title: Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8.
abstract: BACKGROUND
  Thiadiazolidinones (TDZD) are small heterocyclic compounds first described as non-ATP competitive inhibitors of glycogen synthase kinase 3β (GSK-3β). In this study, we analyzed the effects of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), on murine GL261 cells growth in vitro and on the growth of established intracerebral murine gliomas in vivo.
  
  
  RESULTS
  Our data show that TDZD-8 decreased proliferation and induced apoptosis of GL261 glioblastoma cells in vitro, delayed tumor growth in vivo, and augmented animal survival. These effects were associated with an early activation of extracellular signal-regulated kinase (ERK) pathway and increased expression of EGR-1 and p21 genes. Also, we observed a sustained activation of the ERK pathway, a concomitant phosphorylation and activation of ribosomal S6 kinase (p90RSK) and an inactivation of GSK-3β by phosphorylation at Ser 9. Finally, treatment of glioblastoma stem cells with TDZD-8 resulted in an inhibition of proliferation and self-renewal of these cells.
  
  
  CONCLUSIONS
  Our results suggest that TDZD-8 uses a novel mechanism to target glioblastoma cells, and that malignant progenitor population could be a target of this compound.
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red sobre Enfermedades neurodegenerativas, Madrid, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Aguilar-Morante
authors.forename: Jose Angel
authors.initials: JA
authors.lastname: Morales-Garcia
authors.forename: Marina
authors.initials: M
authors.lastname: Sanz-SanCristobal
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Garcia-Cabezas
authors.forename: Angel
authors.initials: A
authors.lastname: Santos
authors.forename: Ana
authors.initials: A
authors.lastname: Perez-Castillo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053143:Caspase 2 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology*; D014184:Transplantation, Homologous; D047368:Tumor Burden / Q000187:drug effects*
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D013830:Thiadiazoles; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D053143:Caspase 2