Molecular Characterization of c-Ablc-Src Kinase Inhibitors Targeted against Murine Tumour Progenitor Cells that Express Stem Cell Markers 英文参考文献.docVIP

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Molecular Characterization of c-Ablc-Src Kinase Inhibitors Targeted against Murine Tumour Progenitor Cells that Express Stem Cell Markers 英文参考文献.doc

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Molecular Characterization of c-Ablc-Src Kinase Inhibitors Targeted against Murine Tumour Progenitor Cells that Express Stem Cell Markers 英文参考文献

MolecularCharacterizationofc-Abl/c-SrcKinase InhibitorsTargetedagainstMurineTumourProgenitor CellsthatExpressStemCellMarkers ThomasKruewel1,5.,SilviaSchenone2.,MarcoRadi3.,GiovanniMaga4,AstridRohrbeck1,5 ,Maurizio Botta3.,JuergenBorlak1,5 * 1CenterforPharmacologyandToxicology,HannoverMedicalSchool,Hannover,Germany,2DepartmentofPharmaceuticalScience,UniversityofGenoa,Genoa,Italy, 3Department of Chemistry and Pharmaceutical Technology, University of Siena, Siena, Italy, 4Institute of Molecular Genetics IMG-CNR, Pavia, Italy, 5Department of MolecularMedicineandMedicalBiotechnology,FraunhoferInstituteofToxicologyandExperimentalMedicine,Hannover,Germany Abstract Background: The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human tumours. Inhibitionoftheirhyperactivityrepresentsamolecularrationaleinthecombatofcancerousdiseases.Hereweexaminedthe effectsofanewfamilyofpyrazolo[3,4-d]pyrimidinesonapanelof11differentmurinelungtumourprogenitorcelllines, thatexpressstemcellmarkers,aswellasonthehumanlungadenocarcinomacelllineA549,thehumanhepatomacellline HepG2andthehumancoloncancercelllineCaCo2toobtaininsightintothemodeofactionoftheseexperimentaldrugs. Methodology/Principal Findings: Treatment with the dual kinase inhibitors blocked c-Abl and c-Src kinase activity efficientlyinthenanomolarrange,inducedapoptosis,reducedcellviabilityandcausedcellcyclearrestpredominantlyat G0/G1phasewhilewesternblotanalysisconfirmedrepressedproteinexpressionofc-Ablandc-Srcaswellastheinteracting partnersp38mitogenactivatedproteinkinase,heterogenousribonucleoproteinK,cyclindependentkinase1andfurther proteins that are crucial for tumour progression. Importantly, a significant repression of the epidermal growth factor receptorwasobservedwhilewholegenomegeneexpressionanalysisevidencedregulationofmanycellcycleregulated genesaswellintegrinandfocaladhesionkinase(FAK)signallingtoimpactcytoskeletondynamics,migration,invasionand metastasis. Conclusions/Significance: Our exp