations,therearepromisingnaturalcompoundsandalternativetherapiesthatmayholdpotentialforimprovingtheoutcomesofpatientswiththisdisease.Futureresearchshouldfocusonconductingclinicaltrialstodeterminethesafety