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Inhibition of Glioblastoma Growth by the Thiadiazolidinone Compound TDZD-8

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 vitr...

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Detalles Bibliográficos
Autores principales: Aguilar-Morante, Diana, Morales-Garcia, Jose Angel, Sanz-SanCristobal, Marina, Garcia-Cabezas, Miguel Angel, Santos, Angel, Perez-Castillo, Ana
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975629/
https://www.ncbi.nlm.nih.gov/pubmed/21079728
http://dx.doi.org/10.1371/journal.pone.0013879
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author Aguilar-Morante, Diana
Morales-Garcia, Jose Angel
Sanz-SanCristobal, Marina
Garcia-Cabezas, Miguel Angel
Santos, Angel
Perez-Castillo, Ana
author_facet Aguilar-Morante, Diana
Morales-Garcia, Jose Angel
Sanz-SanCristobal, Marina
Garcia-Cabezas, Miguel Angel
Santos, Angel
Perez-Castillo, Ana
author_sort Aguilar-Morante, Diana
collection PubMed
description 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. 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-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/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.
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spelling pubmed-29756292010-11-15 Inhibition of Glioblastoma Growth by the Thiadiazolidinone Compound TDZD-8 Aguilar-Morante, Diana Morales-Garcia, Jose Angel Sanz-SanCristobal, Marina Garcia-Cabezas, Miguel Angel Santos, Angel Perez-Castillo, Ana PLoS One Research Article 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. 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-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/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. Public Library of Science 2010-11-08 /pmc/articles/PMC2975629/ /pubmed/21079728 http://dx.doi.org/10.1371/journal.pone.0013879 Text en Aguilar-Morante et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Aguilar-Morante, Diana
Morales-Garcia, Jose Angel
Sanz-SanCristobal, Marina
Garcia-Cabezas, Miguel Angel
Santos, Angel
Perez-Castillo, Ana
Inhibition of Glioblastoma Growth by the Thiadiazolidinone Compound TDZD-8
title Inhibition of Glioblastoma Growth by the Thiadiazolidinone Compound TDZD-8
title_full Inhibition of Glioblastoma Growth by the Thiadiazolidinone Compound TDZD-8
title_fullStr Inhibition of Glioblastoma Growth by the Thiadiazolidinone Compound TDZD-8
title_full_unstemmed Inhibition of Glioblastoma Growth by the Thiadiazolidinone Compound TDZD-8
title_short Inhibition of Glioblastoma Growth by the Thiadiazolidinone Compound TDZD-8
title_sort inhibition of glioblastoma growth by the thiadiazolidinone compound tdzd-8
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975629/
https://www.ncbi.nlm.nih.gov/pubmed/21079728
http://dx.doi.org/10.1371/journal.pone.0013879
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