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Sunitinib-Containing Carborane Pharmacophore with the Ability to Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, Exhibits Powerful In Vivo Anti-Glioblastoma Activity

SIMPLE SUMMARY: Glioblastoma is one of the most aggressive central nervous system tumors. Combinations of therapies, such as tyrosine kinase receptor inhibition and boron neutron capture therapy (BNCT), could offer greater patients benefits over single-therapies. The aim of our study was to assess t...

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Autores principales: Alamón, Catalina, Dávila, Belén, García, María Fernanda, Sánchez, Carina, Kovacs, Mariángeles, Trias, Emiliano, Barbeito, Luis, Gabay, Martín, Zeineh, Nidal, Gavish, Moshe, Teixidor, Francesc, Viñas, Clara, Couto, Marcos, Cerecetto, Hugo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698965/
https://www.ncbi.nlm.nih.gov/pubmed/33218150
http://dx.doi.org/10.3390/cancers12113423
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author Alamón, Catalina
Dávila, Belén
García, 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_facet Alamón, Catalina
Dávila, Belén
García, 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_sort Alamón, Catalina
collection PubMed
description SIMPLE SUMMARY: Glioblastoma is one of the most aggressive central nervous system tumors. Combinations of therapies, such as tyrosine kinase receptor inhibition and boron neutron capture therapy (BNCT), could offer greater patients benefits over single-therapies. The aim of our study was to assess the potential of sunitinib-carborane hybrid compound 1 as an anti-glioblastoma agent. We confirmed for 1 the ability to inhibit tyrosine kinase receptors, which could promote canonical and non-canonical effects, absence of mutagenicity, ability to cross the blood–brain barrier, and powerful in vivo anti-glioblastoma activity. The overall attractive profile of 1 makes it an interesting compound for a bimodal therapeutic strategy against high grade gliomas. ABSTRACT: 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.
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spelling pubmed-76989652020-11-29 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 Dávila, Belén García, María Fernanda Sánchez, Carina Kovacs, Mariángeles Trias, Emiliano Barbeito, Luis Gabay, Martín Zeineh, Nidal Gavish, Moshe Teixidor, Francesc Viñas, Clara Couto, Marcos Cerecetto, Hugo Cancers (Basel) Article SIMPLE SUMMARY: Glioblastoma is one of the most aggressive central nervous system tumors. Combinations of therapies, such as tyrosine kinase receptor inhibition and boron neutron capture therapy (BNCT), could offer greater patients benefits over single-therapies. The aim of our study was to assess the potential of sunitinib-carborane hybrid compound 1 as an anti-glioblastoma agent. We confirmed for 1 the ability to inhibit tyrosine kinase receptors, which could promote canonical and non-canonical effects, absence of mutagenicity, ability to cross the blood–brain barrier, and powerful in vivo anti-glioblastoma activity. The overall attractive profile of 1 makes it an interesting compound for a bimodal therapeutic strategy against high grade gliomas. ABSTRACT: 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. MDPI 2020-11-18 /pmc/articles/PMC7698965/ /pubmed/33218150 http://dx.doi.org/10.3390/cancers12113423 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alamón, Catalina
Dávila, Belén
García, María Fernanda
Sánchez, Carina
Kovacs, Mariángeles
Trias, Emiliano
Barbeito, Luis
Gabay, Martín
Zeineh, Nidal
Gavish, Moshe
Teixidor, Francesc
Viñas, Clara
Couto, Marcos
Cerecetto, Hugo
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 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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698965/
https://www.ncbi.nlm.nih.gov/pubmed/33218150
http://dx.doi.org/10.3390/cancers12113423
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