| Autor: |
Rebollido-Rios R; Faculty of Medicine and University Hospital of Cologne, Department I of Internal Medicine, University of Cologne, Cologne, Germany., Venton G; Service of Haematology and Cellular Therapy, Centre Hospitalier Universitaire La Conception, Marseille, France., Sánchez-Redondo S; Microenvironment and Metastasis Laboratory, Molecular Oncology Programme. Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Iglesias I Felip C; Anatomy Pathology Department, Vall d'Hebron Hospital, Barcelona-UAB, Barcelona, Spain., Fournet G; Institut de Chimie et Biochimie Moléculaire et Supramoléculaire, UMR-CNRS 5246, Université de Lyon, Université Claude Bernard-Lyon1, Villeurbanne, France., González E; Oncology Research Program, Vall d'Hebron Research Institute, Barcelona, Spain., Romero Fernández W; Department of Cell and Molecular Biology, Computational Biology and Bioinformatics, Uppsala Universitet, Uppsala, Sweden., Borroto Escuela DO; Department of Cell and Molecular Biology, Computational Biology and Bioinformatics, Uppsala Universitet, Uppsala, Sweden., Di Stefano B; Dichirons-Department of Surgical, Laboratory of Biology and Regenerative Medicine-Plastic Surgery- BIOPLAST, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy., Penarroche-Díaz R; Reixmor, Barcelona, Spain., Martin G; Unit of Research in Cellular and Molecular Biology, Advanced Biodesign-ABD, Saint Priest, France., Ceylan I; Unit of Research in Cellular and Molecular Biology, Advanced Biodesign-ABD, Saint Priest, France., Costello R; Service of Haematology and Cellular Therapy, Centre Hospitalier Universitaire La Conception, Marseille, France., Perez-Alea M; Oncology Research Program, Vall d'Hebron Research Institute, Barcelona, Spain. mileidys.perez@gmail.com.; Unit of Research in Cellular and Molecular Biology, Advanced Biodesign-ABD, Saint Priest, France. mileidys.perez@gmail.com. |
| Abstrakt: |
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 H 2 O 2 . 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. |
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