Document Detail


Targeting SOD1 reduces experimental non–small-cell lung cancer.
MedLine Citation:
PMID:  24292713     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Approximately 85% of lung cancers are non–small-cell lung cancers (NSCLCs), which are often diagnosed at an advanced stage and associated with poor prognosis. Currently, there are very few therapies available for NSCLCs due to the recalcitrant nature of this cancer. Mutations that activate the small GTPase KRAS are found in 20% to 30% of NSCLCs. Here, we report that inhibition of superoxide dismutase 1 (SOD1) by the small molecule ATN-224 induced cell death in various NSCLC cells, including those harboring KRAS mutations. ATN-224–dependent SOD1 inhibition increased superoxide, which diminished enzyme activity of the antioxidant glutathione peroxidase, leading to an increase in intracellular hydrogen peroxide (H(2)O(2)) levels. We found that ATN-224–induced cell death was mediated through H(2)O(2)-dependent activation of P38 MAPK and that P38 activation led to a decrease in the antiapoptotic factor MCL1, which is often upregulated in NSCLC. Treatment with both ATN-224 and ABT-263, an inhibitor of the apoptosis regulators BCL2/BCLXL, augmented cell death. Furthermore, we demonstrate that ATN-224 reduced tumor burden in a mouse model of NSCLC. Our results indicate that antioxidant inhibition by ATN-224 has potential clinical applications as a single agent, or in combination with other drugs, for the treatment of patients with various forms of NSCLC, including KRAS-driven cancers.
Authors:
Andrea Glasauer; Laura A Sena; Lauren P Diebold; Andrew P Mazar; Navdeep S Chandel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  124     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2014-02-12     Completed Date:  2014-03-03     Revised Date:  2014-05-26    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  117-28     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Aniline Compounds / pharmacology
Animals
Antineoplastic Agents / pharmacology*
Apoptosis
Carcinoma, Non-Small-Cell Lung / drug therapy*,  enzymology,  pathology
Cell Adhesion
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Hydrogen Peroxide / metabolism
Lung Neoplasms / drug therapy*,  enzymology,  pathology
MAP Kinase Signaling System
Mice
Mice, Inbred C57BL
Mice, Transgenic
Molybdenum / pharmacology*
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Sulfonamides / pharmacology
Superoxide Dismutase / antagonists & inhibitors*,  genetics,  metabolism
Tumor Burden / drug effects
Tumor Suppressor Protein p53 / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
CA060553/CA/NCI NIH HHS; F30ES019815/ES/NIEHS NIH HHS; P30 CA060553/CA/NCI NIH HHS; R01CA123067/CA/NCI NIH HHS; T32-HL76139/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Aniline Compounds; 0/Antineoplastic Agents; 0/MCL1 protein, human; 0/Myeloid Cell Leukemia Sequence 1 Protein; 0/Sulfonamides; 0/Tumor Suppressor Protein p53; 81AH48963U/Molybdenum; 91U3TGV99T/tetrathiomolybdate; BBX060AN9V/Hydrogen Peroxide; EC 1.15.1.-/superoxide dismutase 1; EC 1.15.1.1/Superoxide Dismutase; XKJ5VVK2WD/navitoclax
Comments/Corrections

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