PMID- 21079728
OWN - NLM
STAT- MEDLINE
DCOM- 20110427
LR  - 20240314
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 11
DP  - 2010 Nov 8
TI  - Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8.
PG  - e13879
LID - 10.1371/journal.pone.0013879 [doi]
LID - e13879
AB  - BACKGROUND: Thiadiazolidinones (TDZD) are small heterocyclic compounds first 
      described as non-ATP competitive inhibitors of glycogen synthase kinase 3beta 
      (GSK-3beta). 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. METHODOLOGY/PRINCIPAL FINDINGS: 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-3beta 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/SIGNIFICANCE: 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.
FAU - Aguilar-Morante, Diana
AU  - Aguilar-Morante D
AD  - Instituto de Investigaciones Biomedicas, Consejo Superior de Investigaciones 
      Cientificas-Universidad Autonoma de Madrid, and Centro de Investigacion Biomedica 
      en Red sobre Enfermedades neurodegenerativas, Madrid, Spain.
FAU - Morales-Garcia, Jose Angel
AU  - Morales-Garcia JA
FAU - Sanz-SanCristobal, Marina
AU  - Sanz-SanCristobal M
FAU - Garcia-Cabezas, Miguel Angel
AU  - Garcia-Cabezas MA
FAU - Santos, Angel
AU  - Santos A
FAU - Perez-Castillo, Ana
AU  - Perez-Castillo A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101108
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione)
RN  - 0 (NF-kappa B)
RN  - 0 (Proliferating Cell Nuclear Antigen)
RN  - 0 (Thiadiazoles)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 3.4.22.- (Caspase 2)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Caspase 2/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Cell Survival/drug effects
MH  - Glioblastoma/metabolism/pathology/*prevention & control
MH  - Glycogen Synthase Kinase 3/antagonists & inhibitors/metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - MAP Kinase Signaling System/drug effects
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitogen-Activated Protein Kinases/drug effects
MH  - NF-kappa B/metabolism
MH  - Neoplasm Transplantation
MH  - Phosphorylation/drug effects
MH  - Proliferating Cell Nuclear Antigen/metabolism
MH  - Thiadiazoles/*pharmacology
MH  - Transplantation, Homologous
MH  - Tumor Burden/*drug effects
PMC - PMC2975629
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/11/17 06:00
MHDA- 2011/04/28 06:00
PMCR- 2010/11/08
CRDT- 2010/11/17 06:00
PHST- 2010/07/01 00:00 [received]
PHST- 2010/10/19 00:00 [accepted]
PHST- 2010/11/17 06:00 [entrez]
PHST- 2010/11/17 06:00 [pubmed]
PHST- 2011/04/28 06:00 [medline]
PHST- 2010/11/08 00:00 [pmc-release]
AID - 10-PONE-RA-20517R1 [pii]
AID - 10.1371/journal.pone.0013879 [doi]
PST - epublish
SO  - PLoS One. 2010 Nov 8;5(11):e13879. doi: 10.1371/journal.pone.0013879.