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

Autores
Cardama, G. A.; González, N.; Ciarlantini, M.; Gandolfi Donadío, L.; Comin, M. J.; Alonso, D. F.; Lorenzano Menna, P.; Gómez, D. E.
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, G. A. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; Argentina
Fil: González, N. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; Argentina
Fil: Ciarlantini, M. Instituto Nacional de Tecnología Industrial. INTI-Química; Argentina
Fil: Gandolfi Donadío, L. Instituto Nacional de Tecnología Industrial. INTI-Química; Argentina
Fil: Comin, M. J. Instituto Nacional de Tecnología Industrial. INTI-Química; Argentina
Fil: Alonso, D. F. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; Argentina
Fil: Lorenzano Menna, P. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; Argentina
Fil: Gómez, D. E. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; Argentina
Fuente
OncoTargets and Therapy, 7
Materia
Cáncer
Biología molecular
Células
Medicina
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/3.0/
Repositorio
Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
Institución
Instituto Nacional de Tecnología Industrial
OAI Identificador
nuevadc:Ciarlantini2014Proapoptotic_pdf
Acceder
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oai_identifier_str nuevadc:Ciarlantini2014Proapoptotic_pdf
network_acronym_str RIINTI
repository_id_str
network_name_str Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
spelling Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cellsCardama, G. A.González, N.Ciarlantini, M.Gandolfi Donadío, L.Comin, M. J.Alonso, D. F.Lorenzano Menna, P.Gómez, D. E.CáncerBiología molecularCélulasMedicinaMalignant 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, G. A. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; ArgentinaFil: González, N. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; ArgentinaFil: Ciarlantini, M. Instituto Nacional de Tecnología Industrial. INTI-Química; ArgentinaFil: Gandolfi Donadío, L. Instituto Nacional de Tecnología Industrial. INTI-Química; ArgentinaFil: Comin, M. J. Instituto Nacional de Tecnología Industrial. INTI-Química; ArgentinaFil: Alonso, D. F. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; ArgentinaFil: Lorenzano Menna, P. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; ArgentinaFil: Gómez, D. E. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; ArgentinaDovepress2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfCiarlantini2014Proapoptotic.pdfhttps://app.inti.gob.ar/greenstone3/sites/localsite/collect/nuevadc/index/assoc/Ciarlant.dir/doc.pdfOncoTargets and Therapy, 7reponame:Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)instname:Instituto Nacional de Tecnología Industrialenginfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/3.0/openAccess2025-09-29T15:01:59Znuevadc:Ciarlantini2014Proapoptotic_pdfinstacron:INTIInstitucionalhttps://app.inti.gob.ar/greenstone3/biblioOrganismo científico-tecnológicohttps://argentina.gob.ar/intihttps://app.inti.gob.ar/greenstone3/oaiserver?verb=Identifypfalcato@inti.gob.arArgentinaopendoar:2025-09-29 15:02:00.455Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI) - Instituto Nacional de Tecnología Industrialfalse
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, G. A.
Cáncer
Biología molecular
Células
Medicina
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, G. A.
González, N.
Ciarlantini, M.
Gandolfi Donadío, L.
Comin, M. J.
Alonso, D. F.
Lorenzano Menna, P.
Gómez, D. E.
author Cardama, G. A.
author_facet Cardama, G. A.
González, N.
Ciarlantini, M.
Gandolfi Donadío, L.
Comin, M. J.
Alonso, D. F.
Lorenzano Menna, P.
Gómez, D. E.
author_role author
author2 González, N.
Ciarlantini, M.
Gandolfi Donadío, L.
Comin, M. J.
Alonso, D. F.
Lorenzano Menna, P.
Gómez, D. E.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cáncer
Biología molecular
Células
Medicina
topic Cáncer
Biología molecular
Células
Medicina
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, G. A. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; Argentina
Fil: González, N. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; Argentina
Fil: Ciarlantini, M. Instituto Nacional de Tecnología Industrial. INTI-Química; Argentina
Fil: Gandolfi Donadío, L. Instituto Nacional de Tecnología Industrial. INTI-Química; Argentina
Fil: Comin, M. J. Instituto Nacional de Tecnología Industrial. INTI-Química; Argentina
Fil: Alonso, D. F. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; Argentina
Fil: Lorenzano Menna, P. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; Argentina
Fil: Gómez, D. E. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular; 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
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 Ciarlantini2014Proapoptotic.pdf
https://app.inti.gob.ar/greenstone3/sites/localsite/collect/nuevadc/index/assoc/Ciarlant.dir/doc.pdf
identifier_str_mv Ciarlantini2014Proapoptotic.pdf
url https://app.inti.gob.ar/greenstone3/sites/localsite/collect/nuevadc/index/assoc/Ciarlant.dir/doc.pdf
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/3.0/
openAccess
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/3.0/
openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Dovepress
publisher.none.fl_str_mv Dovepress
dc.source.none.fl_str_mv OncoTargets and Therapy, 7
reponame:Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
instname:Instituto Nacional de Tecnología Industrial
reponame_str Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
collection Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
instname_str Instituto Nacional de Tecnología Industrial
repository.name.fl_str_mv Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI) - Instituto Nacional de Tecnología Industrial
repository.mail.fl_str_mv pfalcato@inti.gob.ar
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score 12.559606

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