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Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models()()

Resistance to chemotherapy remains a major challenge in the treatment of human glioblastoma (GBM). Glycogen synthase kinase-3β (GSK-3β), a positive regulator of NF-κB–mediated survival and chemoresistance of cancer cells, has been identified as a potential therapeutic target in human GBM. Our object...

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Autores principales: Ugolkov, Andrey, Qiang, Wenan, Bondarenko, Gennadiy, Procissi, Daniel, Gaisina, Irina, James, C. David, Chandler, James, Kozikowski, Alan, Gunosewoyo, Hendra, O'Halloran, Thomas, Raizer, Jeffrey, Mazar, Andrew P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496477/
https://www.ncbi.nlm.nih.gov/pubmed/28672195
http://dx.doi.org/10.1016/j.tranon.2017.06.003
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author Ugolkov, Andrey
Qiang, Wenan
Bondarenko, Gennadiy
Procissi, Daniel
Gaisina, Irina
James, C. David
Chandler, James
Kozikowski, Alan
Gunosewoyo, Hendra
O'Halloran, Thomas
Raizer, Jeffrey
Mazar, Andrew P.
author_facet Ugolkov, Andrey
Qiang, Wenan
Bondarenko, Gennadiy
Procissi, Daniel
Gaisina, Irina
James, C. David
Chandler, James
Kozikowski, Alan
Gunosewoyo, Hendra
O'Halloran, Thomas
Raizer, Jeffrey
Mazar, Andrew P.
author_sort Ugolkov, Andrey
collection PubMed
description Resistance to chemotherapy remains a major challenge in the treatment of human glioblastoma (GBM). Glycogen synthase kinase-3β (GSK-3β), a positive regulator of NF-κB–mediated survival and chemoresistance of cancer cells, has been identified as a potential therapeutic target in human GBM. Our objective was to determine the antitumor effect of GSK-3 inhibitor 9-ING-41 in combination with chemotherapy in patient-derived xenograft (PDX) models of human GBM. We utilized chemoresistant PDX models of GBM, GBM6 and GBM12, to study the effect of 9-ING-41 used alone and in combination with chemotherapy on tumor progression and survival. GBM6 and GBM12 were transfected by reporter constructs to enable bioluminescence imaging, which was used to stage animals prior to treatment and to follow intracranial GBM tumor growth. Immunohistochemical staining, apoptosis assay, and immunoblotting were used to assess the expression of GSK-3β and the effects of treatment in these models. We found that 9-ING-41 significantly enhanced 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) antitumor activity in staged orthotopic GBM12 (no response to CCNU) and GBM6 (partial response to CCNU) PDX models, as indicated by a decrease in tumor bioluminescence in mouse brain and a significant increase in overall survival. Treatment with the combination of CCNU and 9-ING-41 resulted in histologically confirmed cures in these studies. Our results demonstrate that the GSK-3 inhibitor 9-ING-41, a clinical candidate currently in Investigational New Drug (IND)-enabling development, significantly enhances the efficacy of CCNU therapy for human GBM and warrants consideration for clinical evaluation in this difficult-to-treat patient population.
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spelling pubmed-54964772017-07-13 Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models()() Ugolkov, Andrey Qiang, Wenan Bondarenko, Gennadiy Procissi, Daniel Gaisina, Irina James, C. David Chandler, James Kozikowski, Alan Gunosewoyo, Hendra O'Halloran, Thomas Raizer, Jeffrey Mazar, Andrew P. Transl Oncol Original article Resistance to chemotherapy remains a major challenge in the treatment of human glioblastoma (GBM). Glycogen synthase kinase-3β (GSK-3β), a positive regulator of NF-κB–mediated survival and chemoresistance of cancer cells, has been identified as a potential therapeutic target in human GBM. Our objective was to determine the antitumor effect of GSK-3 inhibitor 9-ING-41 in combination with chemotherapy in patient-derived xenograft (PDX) models of human GBM. We utilized chemoresistant PDX models of GBM, GBM6 and GBM12, to study the effect of 9-ING-41 used alone and in combination with chemotherapy on tumor progression and survival. GBM6 and GBM12 were transfected by reporter constructs to enable bioluminescence imaging, which was used to stage animals prior to treatment and to follow intracranial GBM tumor growth. Immunohistochemical staining, apoptosis assay, and immunoblotting were used to assess the expression of GSK-3β and the effects of treatment in these models. We found that 9-ING-41 significantly enhanced 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) antitumor activity in staged orthotopic GBM12 (no response to CCNU) and GBM6 (partial response to CCNU) PDX models, as indicated by a decrease in tumor bioluminescence in mouse brain and a significant increase in overall survival. Treatment with the combination of CCNU and 9-ING-41 resulted in histologically confirmed cures in these studies. Our results demonstrate that the GSK-3 inhibitor 9-ING-41, a clinical candidate currently in Investigational New Drug (IND)-enabling development, significantly enhances the efficacy of CCNU therapy for human GBM and warrants consideration for clinical evaluation in this difficult-to-treat patient population. Neoplasia Press 2017-06-30 /pmc/articles/PMC5496477/ /pubmed/28672195 http://dx.doi.org/10.1016/j.tranon.2017.06.003 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original article
Ugolkov, Andrey
Qiang, Wenan
Bondarenko, Gennadiy
Procissi, Daniel
Gaisina, Irina
James, C. David
Chandler, James
Kozikowski, Alan
Gunosewoyo, Hendra
O'Halloran, Thomas
Raizer, Jeffrey
Mazar, Andrew P.
Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models()()
title Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models()()
title_full Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models()()
title_fullStr Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models()()
title_full_unstemmed Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models()()
title_short Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models()()
title_sort combination treatment with the gsk-3 inhibitor 9-ing-41 and ccnu cures orthotopic chemoresistant glioblastoma in patient-derived xenograft models()()
topic Original article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496477/
https://www.ncbi.nlm.nih.gov/pubmed/28672195
http://dx.doi.org/10.1016/j.tranon.2017.06.003
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