Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

Autores
Cardama, Georgina Alexandra; González, Nazareno; Ciarlantini, Matias Sebastián; Gandolfi Donadío, Lucía; Comin, Maria Julieta; Alonso, Daniel Fernando; Lorenzano Menna, Pablo; Gomez, Daniel Eduardo
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180–Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models.
Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: González, Nazareno. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ciarlantini, Matias Sebastián. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Gandolfi Donadío, Lucía. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Comin, Maria Julieta. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Glioma
Rac1
Invasion
Rho GTPases
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/36004
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/36004
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cellsCardama, Georgina AlexandraGonzález, NazarenoCiarlantini, Matias SebastiánGandolfi Donadío, LucíaComin, Maria JulietaAlonso, Daniel FernandoLorenzano Menna, PabloGomez, Daniel EduardoGliomaRac1InvasionRho GTPaseshttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180–Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models.Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: González, Nazareno. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ciarlantini, Matias Sebastián. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Gandolfi Donadío, Lucía. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Comin, Maria Julieta. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaDove Press2014-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/36004Cardama, Georgina Alexandra; González, Nazareno; Ciarlantini, Matias Sebastián; Gandolfi Donadío, Lucía; Comin, Maria Julieta; et al.; Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells; Dove Press; Oncotargets and Therapy; 2014; 7; 7-2014; 2021-20331178-6930CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.dovepress.com/proapoptotic-and-antiinvasive-activity-of-rac1-small-molecule-inhibito-peer-reviewed-article-OTTinfo:eu-repo/semantics/altIdentifier/doi/10.2147/OTT.S67998info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:25:59Zoai:ri.conicet.gov.ar:11336/36004instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:25:59.631CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells
title Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells
spellingShingle Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells
Cardama, Georgina Alexandra
Glioma
Rac1
Invasion
Rho GTPases
title_short Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells
title_full Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells
title_fullStr Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells
title_full_unstemmed Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells
title_sort Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells
dc.creator.none.fl_str_mv Cardama, Georgina Alexandra
González, Nazareno
Ciarlantini, Matias Sebastián
Gandolfi Donadío, Lucía
Comin, Maria Julieta
Alonso, Daniel Fernando
Lorenzano Menna, Pablo
Gomez, Daniel Eduardo
author Cardama, Georgina Alexandra
author_facet Cardama, Georgina Alexandra
González, Nazareno
Ciarlantini, Matias Sebastián
Gandolfi Donadío, Lucía
Comin, Maria Julieta
Alonso, Daniel Fernando
Lorenzano Menna, Pablo
Gomez, Daniel Eduardo
author_role author
author2 González, Nazareno
Ciarlantini, Matias Sebastián
Gandolfi Donadío, Lucía
Comin, Maria Julieta
Alonso, Daniel Fernando
Lorenzano Menna, Pablo
Gomez, Daniel Eduardo
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Glioma
Rac1
Invasion
Rho GTPases
topic Glioma
Rac1
Invasion
Rho GTPases
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180–Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models.
Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: González, Nazareno. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ciarlantini, Matias Sebastián. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Gandolfi Donadío, Lucía. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Comin, Maria Julieta. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180–Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models.
publishDate 2014
dc.date.none.fl_str_mv 2014-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/36004
Cardama, Georgina Alexandra; González, Nazareno; Ciarlantini, Matias Sebastián; Gandolfi Donadío, Lucía; Comin, Maria Julieta; et al.; Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells; Dove Press; Oncotargets and Therapy; 2014; 7; 7-2014; 2021-2033
1178-6930
CONICET Digital
CONICET
url http://hdl.handle.net/11336/36004
identifier_str_mv Cardama, Georgina Alexandra; González, Nazareno; Ciarlantini, Matias Sebastián; Gandolfi Donadío, Lucía; Comin, Maria Julieta; et al.; Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells; Dove Press; Oncotargets and Therapy; 2014; 7; 7-2014; 2021-2033
1178-6930
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.dovepress.com/proapoptotic-and-antiinvasive-activity-of-rac1-small-molecule-inhibito-peer-reviewed-article-OTT
info:eu-repo/semantics/altIdentifier/doi/10.2147/OTT.S67998
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Dove Press
publisher.none.fl_str_mv Dove Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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