RESUMEN
Acute promyelocytic leukemia (APL) is characterized by specific t(15;17), distinct morphologic picture, and clinical coagulopathy that contribute to the morbidity and mortality of the disease. This study aims to investigate the effects of antitelomerase compound BIBR1532 on APL cells (NB4). BIBR 1532 exerts a direct short-term growth suppressive effect in a concentration-dependent manner probably through downregulation of c-Myc and hTERT expression. Our results also suggest that induction of p21 and subsequent disturbance of Bax/Bcl-2 balanced ratio as well as decreased telomerase activity may be rational mechanisms for the potent/direct short-term cytotoxicity of high doses of BIBR1532 against NB4 cells.
Asunto(s)
Aminobenzoatos/farmacología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Naftalenos/farmacología , Proteínas Proto-Oncogénicas c-myc/genética , Telomerasa/genética , Proteínas de Unión al GTP rho/genética , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Telomerasa/antagonistas & inhibidores , Telomerasa/metabolismo , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo , Proteínas de Unión al GTP rho/metabolismoRESUMEN
RAS mutations occur frequently in acute myeloid leukaemia and myelodysplasia, suggesting a functional role for this oncogene in leukaemogenesis. We show here, for the first time, that both N-RAS and H-RAS can impair erythroid differentiation of erythroleukaemia cells induced with hexamethylene bisacetamide. Transformation by RAS allowed extended proliferation in the presence of inducer and also inhibited maturation as measured by impaired haemoglobinization and reduction in cell size. These data provide an interesting counterpoint to the effect of mutant RAS on monocytic cells, where it has a potentiating effect on differentiation and may indicate a causal link between the activation of RAS and erythroid lineage dysplasia in preleukaemia.