Publication: Bases moleculares de la actividad antitumoral de nuevo agentes terapéuticos derivados de la hispanolona
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2021-06-10
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Universidad Complutense de Madrid
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Abstract
Los productos naturales desempeñan un papel fundamental en la búsqueda de nuevos agentes bioactivos en numerosas áreas terapéuticas, entre las que destaca el cáncer. En este trabajo nos hemos centrado en la evaluación del potencial antitumoral de un diterpeno labdánico derivado de la hispanolona, α-Hispanolol (α-H), frente a glioblastoma, uno de los tumores más letales del sistema nervioso central. Los resultados obtenidos muestran que α-H ejerce efectos citotóxicos en las líneas celulares de glioblastoma humano U87 yU373, de forma concentración- y tiempo-dependiente, sin alterar la supervivencia de las células no tumorales. Además, inhibe el crecimiento tumoral en un modelo in vivo, no habiéndose observado signos aparentes de toxicidad. También hemos descrito que el mecanismo a través del cual α-H induce la muerte de las células, implica la puesta en marcha de vías de señalización apoptóticas. Así, el tratamiento con el diterpeno altera el ciclo celular con un aumento significativo del número de células que se encuentran en apoptosis, y provoca cambios morfológicos característicos de este proceso. Nuestros datos han confirmado la implicación de la vía extrínseca e intrínseca, tal y como lo demuestra la activación de las caspasas 8, 9 y 3, la disminución de la expresión de proteínas antiapoptóticas (Bcl-2 y Bcl-xL) y el aumento de la expresión de proteínas proapoptóticas (Bax y Bid)...
Natural products play an important role in the search for new bioactive agents in numerous therapeutic areas, most notably cancer. In this work, we have focused on the evaluation of the antitumor potential of a hispanolone-derived labdane diterpene, α-Hispanolol (α-H), against glioblastoma, one of the most lethal tumors of the centralnervous system. The results obtained show that α-H exerts cytotoxic effects on human glioblastoma cell lines U87 and U373, in a concentration- and time- dependent manner, without affecting the survival of non-tumor cells. Furthermore, it inhibits tumor growth in an in vivo model, with no apparent signs of toxicity. We have also described that the mechanism through which α-H induces cell death involves the activation of apoptotic signaling pathways. Thus, treatment with diterpene alters the cell cycle with a significant increase in the number of apoptotic cells and causes characteristic morphological changes in this process. Our data have confirmed the involvement of the extrinsic and the intrinsic pathways, as demonstrated by the activation of caspases 8, 9 and 3, down regulation ofthe anti-apoptotic proteins (Bcl-2 and Bcl-xL) and the increase in the expression of pro-apoptotic proteins (Bid and Bax)...
Natural products play an important role in the search for new bioactive agents in numerous therapeutic areas, most notably cancer. In this work, we have focused on the evaluation of the antitumor potential of a hispanolone-derived labdane diterpene, α-Hispanolol (α-H), against glioblastoma, one of the most lethal tumors of the centralnervous system. The results obtained show that α-H exerts cytotoxic effects on human glioblastoma cell lines U87 and U373, in a concentration- and time- dependent manner, without affecting the survival of non-tumor cells. Furthermore, it inhibits tumor growth in an in vivo model, with no apparent signs of toxicity. We have also described that the mechanism through which α-H induces cell death involves the activation of apoptotic signaling pathways. Thus, treatment with diterpene alters the cell cycle with a significant increase in the number of apoptotic cells and causes characteristic morphological changes in this process. Our data have confirmed the involvement of the extrinsic and the intrinsic pathways, as demonstrated by the activation of caspases 8, 9 and 3, down regulation ofthe anti-apoptotic proteins (Bcl-2 and Bcl-xL) and the increase in the expression of pro-apoptotic proteins (Bid and Bax)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, leída el 02-12-2020