Publication: Acción antitumoral de análogos alquilfosfolípidos y aproximaciones nanotecnológicas en cáncer gástrico
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2021-03-18
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Universidad Complutense de Madrid
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Abstract
Aunque su incidencia y mortalidad han disminuido en los últimos años, el cáncer gástrico (CG) sigue siendo uno de los cánceres más diagnosticados, y supone la tercera causa de muerte por cáncer en todo el mundo. Por ello, es necesario buscar nuevas aproximaciones terapéuticas, que mejoren las perspectivas de supervivencia de este tipo de tumor. Uno de los motivos para la recurrencia tumoral o la resistencia a los tratamientos es la existencia en los tumores de células stem cancerosas (CSCs, Cancer Stem Cells) que mantienen y regeneran el tumor. Por ello, encontrar tratamientos que se dirijan también a CSCs es importante para la supervivencia del CG.La edelfosina (EDLF) es el prototipo de una familia de compuestos denominados análogos alquilfosfolípidos, que ha mostrado una potente actividad antitumoral tanto in vitro como in vivo. A diferencia de otros agentes antitumorales, la diana de estos compuestos no es el material genético de la célula, sino sus membranas. Se ha demostrado que esta familia de compuestos induce apoptosis en diversos modelos tumorales, y su mecanismo de acción varía en función del tipo celular. En células de tumores hematológicos, induce apoptosis por activación intracelular de Fas/CD95 y la cascada de señalización posterior; independientemente de la presencia del ligando de este receptor de muerte. En células de tumores sólidos, la inducción de apoptosis ocurre tras una situación de estrés de retículo endoplásmico que la célula no es capaz de solucionar. Además, la EDLF tiene otros efectos sobre la célula como la interferencia en el metabolismo lipídico, o alteración de rutas celulares de supervivencia (PI3K/Akt), proliferación celular (MAPK/ERK) y muerte celular (SAPK/JNK)...
Although its incidence and mortality have declined over the last decade, gastric cancer (GC) is still one of the most frequently diagnosed cancers, and is the third leading cause of cancer-related deaths worldwide. Therefore, there is an urgent need to find new therapeutic approaches that improve gastric cancer outcome. Cancer Stem Cells (CSCs), with unlimited self-renewal, differentiation, and tumor-regenerating capacities, contribute significantly to drug resistance, relapse, and metastasis. Hence, finding new treatments targeted to these cells is important for gastric cancer survival. Edelfosine (EDLF) is the prototype molecule of a family of anticancer drugs collectively known as synthetic alkylphospholipids. This drug has shown a potent antitumor activity both in vitro and in vivo in a rather selective way. Unlike other chemotherapeutic agents, EDLF targets cellular membranes instead of DNA. EDLF induces apoptosis in several tumor models, and its mechanism of action depends on the cell type. In hematological tumors, EDLF induces apoptosis by intracellular activation of Fas/CD95, and the subsequent downstream signaling pathway, regardless of the presence of the ligand FasL. In solid tumor cells, EDLF-induced apoptosis induction relies on a sustained endoplasmic reticulum stress situation. Moreover, EDLF exerts additional effects on the cell, including lipid metabolism interference or alteration in survival (PI3K/Akt), proliferation (MAPK/ERK), and cell death signaling (SAPK/JNK) pathways...
Although its incidence and mortality have declined over the last decade, gastric cancer (GC) is still one of the most frequently diagnosed cancers, and is the third leading cause of cancer-related deaths worldwide. Therefore, there is an urgent need to find new therapeutic approaches that improve gastric cancer outcome. Cancer Stem Cells (CSCs), with unlimited self-renewal, differentiation, and tumor-regenerating capacities, contribute significantly to drug resistance, relapse, and metastasis. Hence, finding new treatments targeted to these cells is important for gastric cancer survival. Edelfosine (EDLF) is the prototype molecule of a family of anticancer drugs collectively known as synthetic alkylphospholipids. This drug has shown a potent antitumor activity both in vitro and in vivo in a rather selective way. Unlike other chemotherapeutic agents, EDLF targets cellular membranes instead of DNA. EDLF induces apoptosis in several tumor models, and its mechanism of action depends on the cell type. In hematological tumors, EDLF induces apoptosis by intracellular activation of Fas/CD95, and the subsequent downstream signaling pathway, regardless of the presence of the ligand FasL. In solid tumor cells, EDLF-induced apoptosis induction relies on a sustained endoplasmic reticulum stress situation. Moreover, EDLF exerts additional effects on the cell, including lipid metabolism interference or alteration in survival (PI3K/Akt), proliferation (MAPK/ERK), and cell death signaling (SAPK/JNK) pathways...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 27-11-2020