Cientistas revelam uma nova abordagem potencial para o tratamento do câncer de fígado
Cientistas dos Institutos Nacionais de Saúde e do Hospital Geral de Massachusetts, em Boston, descobriram uma nova abordagem potencial contra o câncer de fígado que pode levar ao desenvolvimento de uma nova classe de medicamentos anticancerígenos.
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)
a , Esquema de estudos de triagem e validação de medicamentos; MoA, mecanismo de ação. b , Gráficos dos resultados da triagem de moléculas pequenas com a biblioteca MIPE em linhas celulares IDHm ICC (SNU1079 e RBE) e linhas celulares WT IDH1 ICC (HUCCT1 e CCLP1). Topo, sensibilidade diferencial ( eixo x ) e significância ( eixo y ; –log (valor P )) de compostos em relação às linhas IDHm versus WT IDH1 . A sensibilidade relativa das células IDHm é denotada pelo tamanho da bolha. Abaixo, classificação de compostos individuais de acordo com a sensibilidade diferencial. A significância foi analisada usando um t de Student bicaudal . P?< 0,05 foi considerado estatisticamente significativo. A triagem foi realizada uma vez usando um perfil concentração-resposta (diluições quintuplicadas passo a passo da droga entre 92,1 µM e 0,006 µM). eGFR, taxa de filtração glomerular estimada. c , Mapa de calor da sensibilidade de YC-1 em 25 linhagens celulares de câncer biliar e em células MMNK1 (duto biliar imortalizado). Linhas de células IDHm são realçadas. d , medições de IC 50 para YC-1 em linhas de células ICC selecionadas de IDHm (vermelho) e WT IDH1 (preto/cinza). Dois experimentos biologicamente independentes são mostrados. e, Resultados compilados da sensibilidade de YC-1 em 1.022 linhagens celulares de câncer. Os dados mostram a fração classificada de linhagens celulares sensíveis a YC-1 em cada tipo de câncer. A triagem foi realizada uma vez usando uma série de diluição dupla de nove pontos de YC-1; IH, XYZ; EH, XYZ; NSCLC, câncer de pulmão de células não pequenas. HI, intra-hepática; EH, extra-hepática. f , Gráfico mostrando que as linhagens de células ICC com alterações genômicas IDH1 / IDH2 , FGFR2 e BAP1 estão entre as mais sensíveis na triagem. 'Sensibilidade YC-1' ( eixo y ) denota valores YC-1 IC 50 transformados em log 10 (?M). Pontos vermelhos representam células RBE, SNU1079 e ICC5 (IDH1 R132C e IDH1 , IDH1 R132S, e mutantes R132L , respectivamente), e o ponto rosa representa células YSCCC (mutante IDH1 R100Q ). Crédito: Natureza Câncer (2023). DOI: 10.1038/s43018-023-00523-0
Cientistas dos Institutos Nacionais de Saúde e do Hospital Geral de Massachusetts, em Boston, descobriram uma nova abordagem potencial contra o câncer de fígado que pode levar ao desenvolvimento de uma nova classe de medicamentos anticancerígenos. Em uma série de experimentos em células e camundongos, os pesquisadores descobriram que uma enzima produzida em células de câncer de fígado poderia converter um grupo de compostos em drogas anticancerígenas, matando células e reduzindo doenças em animais.
Os pesquisadores sugerem que essa enzima pode se tornar um alvo potencial para o desenvolvimento de novos medicamentos contra doenças hepáticas e talvez outros tipos de câncer e doenças também.
"Encontramos uma molécula que mata as células de um raro câncer de fígado de uma maneira única", disse o cientista translacional Matthew Hall, Ph.D., um dos líderes do trabalho no Centro Nacional do NIH para o Desenvolvimento de Ciências Translacionais (NCATS). "Ele surgiu de uma triagem para encontrar moléculas que matam seletivamente as células cancerígenas do fígado humano. Deu muito trabalho descobrir que a molécula é convertida por uma enzima nessas células cancerígenas do fígado, criando uma droga anticancerígena tóxica".
Hall, Nabeel Bardeesy, Ph.D., especialista em câncer de fígado do Hospital Geral de Massachusetts e seus colegas relataram seus resultados em 13 de março na Nature Cancer.
