Publication: Incremento de la actividad antiangiogénica y antitumoral tras la acetilación del inhibidor del FGF 2,5-Dihidroxifenil sulfonato
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2017-10-05
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Universidad Complutense de Madrid
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Abstract
A pesar del uso de terapias multimodales que incluyen cirugía, radioterapia y quimioterapia, el glioblastoma sigue presentado muy mal pronóstico. La angiogénesis patológica, la invasión agresiva y la rápida difusión en el cerebro son características del glioblastoma. Además, tanto en éste como en otros tipos de tumores, se ha constatado el papel de la inflamación en la progresión tumoral. Las evidencias sugieren que el factor de crecimiento para fibroblastos (FGF) actúa como un promotor de la angiogénesis y progresión tumorales. Aunque los FGFs fueron inicialmente descritos como inductores de la angiogenesis, fueron rápidamente reconocidos como factores mitogénicos de amplio espectro. Es más, en la última década se ha demostrado la participación de estas proteínas en los procesos inflamatorios. El dobesilato (2,5-dihidroxifenil sulfonato, DHPS) se ha identificado recientemente como el miembro más potente de una familia de inhibidores del FGF encabezadas por el ácido gentísico, uno de los principales catabolitos de la aspirina. Recientemente, un derivado del DHPS, el 2,5-diacetoxifenil sulfonato (DAPS) ha demostrado sumar a su efecto inhibitorio sobre el FGF, su capacidad de inhibir la actividad ciclooxigenasa (COX). El objetivo principal de este trabajo es evaluar la eficacia del DAPS para inhibir la angiogénesis y la progresión tumoral in vivo. Empleando cultivos celulares de células C6 de glioma de rata se ha demostrado el efecto anti-proliferativo del DAPS, aunque resulta menos potente in vitro que la molécula parental, DHPS. Sin embargo, el DAPS presentó mayor eficacia anti-angiogénica y anti-tumoral que el DHPS en los ensayos in vivo. El DAPS demostró mayor actividad inhibitoria sobre la angiogénesis inducida por FGF-1 en esponjas implantadas subcutáneamente en ratas e inhibió más eficazmente la progresión de gliomas subcutáneos en ratas, reduciendo la vascularización tumoral e incrementando la apoptosis. El DAPS mostró eficacia oral para estas acciones y sus efectos se acompañaron de una reducción de la infiltración leucocitaria. Los resultados sugieren que la acetilación del dobesilato aumenta su capacidad anti-inflamatoria, anti-angiogénica y anti-tumoral, probablemente debido a que el DAPS aúna la capacidad inhibitoria sobre el FGF con un efecto inhibitorio sobre la COX. El DAPS representa una prometedora estrategia en el tratamiento de los gliomas.
Gliomas are the most frequent and lethal intracranial tumors. Despite recent advances in its treatment by the use of multimodal therapies including surgery, radiotherapy and chemotherapy, and the significant improvements in survival, the prognosis for this disease remains devastating. The primary therapy for glioma consists in surgery followed by radio- and chemotherapy with temozolomide. Chemotherapy interferes with the growth and reproduction of tumor cells but is a nonspecific, often ineffective therapy that also affects normal cells, especially those that divide rapidly. The serious side effects that may result, together with economical and emotional costs, emphasizes the serious need to develop new therapeutic strategies for this devastating disease. Both the recent advances in the understanding of tumor pathogenesis and the appreciation of complications associated with the medications currently used to treat glioma have provided important incentive for finding new treatment alternatives. The hallmarks that confer its elevated malignancy to glioma are uncontrolled cellular proliferation, diffuse infiltration, and high resistance to apoptosis, robust angiogenesis and large molecular heterogeneity present in malignant gliomas. Strategies targeted to inhibit or reverse these key features would logically have therapeutic relevance in the management of gliomas. Several growth factors such as epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) and its cognate receptors have been implicated in gliomagenesis. FGF and VEGF are two potent inducers of tumor angiogenesis, both representing clear targets for the treatment of glioma. Preclinical anti-angiogenic therapeutic studies with inhibitors of VEGF produced encouraging results but efficacy in clinical trials was limited, and serious side effects have been manifested. It is generally accepted that the resistance to treatment with substances that inhibit VEGF is due to the overexpression and activation of FGF caused by the treatment itself. It is possible that inhibition of FGF instead of VEGF in the pathological angiogenesis of glioma is a more appropriate approach, given that the inhibition of FGF also suppresses the angiogenesis induced by VEGF, even as FGF induces angiogenesis dependently and independently of VEGF. For this reason, the inhibition of FGF signaling has been suggested as a strategy to overcome resistance to anti-VEGF therapy...
Gliomas are the most frequent and lethal intracranial tumors. Despite recent advances in its treatment by the use of multimodal therapies including surgery, radiotherapy and chemotherapy, and the significant improvements in survival, the prognosis for this disease remains devastating. The primary therapy for glioma consists in surgery followed by radio- and chemotherapy with temozolomide. Chemotherapy interferes with the growth and reproduction of tumor cells but is a nonspecific, often ineffective therapy that also affects normal cells, especially those that divide rapidly. The serious side effects that may result, together with economical and emotional costs, emphasizes the serious need to develop new therapeutic strategies for this devastating disease. Both the recent advances in the understanding of tumor pathogenesis and the appreciation of complications associated with the medications currently used to treat glioma have provided important incentive for finding new treatment alternatives. The hallmarks that confer its elevated malignancy to glioma are uncontrolled cellular proliferation, diffuse infiltration, and high resistance to apoptosis, robust angiogenesis and large molecular heterogeneity present in malignant gliomas. Strategies targeted to inhibit or reverse these key features would logically have therapeutic relevance in the management of gliomas. Several growth factors such as epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) and its cognate receptors have been implicated in gliomagenesis. FGF and VEGF are two potent inducers of tumor angiogenesis, both representing clear targets for the treatment of glioma. Preclinical anti-angiogenic therapeutic studies with inhibitors of VEGF produced encouraging results but efficacy in clinical trials was limited, and serious side effects have been manifested. It is generally accepted that the resistance to treatment with substances that inhibit VEGF is due to the overexpression and activation of FGF caused by the treatment itself. It is possible that inhibition of FGF instead of VEGF in the pathological angiogenesis of glioma is a more appropriate approach, given that the inhibition of FGF also suppresses the angiogenesis induced by VEGF, even as FGF induces angiogenesis dependently and independently of VEGF. For this reason, the inhibition of FGF signaling has been suggested as a strategy to overcome resistance to anti-VEGF therapy...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Fisiología Humana, leída el 30-10-2015