Cargando…

A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer

SIMPLE SUMMARY: Lung cancer is the main cause of cancer-related deaths worldwide, mainly due to treatment resistance. For that reason, it is necessary to develop novel therapeutic strategies to overcome this phenomenon. The aim of our study was to design and characterize a synthetic anionophore, LAI...

Descripción completa

Detalles Bibliográficos
Autores principales: Molero-Valenzuela, Adrià, Fontova, Pere, Alonso-Carrillo, Daniel, Carreira-Barral, Israel, Torres, Ana Aurora, García-Valverde, María, Benítez-García, Cristina, Pérez-Tomás, Ricardo, Quesada, Roberto, Soto-Cerrato, Vanessa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324127/
https://www.ncbi.nlm.nih.gov/pubmed/35884450
http://dx.doi.org/10.3390/cancers14143387
_version_ 1784756730944552960
author Molero-Valenzuela, Adrià
Fontova, Pere
Alonso-Carrillo, Daniel
Carreira-Barral, Israel
Torres, Ana Aurora
García-Valverde, María
Benítez-García, Cristina
Pérez-Tomás, Ricardo
Quesada, Roberto
Soto-Cerrato, Vanessa
author_facet Molero-Valenzuela, Adrià
Fontova, Pere
Alonso-Carrillo, Daniel
Carreira-Barral, Israel
Torres, Ana Aurora
García-Valverde, María
Benítez-García, Cristina
Pérez-Tomás, Ricardo
Quesada, Roberto
Soto-Cerrato, Vanessa
author_sort Molero-Valenzuela, Adrià
collection PubMed
description SIMPLE SUMMARY: Lung cancer is the main cause of cancer-related deaths worldwide, mainly due to treatment resistance. For that reason, it is necessary to develop novel therapeutic strategies to overcome this phenomenon. The aim of our study was to design and characterize a synthetic anionophore, LAI-1, that would be able to efficiently disrupt lysosomal activity, leading to autophagy blockage, one of the most important resistance mechanisms in cancer cells. We confirmed that LAI-1 selectively localized in lysosomes, deacidifying them. This effect produced a blockage of autophagy, characterized by an abrogation of autophagosomes and lysosomes fusion. Moreover, LAI-1 produced cell death in lung cancer cells from different histological subtypes, inducing cytotoxicity more efficiently than other known autophagy inhibitors. Finally, LAI-1 was evaluated in combination therapy, showing sensitization to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a novel late-stage autophagy inhibitor with potential therapeutic applications in tumors with cytoprotective autophagy. ABSTRACT: 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.
format Online
Article
Text
id pubmed-9324127
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-93241272022-07-27 A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer Molero-Valenzuela, Adrià Fontova, Pere Alonso-Carrillo, Daniel Carreira-Barral, Israel Torres, Ana Aurora García-Valverde, María Benítez-García, Cristina Pérez-Tomás, Ricardo Quesada, Roberto Soto-Cerrato, Vanessa Cancers (Basel) Article SIMPLE SUMMARY: Lung cancer is the main cause of cancer-related deaths worldwide, mainly due to treatment resistance. For that reason, it is necessary to develop novel therapeutic strategies to overcome this phenomenon. The aim of our study was to design and characterize a synthetic anionophore, LAI-1, that would be able to efficiently disrupt lysosomal activity, leading to autophagy blockage, one of the most important resistance mechanisms in cancer cells. We confirmed that LAI-1 selectively localized in lysosomes, deacidifying them. This effect produced a blockage of autophagy, characterized by an abrogation of autophagosomes and lysosomes fusion. Moreover, LAI-1 produced cell death in lung cancer cells from different histological subtypes, inducing cytotoxicity more efficiently than other known autophagy inhibitors. Finally, LAI-1 was evaluated in combination therapy, showing sensitization to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a novel late-stage autophagy inhibitor with potential therapeutic applications in tumors with cytoprotective autophagy. ABSTRACT: 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. MDPI 2022-07-12 /pmc/articles/PMC9324127/ /pubmed/35884450 http://dx.doi.org/10.3390/cancers14143387 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Molero-Valenzuela, Adrià
Fontova, Pere
Alonso-Carrillo, Daniel
Carreira-Barral, Israel
Torres, Ana Aurora
García-Valverde, María
Benítez-García, Cristina
Pérez-Tomás, Ricardo
Quesada, Roberto
Soto-Cerrato, Vanessa
A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer
title A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer
title_full A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer
title_fullStr A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer
title_full_unstemmed A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer
title_short A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer
title_sort novel late-stage autophagy inhibitor that efficiently targets lysosomes inducing potent cytotoxic and sensitizing effects in lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324127/
https://www.ncbi.nlm.nih.gov/pubmed/35884450
http://dx.doi.org/10.3390/cancers14143387
work_keys_str_mv AT molerovalenzuelaadria anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT fontovapere anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT alonsocarrillodaniel anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT carreirabarralisrael anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT torresanaaurora anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT garciavalverdemaria anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT benitezgarciacristina anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT pereztomasricardo anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT quesadaroberto anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT sotocerratovanessa anovellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT molerovalenzuelaadria novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT fontovapere novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT alonsocarrillodaniel novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT carreirabarralisrael novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT torresanaaurora novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT garciavalverdemaria novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT benitezgarciacristina novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT pereztomasricardo novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT quesadaroberto novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer
AT sotocerratovanessa novellatestageautophagyinhibitorthatefficientlytargetslysosomesinducingpotentcytotoxicandsensitizingeffectsinlungcancer