Panorama dos nutlins como protótipo para terapia do câncer
Palavras-chave:
nutlins, p53, MDM2, câncerResumo
A p53 é uma proteína supressora tumoral que desempenha papel crucial nadefesa da célula contra mutações deletérias e transformações cancerosas. Ela é
ativada por meio da ação de agentes genotóxicos (irradiação ultravioleta, estresse oxidativo, drogas citotóxicas) ou mesmo não genotóxicos (hipóxia, hipertermia, depleção de ribonucleotídeos). Uma vez ativada, a p53 coordena o sistema de reparo da célula levando-a à parada do ciclo celular, à senescência ou à apoptose. A via de sinalização da proteína p53 encontra-se inativada em todos os tipos de câncer e este fato tem chamado a atenção de muitos pesquisadores no sentido do desenvolvimento de novas terapias farmacológicas baseadas no reestabelecimento dessa via. Os níveis de p53 na célula estão sob o rígido controle do regulador negativo MDM2 via ubiquitinação. A p53 também controla a transcrição do MDM2 gerando uma regulação por feedback em que as duas proteínas mutuamente controlam seus níveis celulares. Dessa forma, foi pensado que o bloqueio da interação p53-MDM2 poderia levar ao efeito farmacológico antitumoral e várias moléculas inibidoras foram testadas para este fim, dentre elas uma família de imidazolinas tetrassubstituídas, chamadas nutlins. Estes compostos podem ativar seletivamente a via de sinalização da p53 in vitro e in vivo em linhagens de tumores humanos que apresentam alta expressão de HDM2 (o tipo humano de MDM2) levando à inibição do crescimento celular e à apoptose. Os inibidores de MDM2 representam uma classe promissora de ativadores da p53 que podem se tornar fármacos efetivos no tratamento do câncer e também no diagnóstico por imagem.
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