Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy

Autores
Couto, Marcos; Alamón, Catalina; García, María; Kovacs, Mariángeles; Trias, Emiliano; Nievas, Susana Isabel; Pozzi, Emiliano César Cayetano; Curotto, Paula; Thorp, Silvia Inés; Dagrosa, María Alejandra; Teixidor, Francesc; Viñas, Clara; Cerecetto, Hugo
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
One of the driving forces of carcinogenesis in humans is the aberrant activation of receptors; consequently, one of the most promising mechanisms for cancer treatment is receptor inhibition by chemotherapy. Although a variety of cancers are initially susceptible to chemotherapy, they eventually develop multi-drug resistance. Anti-tumor agents overcoming resistance and acting through two or more ways offer greater therapeutic benefits over single-mechanism entities. In this study, we report on a new family of bifunctional compounds that, offering the possibility of dual action (drug + radiotherapy combinations), may result in significant clinical benefits. This new family of compounds combines two fragments: the drug fragment is a lapatinib group, which inhibits the tyrosine kinase receptor activity, and an icosahedral boron cluster used as agents for neutron capture therapy (BNCT). The developed compounds were evaluated in vitro against different tyrosine kinase receptors (TKRs)-expressing tumoral cells, and in vitro-BNCT experiments were performed for two of the most promising hybrids, 19 and 22. We identified hybrid 19 with excellent selectivity to inhibit cell proliferation and ability to induce necrosis/apoptosis of glioblastoma U87 MG cell line. Furthermore, derivative 22, bearing a water-solubility-enhancing moiety, showed moderate inhibition of cell proliferation in both U87 MG and colorectal HT-29 cell lines. Additionally, the HT-29 cells accumulated adequate levels of boron after hybrids 19 and 22 incubations rendering, and after neutron irradiation, higher BNCT-effects than BPA. The attractive profile of developed hybrids makes them interesting agents for combined therapy.
Fil: Couto, Marcos. Universidad de la República; Uruguay
Fil: Alamón, Catalina. Universidad de la República. Facultad de Ciencias; Uruguay
Fil: García, María. Universidad de la República. Facultad de Ciencias; Uruguay
Fil: Kovacs, Mariángeles. Instituto Pasteur; Francia
Fil: Trias, Emiliano. Instituto Pasteur; Francia
Fil: Nievas, Susana Isabel. Comisión Nacional de Energía Atómica; Argentina
Fil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; Argentina
Fil: Curotto, Paula. Comisión Nacional de Energía Atómica; Argentina
Fil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; Argentina
Fil: Dagrosa, María Alejandra. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Teixidor, Francesc. Consejo Superior de Investigaciones Científicas; España
Fil: Viñas, Clara. Consejo Superior de Investigaciones Científicas; España
Fil: Cerecetto, Hugo. Universidad de la República. Facultad de Química. Departamento de Química Orgánica; Uruguay
Materia
BORON CLUSTERS
IN VITRO BNCT EFFECT
LAPATINIB
TYROSINE KINASE INHIBITORS
[1,2,3]TRIAZOLYL LINKER
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/169051
Acceder
id CONICETDig_ef67853eb0e4bebfcfce3cb5a2ae5f06
oai_identifier_str oai:ri.conicet.gov.ar:11336/169051
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture TherapyCouto, MarcosAlamón, CatalinaGarcía, MaríaKovacs, MariángelesTrias, EmilianoNievas, Susana IsabelPozzi, Emiliano César CayetanoCurotto, PaulaThorp, Silvia InésDagrosa, María AlejandraTeixidor, FrancescViñas, ClaraCerecetto, HugoBORON CLUSTERSIN VITRO BNCT EFFECTLAPATINIBTYROSINE KINASE INHIBITORS[1,2,3]TRIAZOLYL LINKERhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3One of the driving forces of carcinogenesis in humans is the aberrant activation of receptors; consequently, one of the most promising mechanisms for cancer treatment is receptor inhibition by chemotherapy. Although a variety of cancers are initially susceptible to chemotherapy, they eventually develop multi-drug resistance. Anti-tumor agents overcoming resistance and acting through two or more ways offer greater therapeutic benefits over single-mechanism entities. In this study, we report on a new family of bifunctional compounds that, offering the possibility of dual action (drug + radiotherapy combinations), may result in significant clinical benefits. This new family of compounds combines two fragments: the drug fragment is a lapatinib group, which inhibits the tyrosine kinase receptor activity, and an icosahedral boron cluster used as agents for neutron capture therapy (BNCT). The developed compounds were evaluated in vitro against different tyrosine kinase receptors (TKRs)-expressing tumoral cells, and in vitro-BNCT experiments were performed for two of the most promising hybrids, 19 and 22. We identified hybrid 19 with excellent selectivity to inhibit cell proliferation and ability to induce necrosis/apoptosis of glioblastoma U87 MG cell line. Furthermore, derivative 22, bearing a water-solubility-enhancing moiety, showed moderate inhibition of cell proliferation in both U87 MG and colorectal HT-29 cell lines. Additionally, the HT-29 cells accumulated adequate levels of boron after hybrids 19 and 22 incubations rendering, and after neutron irradiation, higher BNCT-effects than BPA. The attractive profile of developed hybrids makes them interesting agents for combined therapy.Fil: Couto, Marcos. Universidad de la República; UruguayFil: Alamón, Catalina. Universidad de la República. Facultad de Ciencias; UruguayFil: García, María. Universidad de la República. Facultad de Ciencias; UruguayFil: Kovacs, Mariángeles. Instituto Pasteur; FranciaFil: Trias, Emiliano. Instituto Pasteur; FranciaFil: Nievas, Susana Isabel. Comisión Nacional de Energía Atómica; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Curotto, Paula. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Dagrosa, María Alejandra. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Teixidor, Francesc. Consejo Superior de Investigaciones Científicas; EspañaFil: Viñas, Clara. Consejo Superior de Investigaciones Científicas; EspañaFil: Cerecetto, Hugo. Universidad de la República. Facultad de Química. Departamento de Química Orgánica; UruguayMPDI2020-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/169051Couto, Marcos; Alamón, Catalina; García, María; Kovacs, Mariángeles; Trias, Emiliano; et al.; Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy; MPDI; Cells; 9; 6; 6-2020; 1-182073-4409CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/2073-4409/9/6/1408info:eu-repo/semantics/altIdentifier/doi/10.3390/cells9061408info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:11:06Zoai:ri.conicet.gov.ar:11336/169051instacron: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:34982025-10-22 12:11:06.972CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy
title Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy
spellingShingle Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy
Couto, Marcos
BORON CLUSTERS
IN VITRO BNCT EFFECT
LAPATINIB
TYROSINE KINASE INHIBITORS
[1,2,3]TRIAZOLYL LINKER
title_short Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy
title_full Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy
title_fullStr Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy
title_full_unstemmed Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy
title_sort Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy
dc.creator.none.fl_str_mv Couto, Marcos
Alamón, Catalina
García, María
Kovacs, Mariángeles
Trias, Emiliano
Nievas, Susana Isabel
Pozzi, Emiliano César Cayetano
Curotto, Paula
Thorp, Silvia Inés
Dagrosa, María Alejandra
Teixidor, Francesc
Viñas, Clara
Cerecetto, Hugo
author Couto, Marcos
author_facet Couto, Marcos
Alamón, Catalina
García, María
Kovacs, Mariángeles
Trias, Emiliano
Nievas, Susana Isabel
Pozzi, Emiliano César Cayetano
Curotto, Paula
Thorp, Silvia Inés
Dagrosa, María Alejandra
Teixidor, Francesc
Viñas, Clara
Cerecetto, Hugo
author_role author
author2 Alamón, Catalina
García, María
Kovacs, Mariángeles
Trias, Emiliano
Nievas, Susana Isabel
Pozzi, Emiliano César Cayetano
Curotto, Paula
Thorp, Silvia Inés
Dagrosa, María Alejandra
Teixidor, Francesc
Viñas, Clara
Cerecetto, Hugo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BORON CLUSTERS
IN VITRO BNCT EFFECT
LAPATINIB
TYROSINE KINASE INHIBITORS
[1,2,3]TRIAZOLYL LINKER
topic BORON CLUSTERS
IN VITRO BNCT EFFECT
LAPATINIB
TYROSINE KINASE INHIBITORS
[1,2,3]TRIAZOLYL LINKER
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv One of the driving forces of carcinogenesis in humans is the aberrant activation of receptors; consequently, one of the most promising mechanisms for cancer treatment is receptor inhibition by chemotherapy. Although a variety of cancers are initially susceptible to chemotherapy, they eventually develop multi-drug resistance. Anti-tumor agents overcoming resistance and acting through two or more ways offer greater therapeutic benefits over single-mechanism entities. In this study, we report on a new family of bifunctional compounds that, offering the possibility of dual action (drug + radiotherapy combinations), may result in significant clinical benefits. This new family of compounds combines two fragments: the drug fragment is a lapatinib group, which inhibits the tyrosine kinase receptor activity, and an icosahedral boron cluster used as agents for neutron capture therapy (BNCT). The developed compounds were evaluated in vitro against different tyrosine kinase receptors (TKRs)-expressing tumoral cells, and in vitro-BNCT experiments were performed for two of the most promising hybrids, 19 and 22. We identified hybrid 19 with excellent selectivity to inhibit cell proliferation and ability to induce necrosis/apoptosis of glioblastoma U87 MG cell line. Furthermore, derivative 22, bearing a water-solubility-enhancing moiety, showed moderate inhibition of cell proliferation in both U87 MG and colorectal HT-29 cell lines. Additionally, the HT-29 cells accumulated adequate levels of boron after hybrids 19 and 22 incubations rendering, and after neutron irradiation, higher BNCT-effects than BPA. The attractive profile of developed hybrids makes them interesting agents for combined therapy.
