title: Apaf-1 inhibitors protect from unwanted cell death in in vivo models of kidney ischemia and chemotherapy induced ototoxicity.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Orzáez
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Sancho
authors.affiliation: Laboratorios SALVAT S.A., Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Marchán
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Mondragón
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Montava
authors.affiliation: Unidad de Biofísica, CSIC, UPV/EHU, Leioa, Spain.
authors.forename: Juan García
authors.initials: JG
authors.lastname: Valero
authors.affiliation: Unidad de Biofísica, CSIC, UPV/EHU, Leioa, Spain.
authors.forename: Olatz
authors.initials: O
authors.lastname: Landeta
authors.affiliation: Unidad de Biofísica, CSIC, UPV/EHU, Leioa, Spain.
authors.forename: Gorka
authors.initials: G
authors.lastname: Basañez
authors.affiliation: Laboratory of Structural Biochemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Rodrigo J
authors.initials: RJ
authors.lastname: Carbajo
authors.affiliation: Laboratory of Structural Biochemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pineda-Lucena
authors.affiliation: Department of Chemical and Biomolecular Nanotechnology and Department of Biological Chemistry and Molecular Modeling, Instituto de Química Avanzada de Cataluña (CSIC), Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bujons
authors.affiliation: Department of Chemical and Biomolecular Nanotechnology and Department of Biological Chemistry and Molecular Modeling, Instituto de Química Avanzada de Cataluña (CSIC), Barcelona, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Moure
authors.affiliation: Department of Chemical and Biomolecular Nanotechnology and Department of Biological Chemistry and Molecular Modeling, Instituto de Química Avanzada de Cataluña (CSIC), Barcelona, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
authors.affiliation: Laboratorios SALVAT S.A., Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lagunas
authors.affiliation: Laboratorios SALVAT S.A., Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Herrero
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain; Instituto de Biomedicina de Valencia (CSIC), Valencia, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez-Payá
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D006367:HeLa Cells; D034381:Hearing Loss / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C506592:APAF1 protein, human; D000970:Antineoplastic Agents; C506593:Apaf1 protein, mouse; C506594:Apaf1 protein, rat; D053477:Apoptotic Protease-Activating Factor 1; D006576:Heterocyclic Compounds, 4 or More Rings; D029961:Zebrafish Proteins; D002945:Cisplatin