A descoberta decorre de uma colaboração entre os pesquisadores do Massachusetts General Hospital e do NCATS. Bardeesy estava originalmente estudando o colangiocarcinoma, um tipo de câncer de fígado que afeta o ducto biliar. O câncer é caracterizado por mutações na enzima IDH1. A equipe de Bardeesy queria encontrar compostos e drogas que pudessem ser eficazes contra a mutação IDH1. Por meio de uma colaboração com o NCATS, Hall e outros cientistas do NCATS testaram rapidamente milhares de medicamentos aprovados e agentes experimentais contra o câncer quanto à sua eficácia na morte de células de colangiocarcinoma, tendo o IDH1 como alvo.
Eles descobriram que várias moléculas, incluindo uma chamada YC-1, poderiam matar as células cancerígenas. No entanto, quando eles olharam para ver como o YC-1 estava funcionando, descobriram que o composto não estava afetando a mutação IDH1.
Os pesquisadores de Massachusetts mostraram que as células de câncer de fígado produziam uma enzima, SULT1A1. A enzima ativou o composto YC-1, tornando-o tóxico para células tumorais em culturas de células cancerígenas e modelos de câncer de fígado em camundongos. Nos modelos animais tratados com YC-1, os tumores hepáticos tiveram crescimento reduzido ou encolheram. Por outro lado, os pesquisadores não encontraram alterações nos tumores tratados com YC-1 em animais com células cancerígenas sem a enzima.
Os pesquisadores examinaram outros bancos de dados de resultados de triagem de drogas em bibliotecas de compostos e drogas para combinar a atividade da droga com a atividade SULT1A1. Eles também analisaram um grande banco de dados do National Cancer Institute de compostos anticancerígenos em busca de possibilidades adicionais para testar sua atividade com a enzima. .
Eles identificaram várias classes de compostos que dependiam do SULT1A1 para sua atividade de matar tumores. Usando métodos computacionais , eles previram outros compostos que provavelmente também dependiam de SULT1A1.
"Uma vez que encontramos o YC-1 ativado por SULT1A1, isso nos levou a perguntar: "Que outros compostos são ativos e podem matar células pelo mesmo mecanismo?" disse Hall. "Podemos identificar outros compostos que estavam sendo desenvolvidos e demonstrar que eles foram também ativo por causa da ativação de SULT1A1? A resposta foi sim. Encontramos outros compostos com o mesmo mecanismo de ação do YC-1."
Os cientistas sugerem que essas descobertas têm implicações mais amplas para o desenvolvimento de novas drogas anticancerígenas . "Acreditamos que essas moléculas têm potencial para ser uma classe inexplorada de drogas anticancerígenas que dependem do SULT1A1 para sua atividade contra tumores", disse Bardeesy.
Os pesquisadores veem YC-1 e moléculas semelhantes como protótipos para o desenvolvimento de compostos que podem ser eficazes contra proteínas importantes nas células. A modificação de diferentes partes dessas moléculas poderia torná-las mais específicas para tais proteínas. Os pesquisadores apontam para a criação de um "kit de ferramentas de moléculas ativadas por SULT1A1" que podem afetar muitos alvos diferentes.
Esse kit de ferramentas é composto por centenas de moléculas conhecidas. Em teoria, o kit de ferramentas cobre muitos tipos de enzimas, chamadas sulfotransferases, que são ativas em diferentes tecidos do corpo. Por exemplo, além de SULT1A1, a sulfotransferase humana SULT4A1 é ativa no cérebro. Ele pode ativar um subconjunto das moléculas no kit de ferramentas. Isso pode ser útil no desenvolvimento de medicamentos específicos para cânceres cerebrais.
"Sabíamos que drogas dependentes de SULT1A1 já haviam sido identificadas", disse Bardeesy. "Nossos resultados sugerem que pode haver outros compostos dependentes de SULT1A1 com faixas de alvos diferentes. A identificação de tais compostos e alvos nas células pode ter implicações potenciais para o desenvolvimento de outros tipos de pequenas moléculas e drogas, não apenas limitadas a esses tipos de câncer. Isso pode se tornar um problema nova abordagem para algumas doenças."
Mais informações: Lei Shi et al, sulfonação dependente de SULT1A1 de alquiladores é uma vulnerabilidade dependente de linhagem de cânceres de fígado, Nature Cancer (2023). DOI: 10.1038/s43018-023-00523-0
Informações do jornal: Nature Cancer