2026-04-18T02:29:29Zhttps://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 5d6bed81-6f03-4ff2-94fa-00171f77c0dd 500 Fontova, Pere 7b91f49e-f990-4362-be5c-11be68a5c156 500 Alonso Carrillo, Daniel 1263c401-2f34-43e9-b121-a8799c7e2fed 600 Carreira Barral, Israel 703d8822-8907-4c5b-9bdd-773fda8112db 600 Torres, Ana Aurora dc995cd1-42bd-47a7-ba8f-4543b391605c 500 García Valverde, María 222 600 Benítez-García, Cristina 154f3305-d2b6-41b6-b586-95950e57e92b 500 Pérez Tomás, Ricardo 3306d7a2-706a-47ab-8490-869a1b191c58 600 Quesada Pato, Roberto 458 600 Soto Cerrato, Vanessa 346bb3c7-0c69-4d62-9045-26b0b8d37a51 600 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 THUMBNAIL Molero-cancers_2022.pdf.jpg Molero-cancers_2022.pdf.jpg IM Thumbnail image/jpeg 3541 https://riubu.ubu.es/bitstream/10259/6766/4/Molero-cancers_2022.pdf.jpg b3a3d29986ff29ac8356111fc9be0f29 MD5 4 LICENSE license.txt license.txt text/plain; charset=utf-8 999 https://riubu.ubu.es/bitstream/10259/6766/3/license.txt b295bcbce42e2caabeb0c623d3860c06 MD5 3 CC-LICENSE license_rdf license_rdf application/rdf+xml; charset=utf-8 908 https://riubu.ubu.es/bitstream/10259/6766/2/license_rdf 0175ea4a2d4caec4bbcc37e300941108 MD5 2 ORIGINAL Molero-cancers_2022.pdf Molero-cancers_2022.pdf application/pdf 4229627 https://riubu.ubu.es/bitstream/10259/6766/1/Molero-cancers_2022.pdf 21528effa2a15170b1ca2c2a86b9753f MD5 1 10259/6766 oai:riubu.ubu.es:10259/6766 2022-07-16 02:05:15.458 Repositorio Institucional de la Universidad de Burgos bubrep@ubu.es RWwgYXV0b3IgY29tbyDDum5pY28gdGl0dWxhciBkZSBsb3MgZGVyZWNob3MgZGUgcHJvcGllZGFkIGludGVsZWN0dWFsIGRlIGxhIG9icmEsIG8gZGlzcG9uaWVuZG8gZGUgbG9zIGRlYmlkb3MgcGVybWlzb3MgZGUgbG9zIG90cm9zIHRpdHVsYXJlcywgc2kgbG9zIGh1YmllcmEsIHkgZW4gdmlydHVkIGRlIGxvcyBkZXJlY2hvcyBxdWUgbGUgY29uZmllcmUgbGEgbGVnaXNsYWNpw7NuIHZpZ2VudGUgc29icmUgcHJvcGllZGFkIGludGVsZWN0dWFsIHkgZGVyZWNob3MgZGUgYXV0b3IsIA0KQVVUT1JJWkEgYSBsYSBVbml2ZXJzaWRhZCBkZSBCdXJnb3MgYSBkaWZ1bmRpciwgZGUgbWFuZXJhIGdyYXR1aXRhLCBlbCBjb250ZW5pZG8gZGUgbG9zIGFyY2hpdm9zIGRpZ2l0YWxlcyBxdWUgY29ycmVzcG9uZGVuIGFsIGRvY3VtZW50byBkZXNjcml0byBhbnRlcmlvcm1lbnRlLCBjb24gY2Fyw6FjdGVyIG5vIGV4Y2x1c2l2byB5IGRlIG1hbmVyYSBww7pibGljYSBlbiBhY2Nlc28gYWJpZXJ0byBhIHRyYXbDqXMgZGUgSW50ZXJuZXQsIHBhcmEgbG8gcXVlIGxhIEJpYmxpb3RlY2EgcHJvY2VkZXLDoSBhIGFyY2hpdmFybG9zIGVuIGVsIFJlcG9zaXRvcmlvIEluc3RpdHVjaW9uYWwuIEFzaW1pc21vIGF1dG9yaXphIGEgbGEgVW5pdmVyc2lkYWQgZGUgQnVyZ29zIGEgcmVhbGl6YXIgbGFzIHRyYW5zZm9ybWFjaW9uZXMgbmVjZXNhcmlhcyBkZSBmb3JtYXRvLCBubyBkZSBjb250ZW5pZG8sIHBhcmEgZ2FyYW50aXphciBsYSBwcmVzZXJ2YWNpw7NuIHkgZWwgYWNjZXNvIGVuIGVsIGZ1dHVyby4NCg0KRWwgYXV0b3IgZGlzcG9uZSwgZW4gdG9kbyBjYXNvLCBkZWwgZGVyZWNobyBhIHJldm9jYXIgZXN0YSBhdXRvcml6YWNpw7NuLg0KDQpMYSBjZXNpw7NuIGRlIGRlcmVjaG9zIGRlIGVzdGEgb2JyYSBzZSBlbmN1ZW50cmEgc3VqZXRhIGEgbGEgbGVnaXNsYWNpw7NuIHZpZ2VudGUgc29icmUgcHJvcGllZGFkIGludGVsZWN0dWFsIHkgZGVyZWNob3MgZGUgYXV0b3Iu