RESUMEN
17-Allylamino-17-demethoxygeldanamycin (17-AAG) induces degradation of Hsp90 client proteins, including Bcr-Abl, however, its clinical use as an anti-tumor agent may be limited by toxicity and modest efficacy. We reasoned that Bcr-Abl targeting by RNA interference (RNAi) might selectively increase the activity of 17-AAG against Bcr-Abl+ leukemia cells. 17-AAG in combination with targeting small interfering RNAs (siRNAs) reduced Bcr-Abl protein levels, triggered increases in markers of apoptosis and decreased cell viability more effectively than did control siRNA and 17-AAG together, or Bcr-Abl targeting siRNA alone. Combination targeting strategies such as this may therefore achieve enhanced therapeutic potency.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzoquinonas/farmacología , Proteínas de Fusión bcr-abl/genética , Marcación de Gen/métodos , Lactamas Macrocíclicas/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Interferencia de ARN , ARN Interferente Pequeño/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismoRESUMEN
We have investigated functional outcome of challenging primary chronic myeloid leukaemia (CML) cells with Bcr-Abl fusion sequence-directed RNA interference (RNAi). We targeted the Bcr-Abl b3a2 variant, by RNAi, in primary chronic phase CML cells, and detected strikingly reduced proliferation of myeloid precursor cells expressing this variant. Lack of an effect in cells expressing a distinct Bcr-Abl variant confirmed the specificity of the response. Through the functional targeting of an oncogene in primary human tumour cells, we have demonstrated that Bcr-Abl enhances CML progenitor cell amplification, and that RNAi may be suitable for development as a specific anti-leukaemia treatment.