RESUMO
La mayor parte de los tumores están estructurados jerárquicamente, siendo la población de células madre del cáncer la encargada de iniciar y mantener el tumor. Estas células madre del cáncer, debido a sus similitudes con las células madre sanas, tienen capacidad de auto-renovación y diferenciación. Existe un balance altamente regulado que controla ambos procesos. De forma que la eliminación de la auto-renovación directamente o la inducción terminal de diferenciación producen la eliminación de las células madre del cáncer y, por lo tanto, la capacidad de mantenimiento y regeneración de la neoplasia. El desarrollo de dos plataformas distintas para buscar compuestos de pequeño tamaño bioactivos que induzcan la diferenciación terminal de las células madre del cáncer ha permitido identificar distintos fármacos con potencial acción neoplásica. Estas plataformas están basadas en cribados de alto rendimiento y alto contenido usando un sistema de células madre embrionarias transformadas y un análisis bioinformático in silico. Usando la leucemia mieloide aguda como modelo de tumor jerárquico, estos compuestos se estudiado ex vivo y in vivo y se han optimizado para su evaluación clínica. Estas plataformas de descubrimiento de fármacos se han validado como una nueva aproximación experimental para identificar nuevos fármacos con actividad diferenciadora anti-tumoral
Most of the tumors are hierarchically organized, with a cellular subpopulation of cancer stem cells in the apex. This population is responsible for the initiation and maintenance of the tumor. Due to their "stem cell"-like properties, cancer stem cells display self-renewal and differentiation potential, both properties are tightly regulated. Thus, direct inhibition of self-renewal or induction of terminal differentiation will eradicate cancer stem cells and, thus, the maintenance and regeneration capacity of the neoplasia will be eliminated. Two distinct drug discovery platforms were developed to identify small bioactive compounds that induce terminal differentiation of cancer stem cells. These platforms are based on highthroughput and high-content screenings using a transformed embryonic stem cell system and an in silico bioinformatics analysis. Using acute myeloid leukemia as a hierarchically organized tumor model, these compounds were studied ex vivo and in vivo and optimized for clinical settings. These platforms have been validated as a new experimental approach to identify differentiating-inducing drugs as anti-neoplastic compounds
Assuntos
Humanos , Preparações Farmacêuticas , Neoplasias/tratamento farmacológico , Células-Tronco , Sistema Hematopoético , Diferenciação Celular , Autorrenovação Celular , Camundongos Endogâmicos , Antígenos CD34 , ADP-Ribosil Ciclase 1RESUMO
BACKGROUND: B-cell chronic lymphocytic leukemia (B-CLL) is a remarkably heterogeneous disorder. Some patients have an indolent disease whereas others undergo a more agressive presentation needing treatment. New therapeutics approaches are necessary for the treatment of B-CLL. Bortezomib (Btz), is a proteasome inhibitor, currently undergoing clinical trials whose function, at least in part, by stabilizing the IkappaBalpha protein and inhibiting NFkappaB activation. OBJECTIVE: The objective of this work was to study the effects of Btz on isolated human B-CLL cells, in vitro, and to correlate the differential rates of apoptosis induction with biological variables. MATERIAL AND METHODS: 31 B-CLL samples, from patients in stage A of Binet were used for this study, and the apoptotic effect of Btz on these cells was measured. RESULTS: Our data show that Btz treatment of B-CLL cells induces apoptosis in a time and dose-dependent manner. The apoptosis induction is mediated in part by inhibition of NFkappaB and is dependent on caspases activation. Interesting, in IgVH mutated cells, Btz have statistically significant differences in their in vitro activity on B-CLL cells according to their BCL-6 mutational status. CONCLUSIONS: Btz is a promising pharmacologic agent for the treatment of B-CLL, but its efficacy seems to be related to IgVH and BCL-6 mutational status, therefore, it could be interesting to further investigate the mechanisms involved in the different behavior of the cells in response to apoptosis induction by this drug (AU)
