2026-04-18T02:27:30Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/67662022-07-16T00:05:15Zcom_10259_3924com_10259_5086com_10259_2604col_10259_3925

00925njm 22002777a 4500 dc Molero-Valenzuela, Adrià author Fontova, Pere author Alonso Carrillo, Daniel author Carreira Barral, Israel author Torres, Ana Aurora author García Valverde, María author Benítez-García, Cristina author Pérez Tomás, Ricardo author Quesada Pato, Roberto author Soto Cerrato, Vanessa author 2022-07 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. 2072-6694 http://hdl.handle.net/10259/6766 10.3390/cancers14143387 2072-6694 Autophagy Treatment resistance Autophagy inhibitor Lysosomal dysfunction Anionophore Lung cancer Treatment sensitization A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer