The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2

Autores
Llorens de los Ríos, María C.; Lanza, Priscila A.; Barbieri, Cecilia L.; González, María L.; Funes Chabán, Macarena; Soria, Gastón; Vera, D. Mariano A.; Carpinella, María Cecilia; Joray, Mariana Belén
Año de publicación
2022
Idioma
español castellano
Tipo de recurso
artículo
Estado
versión aceptada
Descripción
Background: Tumor angiogenesis is considered as a crucial pathologic feature of cancer with a key role in multidrug resistance (MDR). Adverse effects of the currently available drugs and the development of resistance to these remain as the hardest obstacles to defeat. Objetive: This work explores flora from Argentina as a source of new chemical entities with antiangiogenic activity. Methods: Tube formation assay using bovine aortic endothelial cells (BAECs) was the experiment of choice to assess antiangiogenic activity. The effect of the pure compound in cell invasiveness was investigated through the trans-well migration assay. The inhibitory effect of the pure compound on VEGFR-2 and PKC isozymes α and β2 activation was studied by molecular and massive dynamic simulations. Cytotoxicity on peripheral blood mononuclear cells and erythrocyte cells was evaluated by means of MTT and hemolysis assay, respectively. In silico prediction of pharmacological properties (ADME) and evaluation of drug-likeness features were performed using the SwissADME online tool. Results: Among the plants screened, T. minuta, showed an outstanding effect with an IC50 of 33.6 ± 3.4 μg/ml. Bio-guided isolation yielded the terthiophene α-terthienylmethanol as its active metabolite. This compound inhibited VEGF-induced tube formation with an IC50 of 2.7 ± 0.4 μM and significantly impaired the invasiveness of bovine aortic endothelial cells (BAECs) as well as of the highly aggressive breast cancer cells, MDA-MB-231, when tested at 10 μM. Direct VEGFR-2 and PKC inhibition were both explored by means of massive molecular dynamics simulations. The results obtained validated the inhibitory effect on protein kinase C (PKC) isozymes α and β2 as the main mechanism underlying its antiangiogenic activity. α-terthienylmethanol showed no evidence of toxicity against peripheral blood mononuclear and erythrocyte cells. Conclusion: These findings support this thiophene as a promising antiangiogenic phytochemical to fight against several types of cancer mainly those with MDR phenotype.
Fil: Llorens de los Ríos, María C. 1 Fundación para el Progreso de la Medicina; Argentina
Fil: Lanza, Priscila A. Universidad Nacional de Mar del Plata. Departamento de Química y Bioquímica; Argentina
Fil: Barbieri, Cecilia L. Universidad Nacional de Mar del Plata. Departamento de Química y Bioquímica; Argentina
Fil: González, María L. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Funes Chabán, Macarena. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Soria, Gastón. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Vera, D. Mariano A. Universidad Nacional de Mar del Plata. Departamento de Química y Bioquímica; Argentina
Fil: Carpinella, María Cecilia. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Joray, Mariana Belén. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fuente
Llorens de los Ríos, María C., Lanza, Priscila A., Barbieri, Cecilia L. ORCID: https://orcid.org/0000-0001-5101-2317 , González, María L., Funes Chabán, Macarena ORCID: https://orcid.org/0000-0002-4038-9327 , Soria, Gastón ORCID: https://orcid.org/0000-0003-2177-5094 , Vera, D. Mariano A. ORCID: https://orcid.org/0000-0003-1433-4741 , Carpinella, María Cecilia ORCID: https://orcid.org/0000-0001-5553-1851 and Joray, Mariana Belén ORCID: https://orcid.org/0000-0001-9042-6926 (2022) The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2. Frontiers in pharmacology (13). ISSN 1663-9812
Materia
QD Química
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/4.0/deed.es
Repositorio
Producción Académica (UCC)
Institución
Universidad Católica de Córdoba
OAI Identificador
oai:pa.bibdigital.uccor.edu.ar:3686
Acceder
id PAUCC_ec307b47ff524ab4f961a453a3d609f3
oai_identifier_str oai:pa.bibdigital.uccor.edu.ar:3686
network_acronym_str PAUCC
repository_id_str 2718
network_name_str Producción Académica (UCC)
