Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity
Resumen:
Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood–brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior.
2020 | |
Carborane FLT3 Sub-G1 arrest Anti-tumor activity |
|
Inglés | |
Universidad de la República | |
COLIBRI | |
https://hdl.handle.net/20.500.12008/31990 | |
Acceso abierto | |
Licencia Creative Commons Atribución (CC - By 4.0) |
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author | Alamón, Catalina |
author2 | Dávila Saralegui, Belén García Melián, María Fernanda Sánchez, Carina Kovacs, Mariángeles Trias, Emiliano Barbeito, Luis Gabay, Martín Zeineh, Nidal Gavish, Moshe Teixidor, Francesc Viñas, Clara Couto, Marcos Cerecetto, Hugo |
author2_role | author author author author author author author author author author author author author |
author_facet | Alamón, Catalina Dávila Saralegui, Belén García Melián, María Fernanda Sánchez, Carina Kovacs, Mariángeles Trias, Emiliano Barbeito, Luis Gabay, Martín Zeineh, Nidal Gavish, Moshe Teixidor, Francesc Viñas, Clara Couto, Marcos Cerecetto, Hugo |
author_role | author |
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collection | COLIBRI |
dc.contributor.filiacion.none.fl_str_mv | Alamón Catalina, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica. Dávila Saralegui Belén, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica. García Melián María Fernanda, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares. Sánchez Carina, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica. Kovacs Mariángeles, Institut Pasteur (Montevideo) Trias Emiliano, Institut Pasteur (Montevideo) Barbeito Luis, Institut Pasteur (Montevideo) Gabay Martín Zeineh Nidal Gavish Moshe Teixidor Francesc Viñas Clara Couto Marcos, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica. Cerecetto Hugo, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares. |
dc.creator.none.fl_str_mv | Alamón, Catalina Dávila Saralegui, Belén García Melián, María Fernanda Sánchez, Carina Kovacs, Mariángeles Trias, Emiliano Barbeito, Luis Gabay, Martín Zeineh, Nidal Gavish, Moshe Teixidor, Francesc Viñas, Clara Couto, Marcos Cerecetto, Hugo |
dc.date.accessioned.none.fl_str_mv | 2022-06-14T13:03:56Z |
dc.date.available.none.fl_str_mv | 2022-06-14T13:03:56Z |
dc.date.issued.none.fl_str_mv | 2020 |
dc.description.abstract.none.fl_txt_mv | Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood–brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior. |
dc.format.extent.es.fl_str_mv | 21 h. |
dc.format.mimetype.es.fl_str_mv | application/pdf |
dc.identifier.citation.es.fl_str_mv | Alamón, C, Dávila Saralegui, B, García Melián, M, [y otros] "Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity". Cancers. [en línea] 2020, 12(11): 3423. 21 h. DOI: 10.3390/cancers12113423 |
dc.identifier.doi.none.fl_str_mv | 10.3390/cancers12113423 |
dc.identifier.issn.none.fl_str_mv | 2072-6694 |
dc.identifier.uri.none.fl_str_mv | https://hdl.handle.net/20.500.12008/31990 |
dc.language.iso.none.fl_str_mv | en eng |
dc.publisher.es.fl_str_mv | MDPI |
dc.relation.ispartof.es.fl_str_mv | Cancers, 2020, 12(11): 3423 |
dc.rights.license.none.fl_str_mv | Licencia Creative Commons Atribución (CC - By 4.0) |
dc.rights.none.fl_str_mv | info:eu-repo/semantics/openAccess |
dc.source.none.fl_str_mv | reponame:COLIBRI instname:Universidad de la República instacron:Universidad de la República |
dc.subject.en.fl_str_mv | Sub-G1 arrest Anti-tumor activity |
dc.subject.es.fl_str_mv | Carborane FLT3 |
dc.title.none.fl_str_mv | Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity |
dc.type.es.fl_str_mv | Artículo |
dc.type.none.fl_str_mv | info:eu-repo/semantics/article |
dc.type.version.none.fl_str_mv | info:eu-repo/semantics/publishedVersion |
description | Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood–brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior. |
eu_rights_str_mv | openAccess |
format | article |
id | COLIBRI_bbc0d4e8895cbcfd6d3492bebf32a37b |
identifier_str_mv | Alamón, C, Dávila Saralegui, B, García Melián, M, [y otros] "Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity". Cancers. [en línea] 2020, 12(11): 3423. 21 h. DOI: 10.3390/cancers12113423 2072-6694 10.3390/cancers12113423 |
instacron_str | Universidad de la República |
institution | Universidad de la República |
