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Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo

Malignant glioma is a severe cancer with a poor prognosis. Local occurrence and rare metastases of malignant glioma make it a suitable target for gene therapy. Several studies have demonstrated the importance of Src kinase in different cancers. However, these studies have focused mainly on Src-defic...

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Autores principales: Stedt, Hanna, Alasaarela, Laura, Samaranayake, Haritha, Pikkarainen, Jere, Määttä, Ann-Marie, Kholová, Ivana, Parker, Aaron S., Ylä-Herttuala, Seppo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390242/
https://www.ncbi.nlm.nih.gov/pubmed/23344000
http://dx.doi.org/10.1038/mtna.2012.13
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author Stedt, Hanna
Alasaarela, Laura
Samaranayake, Haritha
Pikkarainen, Jere
Määttä, Ann-Marie
Kholová, Ivana
Parker, Aaron S.
Ylä-Herttuala, Seppo
author_facet Stedt, Hanna
Alasaarela, Laura
Samaranayake, Haritha
Pikkarainen, Jere
Määttä, Ann-Marie
Kholová, Ivana
Parker, Aaron S.
Ylä-Herttuala, Seppo
author_sort Stedt, Hanna
collection PubMed
description Malignant glioma is a severe cancer with a poor prognosis. Local occurrence and rare metastases of malignant glioma make it a suitable target for gene therapy. Several studies have demonstrated the importance of Src kinase in different cancers. However, these studies have focused mainly on Src-deficient mice or pharmacological inhibitors of Src. In this study we have used Src small hairpin RNAs (shRNAs) in a lentiviral backbone to mimic a long-term stable treatment and determined the role of Src in tumor tissues. Efficacy of Src shRNAs was confirmed in vitro demonstrating up to 90% target gene inhibition. In a mouse malignant glioma model, Src shRNA tumors were almost 50-fold smaller in comparison to control tumors and had significantly reduced vascularity. In a syngenic rat intracranial glioma model, Src shRNA-transduced tumors were smaller and these rats had a survival benefit over the control rats. In vivo treatment was enhanced by chemotherapy and histone deacetylase inhibition. Our results emphasise the importance of Src in tumorigenesis and demonstrate that it can be efficiently inhibited in vitro and in vivo in two independent malignant glioma models. In conclusion, Src is a potential target for RNA interference-mediated treatment of malignant glioma.
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spelling pubmed-33902422012-07-05 Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo Stedt, Hanna Alasaarela, Laura Samaranayake, Haritha Pikkarainen, Jere Määttä, Ann-Marie Kholová, Ivana Parker, Aaron S. Ylä-Herttuala, Seppo Mol Ther Nucleic Acids Original Article Malignant glioma is a severe cancer with a poor prognosis. Local occurrence and rare metastases of malignant glioma make it a suitable target for gene therapy. Several studies have demonstrated the importance of Src kinase in different cancers. However, these studies have focused mainly on Src-deficient mice or pharmacological inhibitors of Src. In this study we have used Src small hairpin RNAs (shRNAs) in a lentiviral backbone to mimic a long-term stable treatment and determined the role of Src in tumor tissues. Efficacy of Src shRNAs was confirmed in vitro demonstrating up to 90% target gene inhibition. In a mouse malignant glioma model, Src shRNA tumors were almost 50-fold smaller in comparison to control tumors and had significantly reduced vascularity. In a syngenic rat intracranial glioma model, Src shRNA-transduced tumors were smaller and these rats had a survival benefit over the control rats. In vivo treatment was enhanced by chemotherapy and histone deacetylase inhibition. Our results emphasise the importance of Src in tumorigenesis and demonstrate that it can be efficiently inhibited in vitro and in vivo in two independent malignant glioma models. In conclusion, Src is a potential target for RNA interference-mediated treatment of malignant glioma. Nature Publishing Group 2012-05 2012-05-01 /pmc/articles/PMC3390242/ /pubmed/23344000 http://dx.doi.org/10.1038/mtna.2012.13 Text en Copyright © 2012 American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by-nc-nd/3.0/ Molecular Therapy-Nucleic Acids is an open-access journal published by Nature Publishing Group. This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Stedt, Hanna
Alasaarela, Laura
Samaranayake, Haritha
Pikkarainen, Jere
Määttä, Ann-Marie
Kholová, Ivana
Parker, Aaron S.
Ylä-Herttuala, Seppo
Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo
title Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo
title_full Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo
title_fullStr Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo
title_full_unstemmed Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo
title_short Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo
title_sort specific inhibition of src kinase impairs malignant glioma growth in vitro and in vivo
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390242/
https://www.ncbi.nlm.nih.gov/pubmed/23344000
http://dx.doi.org/10.1038/mtna.2012.13
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