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Targeting SOD1 reduces experimental non-small-cell lung cancer

Glasauer, A., Sena, L. A., Diebold, L. P., Mazar, A. P., & Chandel, N. S. (2013). Targeting SOD1 reduces experimental non-small-cell lung cancer. The Journal of clinical investigation, 124(1). doi:10.1172/JCI71714

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.

2 comments… add one
  • Isaac 17/09/2015, 9:32 pm

    I wonder how true these claims are: http://j.mp/1MkkISI

  • Edward 20/09/2015, 11:35 am

    Isaac, don’t know about the lung cancer, but do know sodium bicarbonate is used for asthma and chlorine gas exposure.

    Bosse, G. M. (1994). Nebulized sodium bicarbonate in the treatment of chlorine gas inhalation. Journal of Toxicology. Clinical Toxicology, 32(3), 233–241. Retrieved from http://www.tandfonline.com/doi/abs/10.3109/15563659409017956

    Mithoefer, J. C., Runser, R. H., & Karetzky, M. S. (1965). The Use of Sodium Bicarbonate in the Treatment of Acute Bronchial Asthma. New England Journal of Medicine, 272(23), 1200–1203. http://doi.org/10.1056/NEJM196506102722303

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