2026-04-18T02:26:01Zhttps://riubu.ubu.es/oai/request

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

Molero-Valenzuela, Adrià Fontova, Pere Alonso Carrillo, Daniel Carreira Barral, Israel Torres, Ana Aurora García Valverde, María Benítez-García, Cristina Pérez Tomás, Ricardo Quesada Pato, Roberto Soto Cerrato, Vanessa 2022-07-15T07:25:17Z 2022-07-15T07:25:17Z 2022-07 2072-6694 http://hdl.handle.net/10259/6766 10.3390/cancers14143387 2072-6694 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. This research was supported by Consejería de Educación de la Junta de Castilla y León (grant BU067P20), MCIN/AEI/10.13039/501100011033 (grant PID2020-117610RB-I00) and Instituto de Salud Carlos III (grant PI18/00441), co-funded by the European Regional Development Fund. ERDF, a way to build Europe. P.F., D.A.-C. and I.C.-B. thank Consejería de Educación de la Junta de Castilla y León, European Social Fund and ERDF for their predoctoral (D.A.-C.) and postdoctoral (P.F. and I.C.-B.) contracts. C.B.-G. thanks the University of Barcelona for a predoctoral fellowship. application/pdf eng MDPI Cancers. 2022, V. 14, n. 14, 3387 https://doi.org/10.3390/cancers14143387 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-117610RB-I00/ES/SMALL MOLECULE TRANSMEMBRANE ANION CARRIERS FOR BIOLOGICAL APPLICATIONS info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI18%2F00441/ES/EVALUACION TERAPEUTICA PRECLINICA EN CANCER DE PULMON DE INHIBIDORES DE SURVIVINA MEDIANTE LA UTILIZACION DE FORMULACIONES NANOENCAPSULADAS Y TERAPIAS COMBINADAS info:eu-repo/grantAgreement/Junta de Castilla y León//BU067P20 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Autophagy Treatment resistance Autophagy inhibitor Lysosomal dysfunction Anionophore Lung cancer Treatment sensitization Medicina Química orgánica Medicine Chemistry, Organic A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Cancers 14 14 3387