RT info:eu-repo/semantics/article
T1 A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer
A1 Molero-Valenzuela, Adrià
A1 Fontova Pale, Pere
A1 Alonso Carrillo, Daniel
A1 Carreira Barral, Israel
A1 Torres, Ana Aurora
A1 García Valverde, María
A1 Benítez-García, Cristina
A1 Pérez Tomás, Ricardo
A1 Quesada Pato, Roberto
A1 Soto Cerrato, Vanessa
K1 Autophagy
K1 Treatment resistance
K1 Autophagy inhibitor
K1 Lysosomal dysfunction
K1 Anionophore
K1 Lung cancer
K1 Treatment sensitization
K1 Medicina
K1 Medicine
K1 Química orgánica
K1 Chemistry, Organic
AB 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.
PB MDPI
SN 2072-6694
YR 2022
FD 2022-07
LK http://hdl.handle.net/10259/6766
UL http://hdl.handle.net/10259/6766
LA eng
NO 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.
DS Repositorio Institucional de la Universidad de Burgos
RD 04-dic-2024