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 6

ATN-224 as a single agent reduces tumor burden in a preclinical KrasG12D Tp53fl/fl–driven mouse model of lung cancer.

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ATN-224 as a single agent reduces tumor burden in a preclinical KrasG12D...
(A) Schematic of experimental design. KP mice were intubated with 107 PFUs of adenoviral Cre and treated 8 wpi with PBS or 4 mg/kg ATN-224 every 2 days for 4 weeks. (B) KP mice were injected i.p. with PBS or 4 mg/kg ATN-224 for 4 weeks, and ATN-224 levels in blood plasma were determined (n = 3). (C–E) Lungs isolated from PBS and ATN-224–treated KP mice were analyzed for (C) lung weight normalized to body weight, (D) number of lesions per whole lung section, and (E) tumor burden per whole lung section (n = 16 PBS, n = 17 ATN-224). Tumor burden was calculated by averaging the tumor area from H&E-stained whole lung sections shown in H (left panel). (F and G) Lungs isolated from PBS and ATN-224–treated KP mice were analyzed for (F) KI67-positive cells per lung section and (G) CC3-positive cells per lung section (n = 5 PBS, n = 5 ATN-224). (H) Representative images of H&E- (left panels), KI67- (middle panels), and CC3-stained (right panels) KP lung sections from PBS and ATN-224–treated mice. H&E-stained images of whole lung sections represent tumor burden. Scale bars: 1 mm (left panels). KI67 (proliferation) and CC3 (cell death) images of tumors; positively stained cells appear in brown and nuclei in blue. Scale bars: 50 μM (middle and right panels). Data are represented as the mean ± SEM. *P < 0.05. **P < 0.01. See also Supplemental Figure 5.