spelling The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2Llorens de los Ríos, María C.Lanza, Priscila A.Barbieri, Cecilia L.González, María L.Funes Chabán, MacarenaSoria, GastónVera, D. Mariano A.Carpinella, María CeciliaJoray, Mariana BelénQD QuímicaBackground: Tumor angiogenesis is considered as a crucial pathologic feature of cancer with a key role in multidrug resistance (MDR). Adverse effects of the currently available drugs and the development of resistance to these remain as the hardest obstacles to defeat. Objetive: This work explores flora from Argentina as a source of new chemical entities with antiangiogenic activity. Methods: Tube formation assay using bovine aortic endothelial cells (BAECs) was the experiment of choice to assess antiangiogenic activity. The effect of the pure compound in cell invasiveness was investigated through the trans-well migration assay. The inhibitory effect of the pure compound on VEGFR-2 and PKC isozymes α and β2 activation was studied by molecular and massive dynamic simulations. Cytotoxicity on peripheral blood mononuclear cells and erythrocyte cells was evaluated by means of MTT and hemolysis assay, respectively. In silico prediction of pharmacological properties (ADME) and evaluation of drug-likeness features were performed using the SwissADME online tool. Results: Among the plants screened, T. minuta, showed an outstanding effect with an IC50 of 33.6 ± 3.4 μg/ml. Bio-guided isolation yielded the terthiophene α-terthienylmethanol as its active metabolite. This compound inhibited VEGF-induced tube formation with an IC50 of 2.7 ± 0.4 μM and significantly impaired the invasiveness of bovine aortic endothelial cells (BAECs) as well as of the highly aggressive breast cancer cells, MDA-MB-231, when tested at 10 μM. Direct VEGFR-2 and PKC inhibition were both explored by means of massive molecular dynamics simulations. The results obtained validated the inhibitory effect on protein kinase C (PKC) isozymes α and β2 as the main mechanism underlying its antiangiogenic activity. α-terthienylmethanol showed no evidence of toxicity against peripheral blood mononuclear and erythrocyte cells. Conclusion: These findings support this thiophene as a promising antiangiogenic phytochemical to fight against several types of cancer mainly those with MDR phenotype.Fil: Llorens de los Ríos, María C. 1 Fundación para el Progreso de la Medicina; ArgentinaFil: Lanza, Priscila A. Universidad Nacional de Mar del Plata. Departamento de Química y Bioquímica; ArgentinaFil: Barbieri, Cecilia L. Universidad Nacional de Mar del Plata. Departamento de Química y Bioquímica; ArgentinaFil: González, María L. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Funes Chabán, Macarena. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Soria, Gastón. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Vera, D. Mariano A. Universidad Nacional de Mar del Plata. Departamento de Química y Bioquímica; ArgentinaFil: Carpinella, María Cecilia. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Joray, Mariana Belén. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina2022-10-31info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://pa.bibdigital.ucc.edu.ar/3686/1/A_LLorensdelosR%C3%ADos_Lanza_Barbieri_Gonz%C3%A1lez_FunesChab%C3%A1n_Soria_Vera_Carpinella_Joray.pdf Llorens de los Ríos, María C., Lanza, Priscila A., Barbieri, Cecilia L. ORCID: https://orcid.org/0000-0001-5101-2317 <https://orcid.org/0000-0001-5101-2317>, González, María L., Funes Chabán, Macarena ORCID: https://orcid.org/0000-0002-4038-9327 <https://orcid.org/0000-0002-4038-9327>, Soria, Gastón ORCID: https://orcid.org/0000-0003-2177-5094 <https://orcid.org/0000-0003-2177-5094>, Vera, D. Mariano A. ORCID: https://orcid.org/0000-0003-1433-4741 <https://orcid.org/0000-0003-1433-4741>, Carpinella, María Cecilia ORCID: https://orcid.org/0000-0001-5553-1851 <https://orcid.org/0000-0001-5553-1851> and Joray, Mariana Belén ORCID: https://orcid.org/0000-0001-9042-6926 <https://orcid.org/0000-0001-9042-6926> (2022) The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2. Frontiers in pharmacology (13). ISSN 1663-9812 reponame:Producción Académica (UCC)instname:Universidad Católica de Córdobaspahttp://pa.bibdigital.ucc.edu.ar/3686/info:eu-repo/semantics/altIdentifier/doi/10.3389/fphar.2022.1007790info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/4.0/deed.es2025-10-16T10:06:27Zoai:pa.bibdigital.uccor.edu.ar:3686instacron:UCCInstitucionalhttp://pa.bibdigital.uccor.edu.ar/Universidad privadaNo correspondehttp://pa.bibdigital.uccor.edu.ar/cgi/oai2bibdir@uccor.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:27182025-10-16 10:06:28.215Producción Académica (UCC) - Universidad Católica de Córdobafalse
dc.title.none.fl_str_mv The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2
title The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2
spellingShingle The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2
Llorens de los Ríos, María C.
