title: GSK-3β inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma Neuro-2A cell line.
abstract: Neuroblastoma is the most common extracranial solid tumor of childhood. While survival rates are high for localized disease, treatment response remains poor for a subset of patients with large tumors or disseminated disease. Thus, there remains much room for improvement in treatment strategies for this disease. Using in vitro and in vivo systems, we present glycogen synthase kinase-3β (GSK-3β) inhibition as a potential mechanism to treat neuroblastoma. Using the specific GSK-3β inhibitor SB415286, we demonstrate that GSK-3β inhibition decreases the viability of Neuro-2A cells, as determined by cell proliferation assay and clonogenic survival. Moreover, we show that GSK-3β inhibition induces apoptosis in neuroblastoma cells, as determined by Annexin V staining and confirmed with DAPI staining. Using flow cytometry, we are able to demonstrate that SB415286 induces the accumulation of cells in the G2/M phase of the cell cycle. Finally, we show that these in vitro results translate into delayed tumor growth in vivo using a heterotopic tumor model in nude mice treated with SB415286. These findings suggest that GSK-3β is a potential molecular target for the treatment of neuroblastoma.
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Dickey
authors.forename: Stephen
authors.initials: S
authors.lastname: Schleicher
authors.forename: Kathleen
authors.initials: K
authors.lastname: Leahy
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Dennis
authors.initials: D
authors.lastname: Hallahan
authors.forename: Dinesh Kumar
authors.initials: DK
authors.lastname: Thotala
mesh_terms: D000627:Aminophenols / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003124:Colorimetry; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014410:Tumor Stem Cell Assay / Q000379:methods; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D008301:Maleimides; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3