Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity

Background: Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological d...

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Autores: Orzáez, Mar, Sancho, Mónica, Marchán, Sandra, Mondragón, Laura, Montava, Rebeca, García Valero, Juan, Landeta Díaz, Olatz, Basáñez Asúa, Gorka, Carbajo, Rodrigo J., Pineda-Lucena, Antonio, Bujons, Jordi, Moure, Alejandra, Messeguer, Angel, Lagunas, Carmen, Herrero, Carmen, Pérez-Payá, Enrique
Tipo de recurso: artículo
Fecha de publicación:2014
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/15910
Acceso en línea:http://hdl.handle.net/10810/15910
Access Level:acceso abierto
Palabra clave:caspase inhibitor
induced apoptosis
myocardial-infarction
cisplatin ototoxicity
accurate docking
binding
activation
glide
identification
procaspase-9
AGRICULTURAL AND BIOLOGICAL SCIENCES
MEDICINE
BIOCHEMISTRY AND MOLECULAR BIOLOGY
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spelling Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced OtotoxicityOrzáez, MarSancho, MónicaMarchán, SandraMondragón, LauraMontava, RebecaGarcía Valero, JuanLandeta Díaz, OlatzBasáñez Asúa, GorkaCarbajo, Rodrigo J.Pineda-Lucena, AntonioBujons, JordiMoure, AlejandraMesseguer, AngelLagunas, CarmenHerrero, CarmenPérez-Payá, Enriquecaspase inhibitorinduced apoptosismyocardial-infarctioncisplatin ototoxicityaccurate dockingbindingactivationglideidentificationprocaspase-9AGRICULTURAL AND BIOLOGICAL SCIENCESMEDICINEBIOCHEMISTRY AND MOLECULAR BIOLOGYBackground: Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is still considered an unmet medical need. Methodology and Principal Findings: The interaction between Apaf-1 and the inhibitors was confirmed by NMR. Target specificity was evaluated in cellular models by siRNa based approaches. Cell recovery was confirmed by MTT, clonogenicity and flow cytometry assays. The efficiency of the compounds as antiapoptotic agents was tested in cellular and in vivo models of protection upon cisplatin induced ototoxicity in a zebrafish model and from hypoxia and reperfusion kidney damage in a rat model of hot ischemia. Conclusions: Apaf-1 inhibitors decreased Cytc release and apoptosome-mediated activation of procaspase-9 preventing cell and tissue damage in ex vivo experiments and in vivo animal models of apoptotic damage. Our results provide evidence that Apaf-1 pharmacological inhibition has therapeutic potential for the treatment of apoptosis-related diseases.This work was supported by grants from the Spanish Ministry of Science and Innovation (MICINN - BIO2007-60066, SAF2008-00048, SAF30542-C01-01 and SAF2010-15512), Laboratorios SALVAT, S.A., Fundacion Renal Tomas de Osma, Generalitat Valenciana Prometeo 2010/005 (partially funded with ERDF), Consolider-Ingenio 2010 (MICINN - CSD2008-00005C) and by the Generalitat Valenciana through Prometeo 2014/061. Moure was funded by a predoctoral fellowship from JAE-pre CSIC. The funders provided financial support and had a role in the data collection, analysis and manuscript preparation of cellular and in vivo model of ototoxicity. The specific roles of these authors are articulated in the 'author contributions' section.Public Library Science201520152014info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/15910reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoIngléshttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110979#abstract0info:eu-repo/semantics/openAccess© 2014 Orzáez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.oai:addi.ehu.eus:10810/159102026-06-18T09:23:17Z
dc.title.none.fl_str_mv Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity
title Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity
spellingShingle Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity
Orzáez, Mar
caspase inhibitor
induced apoptosis
myocardial-infarction
cisplatin ototoxicity
accurate docking
binding
activation
glide
identification
procaspase-9
AGRICULTURAL AND BIOLOGICAL SCIENCES
MEDICINE
BIOCHEMISTRY AND MOLECULAR BIOLOGY
title_short Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity
title_full Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity
title_fullStr Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity
title_full_unstemmed Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity
title_sort Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity
dc.creator.none.fl_str_mv Orzáez, Mar
Sancho, Mónica
Marchán, Sandra
Mondragón, Laura
Montava, Rebeca
García Valero, Juan
Landeta Díaz, Olatz
Basáñez Asúa, Gorka
Carbajo, Rodrigo J.
Pineda-Lucena, Antonio
Bujons, Jordi
Moure, Alejandra
Messeguer, Angel
Lagunas, Carmen
Herrero, Carmen
Pérez-Payá, Enrique
author Orzáez, Mar
author_facet Orzáez, Mar
Sancho, Mónica
Marchán, Sandra
Mondragón, Laura
Montava, Rebeca
García Valero, Juan
Landeta Díaz, Olatz
Basáñez Asúa, Gorka
Carbajo, Rodrigo J.
Pineda-Lucena, Antonio
Bujons, Jordi
Moure, Alejandra
Messeguer, Angel
Lagunas, Carmen
Herrero, Carmen
Pérez-Payá, Enrique
author_role author
author2 Sancho, Mónica
Marchán, Sandra
Mondragón, Laura
Montava, Rebeca
García Valero, Juan
Landeta Díaz, Olatz
Basáñez Asúa, Gorka
Carbajo, Rodrigo J.
Pineda-Lucena, Antonio
Bujons, Jordi
Moure, Alejandra
Messeguer, Angel
Lagunas, Carmen
Herrero, Carmen
Pérez-Payá, Enrique
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv caspase inhibitor
induced apoptosis
myocardial-infarction
cisplatin ototoxicity
accurate docking
binding
activation
glide
identification
procaspase-9
AGRICULTURAL AND BIOLOGICAL SCIENCES
MEDICINE
BIOCHEMISTRY AND MOLECULAR BIOLOGY
topic caspase inhibitor
induced apoptosis
myocardial-infarction
cisplatin ototoxicity
accurate docking
binding
activation
glide
identification
procaspase-9
AGRICULTURAL AND BIOLOGICAL SCIENCES
MEDICINE
BIOCHEMISTRY AND MOLECULAR BIOLOGY
description Background: Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is still considered an unmet medical need. Methodology and Principal Findings: The interaction between Apaf-1 and the inhibitors was confirmed by NMR. Target specificity was evaluated in cellular models by siRNa based approaches. Cell recovery was confirmed by MTT, clonogenicity and flow cytometry assays. The efficiency of the compounds as antiapoptotic agents was tested in cellular and in vivo models of protection upon cisplatin induced ototoxicity in a zebrafish model and from hypoxia and reperfusion kidney damage in a rat model of hot ischemia. Conclusions: Apaf-1 inhibitors decreased Cytc release and apoptosome-mediated activation of procaspase-9 preventing cell and tissue damage in ex vivo experiments and in vivo animal models of apoptotic damage. Our results provide evidence that Apaf-1 pharmacological inhibition has therapeutic potential for the treatment of apoptosis-related diseases.
publishDate 2014
dc.date.none.fl_str_mv 2014
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/15910
url http://hdl.handle.net/10810/15910
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110979#abstract0
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library Science
publisher.none.fl_str_mv Public Library Science
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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