instname_str | Universidad de la República |
language | eng |
language_invalid_str_mv | en |
network_acronym_str | COLIBRI |
network_name_str | COLIBRI |
oai_identifier_str | oai:colibri.udelar.edu.uy:20.500.12008/31990 |
publishDate | 2020 |
reponame_str | COLIBRI |
repository.mail.fl_str_mv | mabel.seroubian@seciu.edu.uy |
repository.name.fl_str_mv | COLIBRI - Universidad de la República |
repository_id_str | 4771 |
rights_invalid_str_mv | Licencia Creative Commons Atribución (CC - By 4.0) |
spelling | Alamón Catalina, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.Dávila Saralegui Belén, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.García Melián María Fernanda, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares.Sánchez Carina, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.Kovacs Mariángeles, Institut Pasteur (Montevideo)Trias Emiliano, Institut Pasteur (Montevideo)Barbeito Luis, Institut Pasteur (Montevideo)Gabay MartínZeineh NidalGavish MosheTeixidor FrancescViñas ClaraCouto Marcos, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.Cerecetto Hugo, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares.2022-06-14T13:03:56Z2022-06-14T13:03:56Z2020Alamón, C, Dávila Saralegui, B, García Melián, M, [y otros] "Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity". Cancers. [en línea] 2020, 12(11): 3423. 21 h. DOI: 10.3390/cancers121134232072-6694https://hdl.handle.net/20.500.12008/3199010.3390/cancers12113423Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood–brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior.Submitted by Verdun Juan Pablo (jverdun@fcien.edu.uy) on 2022-06-13T16:49:59Z No. of bitstreams: 2 license_rdf: 19875 bytes, checksum: 9fdbed07f52437945402c4e70fa4773e (MD5) 10.3390cancers12113423.pdf: 5603806 bytes, checksum: 105210021842c68e20b999fd047d41d5 (MD5)Approved for entry into archive by Faget Cecilia (lfaget@fcien.edu.uy) on 2022-06-14T12:53:18Z (GMT) No. of bitstreams: 2 license_rdf: 19875 bytes, checksum: 9fdbed07f52437945402c4e70fa4773e (MD5) 10.3390cancers12113423.pdf: 5603806 bytes, checksum: 105210021842c68e20b999fd047d41d5 (MD5)Made available in DSpace by Luna Fabiana (fabiana.luna@seciu.edu.uy) on 2022-06-14T13:03:56Z (GMT). No. of bitstreams: 2 license_rdf: 19875 bytes, checksum: 9fdbed07f52437945402c4e70fa4773e (MD5) 10.3390cancers12113423.pdf: 5603806 bytes, checksum: 105210021842c68e20b999fd047d41d5 (MD5) Previous issue date: 202021 h.application/pdfenengMDPICancers, 2020, 12(11): 3423Las obras depositadas en el Repositorio se rigen por la Ordenanza de los Derechos de la Propiedad Intelectual de la Universidad de la República.(Res. Nº 91 de C.D.C. de 8/III/1994 – D.O. 7/IV/1994) y por la Ordenanza del Repositorio Abierto de la Universidad de la República (Res. Nº 16 de C.D.C. de 07/10/2014)info:eu-repo/semantics/openAccessLicencia Creative Commons Atribución (CC - By 4.0)CarboraneFLT3Sub-G1 arrestAnti-tumor activitySunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activityArtículoinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionreponame:COLIBRIinstname:Universidad de la Repúblicainstacron:Universidad de la RepúblicaAlamón, CatalinaDávila Saralegui, BelénGarcía Melián, María FernandaSánchez, CarinaKovacs, MariángelesTrias, EmilianoBarbeito, LuisGabay, MartínZeineh, NidalGavish, MosheTeixidor, FrancescViñas, ClaraCouto, MarcosCerecetto, HugoLICENSElicense.txtlicense.txttext/plain; charset=utf-84267http://localhost:8080/xmlui/bitstream/20.500.12008/31990/5/license.txt6429389a7df7277b72b7924fdc7d47a9MD55CC-LICENSElicense_urllicense_urltext/plain; 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- Universidad de la Repúblicafalse |
spellingShingle | Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity Alamón, Catalina Carborane FLT3 Sub-G1 arrest Anti-tumor activity |
status_str | publishedVersion |
title | Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity |
title_full | Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity |
title_fullStr | Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity |
title_full_unstemmed | Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity |
title_short | Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity |
title_sort | Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity |
topic | Carborane FLT3 Sub-G1 arrest Anti-tumor activity |
url | https://hdl.handle.net/20.500.12008/31990 |