Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer

Autor: Régis Costello, Guillaume Martin, Rocio Rebollido-Rios, Sara Sanchez-Redondo, Wilber Romero Fernández, Elena González, Geoffroy Venton, Guy Fournet, Mileidys Perez-Alea, Carmela Iglesias I Felip, Barbara Di Stefano, Dasiel Oscar Borroto Escuela, Reinier Penarroche-Díaz, Ismail Ceylan
Přispěvatelé: University of Cologne, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Spanish National Cancer Research Center (CNIO), Synthèse de Molécules d'Intérêt Thérapeutique (SMITh), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Rebollido-Rios, Rocio, Venton, Geoffroy, Sánchez-Redondo, Sara, Iglesias I Felip, Carmela, Fournet, Guy, González, Elena, Romero Fernández, Wilber, Borroto Escuela, Dasiel Oscar, Di Stefano, Barbara, Penarroche-Díaz, Reinier, Martin, Guillaume, Ceylan, Ismail, Costello, Regi, Perez-Alea, Mileidys
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Cancer Research
Lung Neoplasms
Cell- och molekylärbiologi
Cell
Aldehyde dehydrogenase
Kaplan-Meier Estimate
Mice
chemistry.chemical_compound
0302 clinical medicine
Carcinoma
Non-Small-Cell Lung
Antineoplastic Combined Chemotherapy Protocols
Cytotoxicity
Middle Aged
Aldehyde Oxidoreductases
Glutathione
Cancer metabolism
Up-Regulation
3. Good health
Cancer therapeutic resistance
medicine.anatomical_structure
Alkynes
030220 oncology & carcinogenesis
Female
[SDV.CAN]Life Sciences [q-bio]/Cancer
Biology
Isozyme
Aldehyde Dehydrogenase 1 Family
Article
03 medical and health sciences
Targeted therapies
Downregulation and upregulation
Cell Line
Tumor
Genetics
medicine
Animals
Humans
Sulfhydryl Compounds
Lung cancer
Molecular Biology
Aged
Cancer och onkologi
Gene Amplification
Retinal Dehydrogenase
Aldehyde Dehydrogenase
medicine.disease
Xenograft Model Antitumor Assays
ALDH1A1
030104 developmental biology
chemistry
Drug Resistance
Neoplasm
Cancer and Oncology
biology.protein
Cancer research
Cisplatin
Reactive Oxygen Species
Cell and Molecular Biology
nonsmall cell lung cancer
Zdroj: Oncogene
Oncogene, Nature Publishing Group, 2020, 39 (13), pp.2756-2771. ⟨10.1038/s41388-020-1184-9⟩
ISSN: 0950-9232
1476-5594
DOI: 10.1038/s41388-020-1184-9⟩
Popis: Aldehyde dehydrogenases (ALDHs) are multifunctional enzymes that oxidize diverse endogenous and exogenous aldehydes. We conducted a meta-analysis based on The Cancer Genome Atlas and Gene Expression Omnibus data and detected genetic alterations in ALDH1A1, ALDH1A3, or ALDH3A1, 86% of which were gene amplification or mRNA upregulation, in 31% of nonsmall cell lung cancers (NSCLCs). The expression of these isoenzymes impacted chemoresistance and shortened survival times in patients. We hypothesized that these enzymes provide an oxidative advantage for the persistence of NSCLC. To test this hypothesis, we used genetic and pharmacological approaches with DIMATE, an irreversible inhibitor of ALDH1/3. DIMATE showed cytotoxicity in 73% of NSCLC cell lines tested and demonstrated antitumor activity in orthotopic xenografts via hydroxynonenal-protein adduct accumulation, GSTO1-mediated depletion of glutathione and increased H2O2. Consistent with this result, ALDH1/3 disruption synergized with ROS-inducing agents or glutathione synthesis inhibitors to trigger cell death. In lung cancer xenografts with high to moderate cisplatin resistance, combination treatment with DIMATE promoted strong synergistic responses with tumor regression. These results indicate that NSCLCs with increased expression of ALDH1A1, ALDH1A3, or ALDH3A1 may be targeted by strategies involving inhibitors of these isoenzymes as monotherapy or in combination with chemotherapy to overcome patient-specific drug resistance.
Databáze: OpenAIRE
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