title: Targeting SOD1 reduces experimental non–small-cell lung cancer.
abstract: 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.forename: Andrea
authors.initials: A
authors.lastname: Glasauer
authors.forename: Laura A
authors.initials: LA
authors.lastname: Sena
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Diebold
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008982:Molybdenum / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C000606290:SOD1 protein, human; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D008982:Molybdenum; C020809:tetrathiomolybdate; D006861:Hydrogen Peroxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C528561:navitoclax