QD Química
title_short The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2
title_full The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2
title_fullStr The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2
title_full_unstemmed The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2
title_sort The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2
dc.creator.none.fl_str_mv Llorens de los Ríos, María C.
Lanza, Priscila A.
Barbieri, Cecilia L.
González, María L.
Funes Chabán, Macarena
Soria, Gastón
Vera, D. Mariano A.
Carpinella, María Cecilia
Joray, Mariana Belén
author Llorens de los Ríos, María C.
author_facet Llorens de los Ríos, María C.
Lanza, Priscila A.
Barbieri, Cecilia L.
González, María L.
Funes Chabán, Macarena
Soria, Gastón
Vera, D. Mariano A.
Carpinella, María Cecilia
Joray, Mariana Belén
author_role author
author2 Lanza, Priscila A.
Barbieri, Cecilia L.
González, María L.
Funes Chabán, Macarena
Soria, Gastón
Vera, D. Mariano A.
Carpinella, María Cecilia
Joray, Mariana Belén
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv QD Química
topic QD Química
dc.description.none.fl_txt_mv Background: Tumor angiogenesis is considered as a crucial pathologic feature of cancer with a key role in multidrug resistance (MDR). Adverse effects of the currently available drugs and the development of resistance to these remain as the hardest obstacles to defeat. Objetive: This work explores flora from Argentina as a source of new chemical entities with antiangiogenic activity. Methods: Tube formation assay using bovine aortic endothelial cells (BAECs) was the experiment of choice to assess antiangiogenic activity. The effect of the pure compound in cell invasiveness was investigated through the trans-well migration assay. The inhibitory effect of the pure compound on VEGFR-2 and PKC isozymes α and β2 activation was studied by molecular and massive dynamic simulations. Cytotoxicity on peripheral blood mononuclear cells and erythrocyte cells was evaluated by means of MTT and hemolysis assay, respectively. In silico prediction of pharmacological properties (ADME) and evaluation of drug-likeness features were performed using the SwissADME online tool. Results: Among the plants screened, T. minuta, showed an outstanding effect with an IC50 of 33.6 ± 3.4 μg/ml. Bio-guided isolation yielded the terthiophene α-terthienylmethanol as its active metabolite. This compound inhibited VEGF-induced tube formation with an IC50 of 2.7 ± 0.4 μM and significantly impaired the invasiveness of bovine aortic endothelial cells (BAECs) as well as of the highly aggressive breast cancer cells, MDA-MB-231, when tested at 10 μM. Direct VEGFR-2 and PKC inhibition were both explored by means of massive molecular dynamics simulations. The results obtained validated the inhibitory effect on protein kinase C (PKC) isozymes α and β2 as the main mechanism underlying its antiangiogenic activity. α-terthienylmethanol showed no evidence of toxicity against peripheral blood mononuclear and erythrocyte cells. Conclusion: These findings support this thiophene as a promising antiangiogenic phytochemical to fight against several types of cancer mainly those with MDR phenotype.