Fil: Couto, Marcos. Universidad de la República; Uruguay
Fil: Alamón, Catalina. Universidad de la República. Facultad de Ciencias; Uruguay
Fil: García, María. Universidad de la República. Facultad de Ciencias; Uruguay
Fil: Kovacs, Mariángeles. Instituto Pasteur; Francia
Fil: Trias, Emiliano. Instituto Pasteur; Francia
Fil: Nievas, Susana Isabel. Comisión Nacional de Energía Atómica; Argentina
Fil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; Argentina
Fil: Curotto, Paula. Comisión Nacional de Energía Atómica; Argentina
Fil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; Argentina
Fil: Dagrosa, María Alejandra. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Teixidor, Francesc. Consejo Superior de Investigaciones Científicas; España
Fil: Viñas, Clara. Consejo Superior de Investigaciones Científicas; España
Fil: Cerecetto, Hugo. Universidad de la República. Facultad de Química. Departamento de Química Orgánica; Uruguay
description One of the driving forces of carcinogenesis in humans is the aberrant activation of receptors; consequently, one of the most promising mechanisms for cancer treatment is receptor inhibition by chemotherapy. Although a variety of cancers are initially susceptible to chemotherapy, they eventually develop multi-drug resistance. Anti-tumor agents overcoming resistance and acting through two or more ways offer greater therapeutic benefits over single-mechanism entities. In this study, we report on a new family of bifunctional compounds that, offering the possibility of dual action (drug + radiotherapy combinations), may result in significant clinical benefits. This new family of compounds combines two fragments: the drug fragment is a lapatinib group, which inhibits the tyrosine kinase receptor activity, and an icosahedral boron cluster used as agents for neutron capture therapy (BNCT). The developed compounds were evaluated in vitro against different tyrosine kinase receptors (TKRs)-expressing tumoral cells, and in vitro-BNCT experiments were performed for two of the most promising hybrids, 19 and 22. We identified hybrid 19 with excellent selectivity to inhibit cell proliferation and ability to induce necrosis/apoptosis of glioblastoma U87 MG cell line. Furthermore, derivative 22, bearing a water-solubility-enhancing moiety, showed moderate inhibition of cell proliferation in both U87 MG and colorectal HT-29 cell lines. Additionally, the HT-29 cells accumulated adequate levels of boron after hybrids 19 and 22 incubations rendering, and after neutron irradiation, higher BNCT-effects than BPA. The attractive profile of developed hybrids makes them interesting agents for combined therapy.
publishDate 2020
dc.date.none.fl_str_mv 2020-06
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/11336/169051
Couto, Marcos; Alamón, Catalina; García, María; Kovacs, Mariángeles; Trias, Emiliano; et al.; Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy; MPDI; Cells; 9; 6; 6-2020; 1-18
2073-4409
CONICET Digital
CONICET
url http://hdl.handle.net/11336/169051
identifier_str_mv Couto, Marcos; Alamón, Catalina; García, María; Kovacs, Mariángeles; Trias, Emiliano; et al.; Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy; MPDI; Cells; 9; 6; 6-2020; 1-18
2073-4409
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.mdpi.com/2073-4409/9/6/1408
info:eu-repo/semantics/altIdentifier/doi/10.3390/cells9061408
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MPDI
publisher.none.fl_str_mv MPDI
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 12.982451

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