A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast 英文参考文献.docVIP

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A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast 英文参考文献.doc

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A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast 英文参考文献

AChemicalGeneticScreenforModulatorsof Asymmetrical2,29-DimericNaphthoquinones CytotoxicityinYeast AshkanEmadi1,AshleyE.Ross2,KathleenM.Cowan3,YolandaM.Fortenberry4,MilenaVuica-Ross3* 1Department ofInternalMedicineandOncology,Johns HopkinsSchool ofMedicine,Baltimore,Maryland,UnitedStates ofAmerica, 2DepartmentofUrology, Johns HopkinsSchoolofMedicine,Baltimore,Maryland,UnitedStatesofAmerica,3DepartmentofPathology,JohnsHopkinsSchoolofMedicine,Baltimore,Maryland,United StatesofAmerica,4DepartmentofPediatrics,JohnsHopkinsSchoolofMedicine,Baltimore,Maryland,UnitedStatesofAmerica Abstract Background:Dimericnaphthoquinones(BiQ)wereoriginallysynthesizedasanewclassofHIVintegraseinhibitorsbuthave shownintegrase-independentcytotoxicityinacutelymphoblasticleukemiacelllinessuggestingtheiruseaspotentialanti- neoplastic agents. The mechanism of this cytotoxicity is unknown. In order to gain insight into the mode of action of binaphthoquinones we performed a systematic high-throughput screen in a yeast isogenic deletion mutant array for enhancedorsuppressedgrowthinthepresenceofbinaphthoquinones. Methodology/Principal findings: Exposure of wild type yeast strains to various BiQs demonstrated inhibition of yeast growthwithIC50sinthemMrange.Drugsensitivityandresistancescreenswereperformedbyexposingarraysofahaploid yeast deletion mutant library to BiQs at concentrations near their IC50.Sensitivity screens identified yeast with deletions affectingmitochondrialfunctionandcellularrespirationashavingincreasedsensitivitytoBiQs.Correspondingtothis,wild typeyeastgrownintheabsenceofafermentablecarbonsourcewereparticularlysensitivetoBiQs,andtreatmentwithBiQs wasshowntodisruptthemitochondrialmembranepotentialandleadtothegenerationofreactiveoxygenspecies(ROS). Furthermore,baselineROSproductioninBiQsensitivemutantstrainswasincreasedcomparedtowildtypeandcouldbe further augmented by the presence of BiQ. Screens for resistance to BiQ action identified the mitochondrial external NAD(P)H dehydro