Fil: Llorens de los Ríos, María C. 1 Fundación para el Progreso de la Medicina; Argentina
Fil: Lanza, Priscila A. Universidad Nacional de Mar del Plata. Departamento de Química y Bioquímica; Argentina
Fil: Barbieri, Cecilia L. Universidad Nacional de Mar del Plata. Departamento de Química y Bioquímica; Argentina
Fil: González, María L. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Funes Chabán, Macarena. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Soria, Gastón. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Vera, D. Mariano A. Universidad Nacional de Mar del Plata. Departamento de Química y Bioquímica; Argentina
Fil: Carpinella, María Cecilia. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Joray, Mariana Belén. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
description Background: Tumor angiogenesis is considered as a crucial pathologic feature of cancer with a key role in multidrug resistance (MDR). Adverse effects of the currently available drugs and the development of resistance to these remain as the hardest obstacles to defeat. Objetive: This work explores flora from Argentina as a source of new chemical entities with antiangiogenic activity. Methods: Tube formation assay using bovine aortic endothelial cells (BAECs) was the experiment of choice to assess antiangiogenic activity. The effect of the pure compound in cell invasiveness was investigated through the trans-well migration assay. The inhibitory effect of the pure compound on VEGFR-2 and PKC isozymes α and β2 activation was studied by molecular and massive dynamic simulations. Cytotoxicity on peripheral blood mononuclear cells and erythrocyte cells was evaluated by means of MTT and hemolysis assay, respectively. In silico prediction of pharmacological properties (ADME) and evaluation of drug-likeness features were performed using the SwissADME online tool. Results: Among the plants screened, T. minuta, showed an outstanding effect with an IC50 of 33.6 ± 3.4 μg/ml. Bio-guided isolation yielded the terthiophene α-terthienylmethanol as its active metabolite. This compound inhibited VEGF-induced tube formation with an IC50 of 2.7 ± 0.4 μM and significantly impaired the invasiveness of bovine aortic endothelial cells (BAECs) as well as of the highly aggressive breast cancer cells, MDA-MB-231, when tested at 10 μM. Direct VEGFR-2 and PKC inhibition were both explored by means of massive molecular dynamics simulations. The results obtained validated the inhibitory effect on protein kinase C (PKC) isozymes α and β2 as the main mechanism underlying its antiangiogenic activity. α-terthienylmethanol showed no evidence of toxicity against peripheral blood mononuclear and erythrocyte cells. Conclusion: These findings support this thiophene as a promising antiangiogenic phytochemical to fight against several types of cancer mainly those with MDR phenotype.
publishDate 2022
dc.date.none.fl_str_mv 2022-10-31
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://pa.bibdigital.ucc.edu.ar/3686/1/A_LLorensdelosR%C3%ADos_Lanza_Barbieri_Gonz%C3%A1lez_FunesChab%C3%A1n_Soria_Vera_Carpinella_Joray.pdf
url http://pa.bibdigital.ucc.edu.ar/3686/1/A_LLorensdelosR%C3%ADos_Lanza_Barbieri_Gonz%C3%A1lez_FunesChab%C3%A1n_Soria_Vera_Carpinella_Joray.pdf
dc.language.none.fl_str_mv spa
language spa
dc.relation.none.fl_str_mv http://pa.bibdigital.ucc.edu.ar/3686/
info:eu-repo/semantics/altIdentifier/doi/10.3389/fphar.2022.1007790
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/4.0/deed.es
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/deed.es
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv Llorens de los Ríos, María C., Lanza, Priscila A., Barbieri, Cecilia L. ORCID: https://orcid.org/0000-0001-5101-2317 <https://orcid.org/0000-0001-5101-2317>, González, María L., Funes Chabán, Macarena ORCID: https://orcid.org/0000-0002-4038-9327 <https://orcid.org/0000-0002-4038-9327>, Soria, Gastón ORCID: https://orcid.org/0000-0003-2177-5094 <https://orcid.org/0000-0003-2177-5094>, Vera, D. Mariano A. ORCID: https://orcid.org/0000-0003-1433-4741 <https://orcid.org/0000-0003-1433-4741>, Carpinella, María Cecilia ORCID: https://orcid.org/0000-0001-5553-1851 <https://orcid.org/0000-0001-5553-1851> and Joray, Mariana Belén ORCID: https://orcid.org/0000-0001-9042-6926 <https://orcid.org/0000-0001-9042-6926> (2022) The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2. Frontiers in pharmacology (13). ISSN 1663-9812
reponame:Producción Académica (UCC)
instname:Universidad Católica de Córdoba
reponame_str Producción Académica (UCC)
collection Producción Académica (UCC)
instname_str Universidad Católica de Córdoba
repository.name.fl_str_mv Producción Académica (UCC) - Universidad Católica de Córdoba
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