环磷酰胺衍生物SLXM-2对小鼠肝癌H_（22）细胞的DNA损伤作用.pdf

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1、16JournalofChinesePharmaceuticalScienceshttp．'／／www．jcps．ac．cnDNAdamagingeffectofSLXM一2，aderivativeofcyclophosphamide，onhepatocarcinomaH22cellsinvivoMingmingChuXiaYuan，XuanJia，TingSun，WeiGuo，XiaoJiang，JingtaoLiu，RuntaoLi，，，．JingrongCui。．StateKeyLaboratoryofNaturalandBiomimeticD

2、rugs，PekingUniversityHealthScienceCenter,Beijing100191，China2．DepartmentofChemicalBiology,SchoolofPharmaceuticalSciences，PekingUniversityHealthScienceCenter,Beij'ing，00191，ChinaAbstract：CompoundSLXM一2．aderivativeofcyclophosphamide(CTX)．hasshownpotentgrowth—inhibitoryeffectontum

3、orcellswith1owtoxicityinpreviousstudies．However,themechanismofitsanti—tumorefect．especiallyonDNAdamage．remainslargelyunclear．ThisstudyinvestigatedtheeffectofSLXM一2onthesurviva1timeofmicetransplantedwiththeasciticfluid—typehepatocarcinoma22(H22)．Wealsoevaluatedthecorrelationbetw

4、eenDNAdamagingefectofSLXM一2anditsanti—tumorefect．andtoprobethepossiblemolecularmechanismforitseffectonH22cells．TheresultssuggestedthatSLXM一2significantly(P<0．05)prolongedthesurviva1timeofmicebearingtheasciticfluidtypeH7，．Furthermore，SLXM一2inducedDNAdamageinadose—dependentmanner

5、inH22cells．FurtherinvestigationrevealedthatSLXM一2significantly(P<0．05)up—regulatedtheexpression1evelsofaseriesofDNAdamage—relatedproteins，suchas7H2AX(Serl39)，P．Chkl(Ser296)，P—Chk2(Thr68)，P—p53(Serl5)，P—p53(Ser20)andp21，anddown—regulatedtheexpressionofP．ATR(Ser428)andP．ATM(Serl9

6、81)．Inconclusion，SLXM一2showedaremarkableanti—tumoractivityonasciticfluid—typeH，，cells．anditsmolecularmechanismisrelatedtoitsDNAdamagingefect．Keywords：SLXM一2：H22；DNAdamage；SCGE：DNAdamage—relatedproteinsCLCnumber：R962Documentcode：AArticleID：1003——1057(2014)1——16——061．IntrOducti0n

7、celldeath【／1．CTXiswidelyusedasachemotherapeuticagentfortreatingmalignantlymphoma，multiplemyeloma，HepatoceIlularcarcinoma(HCC)isoneofthemostleukemia，breastcancerandsoonNevertheless．CTXcommoncancersandthethirdmostcommoncauseofhasvarioustoxicefects，suchasbonemarrowsuppression，canc

8、ermortalityworldwide-JJ．Over600000newHCCheartinflammat