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Dual disruption of ...
Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer
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- Rebollido-Rios, Rocio (author)
- Univ Cologne, Fac Med, Dept Internal Med 1, Cologne, Germany.;Univ Cologne, Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany.
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- Venton, Geoffroy (author)
- Ctr Hosp Univ La Conception, Serv Haematol & Cellular Therapy, Marseille, France.
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- Sanchez-Redondo, Sara (author)
- Spanish Natl Canc Res Ctr CNIO, Microenvironm & Metastasis Lab, Mol Oncol Programme, Madrid, Spain.
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- Iglesias i Felip, Carmela (author)
- Barcelona UAB, Dept Anat Pathol, Vall dHebron Hosp, Barcelona, Spain.
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- Fournet, Guy (author)
- Univ Claude Bernard Lyon1, Inst Chim & Biochim Mol & Supramol, CNRS, UMR 5246,Univ Lyon, Villeurbanne, France.
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- Gonzalez, Elena (author)
- Vall dHebron Res Inst, Oncol Res Program, Barcelona, Spain.
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- Romero Fernandez, Wilber (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik
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- Escuela, Dasiel Oscar Borroto (author)
- Karolinska Institutet,Uppsala universitet,Beräkningsbiologi och bioinformatik
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- Di Stefano, Barbara (author)
- Univ Palermo, Dichirons Dept Surg, Lab Biol & Regenerat Med Plast Surg BIOPLAST, Oncol & Stomatol Sci, Palermo, Italy.
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- Penarroche-Diaz, Reinier (author)
- Reixmor, Barcelona, Spain.
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- Martin, Guillaume (author)
- Adv Biodesign ABD, Unit Res Cellular & Mol Biol, St Priest, France.
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- Ceylan, Ismail (author)
- Adv Biodesign ABD, Unit Res Cellular & Mol Biol, St Priest, France.
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- Costello, Regis (author)
- Ctr Hosp Univ La Conception, Serv Haematol & Cellular Therapy, Marseille, France.
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- Perez-Alea, Mileidys (author)
- Vall dHebron Res Inst, Oncol Res Program, Barcelona, Spain.;Adv Biodesign ABD, Unit Res Cellular & Mol Biol, St Priest, France.
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Univ Cologne, Fac Med, Dept Internal Med 1, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany. Ctr Hosp Univ La Conception, Serv Haematol & Cellular Therapy, Marseille, France. (creator_code:org_t)
- 2020-02-03
- 2020
- English.
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In: Oncogene. - : NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 39:13, s. 2756-2771
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
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Oncogene
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Rebollido-Rios, ...
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Venton, Geoffroy
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Sanchez-Redondo, ...
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Iglesias i Felip ...
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Fournet, Guy
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Gonzalez, Elena
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Romero Fernandez ...
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Escuela, Dasiel ...
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Di Stefano, Barb ...
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Penarroche-Diaz, ...
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Martin, Guillaum ...
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Ceylan, Ismail
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Costello, Regis
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Perez-Alea, Mile ...
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Oncogene
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Uppsala University
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Karolinska Institutet