Targeting SOD1 reduces experimental non–small-cell lung cancer
Andrea Glasauer, … , Andrew P. Mazar, Navdeep S. Chandel
Andrea Glasauer, … , Andrew P. Mazar, Navdeep S. Chandel
Published December 2, 2013
Citation Information: J Clin Invest. 2014;124(1):117-128. https://doi.org/10.1172/JCI71714.
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Research Article Oncology

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 (H2O2) levels. We found that ATN-224–induced cell death was mediated through H2O2-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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Figure 5

ATN-224–mediated SOD1 inhibition induces cell death in KrasG12D Tp53fl/fl–driven mouse lung cancer cells.

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ATN-224–mediated SOD1 inhibition induces cell death in KrasG12D Tp53fl/f...
(A) KP cells were treated with increasing doses of ATN-224 (5, 10, 15, and 20 μM), and cell death (96 hours) by trypan blue staining was determined (n = 4). Statistical significance was determined by comparing 0 μM ATN-224 with increasing concentrations. (B) KP cells were treated with 15 μM ATN-224 alone or with 100 μM MnTBAP or 20 μM ebselen, and cell death (96 hours) was determined (n = 3). (C) Analysis of soft agar colonies of KP cells treated with 10 μM ATN-224 alone or with 100 μM MnTBAP (3 weeks) (n = 5). (D) KP cells were treated with 15 μM ATN-224 alone or with 100 μM MnTBAP or 20 μM ebselen. Lysates (48 hours) were immunoblotted for phospho-P38 MAPK (pP38) and MCL1. Total P38 MAPK was used as a loading control. (E) KP cells were treated with 15 μM ATN-224 alone or with 10 μM of the P38 MAPK inhibitor SB203580. Cell death (96 hours) was determined (n = 4). Data are represented as the mean ± SEM. *P < 0.05. **P < 0.01. See also Supplemental Figure 4.