Carboxyamidotriazole-Orotate Inhibits the Growth of Imatinib-Resistant Chronic Myeloid Leukaemia Cells and Modulates Exosomes-Stimulated Angiogenesis 英文参考文献.docVIP

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Carboxyamidotriazole-Orotate Inhibits the Growth of Imatinib-Resistant Chronic Myeloid Leukaemia Cells and Modulates Exosomes-Stimulated Angiogenesis 英文参考文献.doc

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Carboxyamidotriazole-Orotate Inhibits the Growth of Imatinib-Resistant Chronic Myeloid Leukaemia Cells and Modulates Exosomes-Stimulated Angiogenesis 英文参考文献

Carboxyamidotriazole-OrotateInhibitstheGrowthof Imatinib-ResistantChronicMyeloidLeukaemiaCellsand ModulatesExosomes-StimulatedAngiogenesis ChiaraCorrado1.,AnnaMariaFlugy1.,SimonaTaverna1.,StefaniaRaimondo1,GiulianaGuggino1, RashidaKarmali2,GiacomoDeLeo1,RiccardoAlessandro1* 1DipartimentodiBiopatologiaeBiotecnologieMedicheeForensi,SezionediBiologiaeGenetica,Universita`diPalermo,Italy,2TacticalTherapeuticsInc.,NewYork,New York,UnitedStatesofAmerica Abstract The Bcr/Abl kinase has been targeted for the treatment of chronic myelogenous leukaemia (CML) by imatinib mesylate. WhileimatinibhasbeenextremelyeffectiveforchronicphaseCML,blastcrisisCMLareoftenresistant. Newtherapeutic optionsarethereforeneededforthisfataldisease.Althoughmorecommoninsolidtumors,increasedmicrovesseldensity wasalsoreportedinchronicmyelogenousleukaemiaandwasassociatedwithasignificantincreaseofangiogenicfactors, suggestingthatvascularityinhematologicmalignanciesisacontrolledprocessandmayplayaroleintheleukaemogenic processthusrepresentinganalternativetherapeutictarget.Carboxyamidotriazole-orotate(CTO)istheorotatesaltformof carboxyamidotriazole (CAI), an orally bioavailable signal transduction inhibitor that invitro has been shown to possess antileukaemic activities. CTO, which has a reduced toxicity, increased oral bioavailability and stronger efficacy when comparedtotheparentalcompound,wastestedinthisstudyforitsabilitytoaffectimatinib-resistantCMLtumorgrowthin a xenograft model. The active cross talk between endothelial cells and leukemic cells in the bone marrow involving exosomesplaysanimportantroleinmodulatingtheprocessofneovascularizationinCML.Wehavethusinvestigatedthe effectsofCTOonexosome-stimulatedangiogenesis.OurresultsindicatethatCTOmaybeeffectiveintargetingbothcancer cellgrowthandthetumormicroenvironment,thussuggestingapotentialtherapeuticutilityforCTOinleukaemiapatients. Citation:CorradoC,FlugyAM,TavernaS,RaimondoS,GugginoG,etal.(2012)Carboxyamidotriazole-OrotateInhibitstheGrowth