Nitrosylcobalamin Potentiates the Anti-Neoplastic Effects of Chemotherapeutic Agents via Suppression of Survival Signaling 英文参考文献.docVIP
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Nitrosylcobalamin Potentiates the Anti-Neoplastic Effects of Chemotherapeutic Agents via Suppression of Survival Signaling 英文参考文献
NitrosylcobalaminPotentiatestheAnti-Neoplastic
EffectsofChemotherapeuticAgentsviaSuppressionof
SurvivalSignaling
JosephA.Bauer1.*,JosephA.Lupica2,3.,HeidiSchmidt1,BeiH.Morrison1,RebeccaM.Haney1,RhondaK.Masci1,RebeccaM.Lee1,JosephA.
DiDonato2,DanielJ.Lindner1,4*
1TaussigCancerCenter,Centerfor Hematologyand OncologyMolecular Therapeutics, TheClevelandClinic Foundation,Cleveland,Ohio,United
States of America, 2Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, United States of
America,3DepartmentofChemistry,ClevelandStateUniversity,Cleveland,Ohio,UnitedStatesofAmerica,4DepartmentofCancerBiology,Lerner
ResearchInstitute,TheClevelandClinicFoundation,Cleveland,Ohio,UnitedStatesofAmerica
Background. Nitrosylcobalamin (NO-Cbl) is a chemotherapeutic pro-drug derived from vitamin B12 that preferentially
delivers nitric oxide (NO) to tumor cells, based upon increased receptor expression. NO-Cbl induces Apo2L/TRAIL-mediated
apoptosisandinhibitssurvivalsignalinginavarietyofmalignantcelllines.Chemotherapeuticagentsoftensimultaneously
induce an apoptotic signal and activation of NF-kB, which has the undesired effect of promoting cell survival. The specific
aims of this study were to 1) measure the anti-tumor effects of NO-Cbl alone and in combination with conventional
chemotherapeutic agents, and to 2) examine the mechanism of action of NO-Cbl as a single agent and in combination
therapy.Methodology.Usinganti-proliferativeassays,electrophoreticmobilityshiftassay(EMSA),immunoblotanalysisand
kinase assays, wedemonstrate an increase in the effectiveness ofchemotherapeutic agents in combination with NO-Cblas
a result of suppressed NF-kB activation. Results. Eighteen chemotherapeutic agents were tested in combination with NO-
Cbl, in thirteen malignant cell lines, resulting in a synergistic anti-proliferative effect in 78% of the combinations tested.
NO-Cbl pre-treatment resulted in decreased NF-kB DNA binding activity, inhibitio
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