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PLoS One ; 9(10): e110979, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25330150

RESUMO

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.


Assuntos
Antineoplásicos/efeitos adversos , Fator Apoptótico 1 Ativador de Proteases/antagonistas & inibidores , Cisplatino/efeitos adversos , Perda Auditiva , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Nefropatias/metabolismo , Traumatismo por Reperfusão/metabolismo , Proteínas de Peixe-Zebra/antagonistas & inibidores , Peixe-Zebra/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Morte Celular/efeitos dos fármacos , Cisplatino/farmacologia , Modelos Animais de Doenças , Células HeLa , Perda Auditiva/induzido quimicamente , Perda Auditiva/metabolismo , Perda Auditiva/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/patologia , Masculino , Camundongos , Ratos , Traumatismo por Reperfusão/patologia , Proteínas de Peixe-Zebra/metabolismo
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