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    Por favor, use este identificador para citar o enlazar este ítem: http://hdl.handle.net/10259/6766

    Título
    A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer
    Autor
    Molero-Valenzuela, Adrià
    Fontova Pale, PereAutoridad UBU Orcid
    Alonso Carrillo, DanielAutoridad UBU Orcid
    Carreira Barral, IsraelAutoridad UBU Orcid
    Torres, Ana Aurora
    García Valverde, MaríaAutoridad UBU Orcid
    Benítez-García, Cristina
    Pérez Tomás, Ricardo
    Quesada Pato, RobertoAutoridad UBU Orcid
    Soto Cerrato, Vanessa
    Publicado en
    Cancers. 2022, V. 14, n. 14, 3387
    Editorial
    MDPI
    Fecha de publicación
    2022-07
    ISSN
    2072-6694
    DOI
    10.3390/cancers14143387
    Resumen
    Overcoming resistance is one of the most challenging features in current anticancer therapy. Autophagy is a cellular process that confers resistance in some advanced tumors, since it enables cancer cells to adapt to stressful situations, such as anticancer treatments. Hence, the inhibition of this cytoprotective autophagy leads to tumor cells sensitization and death. In this regard, we designed a novel potent anionophore compound that specifically targets lysosomes, called LAI-1 (late-stage autophagy inhibitor-1), and evaluated its role in blocking autophagy and its potential anticancer effects in three lung cancer cell lines from different histological subtypes. Compared to other autophagy inhibitors, such as chloroquine and 3-Methyladenine, the LAI-1 treatment induced more potent anticancer effects in all tested cancer cells. LAI-1 was able to efficiently target and deacidify lysosomes, while acidifying cytoplasmic pH. Consequently, LAI-1 efficiently blocked autophagy, indicated by the increased LC3-II/I ratio and p62/SQSTM1 levels. Moreover, no colocalization was observed between autophagosomes, marked with LC3 or p62/SQSTM1, and lysosomes, stained with LAMP-1, after the LAI-1 treatment, indicating the blockage of autophagolysosome formation. Furthermore, LAI-1 induced cell death by activating apoptosis (enhancing the cleavage of caspase-3 and PARP) or necrosis, depending on the cancer cell line. Finally, LAI-1 sensitized cancer cells to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a new late-stage autophagy inhibitor that causes lysosomal dysfunction and the blockage of autophagolysosome formation, as well as potently induces cancer cell death and sensitization to conventional treatments at lower concentrations than other known autophagy inhibitors, appearing as a potential new therapeutic approach to overcome cancer resistance.
    Palabras clave
    Autophagy
    Treatment resistance
    Autophagy inhibitor
    Lysosomal dysfunction
    Anionophore
    Lung cancer
    Treatment sensitization
    Materia
    Medicina
    Medicine
    Química orgánica
    Chemistry, Organic
    URI
    http://hdl.handle.net/10259/6766
    Versión del editor
    https://doi.org/10.3390/cancers14143387
    Aparece en las colecciones
    • Artículos BIOORG
    Atribución 4.0 Internacional
    Documento(s) sujeto(s) a una licencia Creative Commons Atribución 4.0 Internacional
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    Nombre:
    Molero-cancers_2022.pdf
    Tamaño:
    4.033Mb
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