Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 150, Issue -, Pages 1-11Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2020.01.186
Keywords
Disulfiram; ATP7B; Metabolic oxidative stress; Radiation oncology; Hypoxia
Funding
- National Institutes of Health, United States [F30 CA213817, R01 CA182804, T32 GM007337, T32 CA078586, P30 CA086862, P01 CA217797, P50 CA174521]
- Iowa Center for Research by Undergraduates and the Biomedical Scholars Summer Undergraduate Research Program
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Therapies for lung cancer patients initially elicit desirable responses, but the presence of hypoxia and drug resistant cells within tumors ultimately lead to treatment failure. Disulfiram (DSF) is an FDA approved, copper chelating agent that can target oxidative metabolic frailties in cancer vs. normal cells and be repurposed as an adjuvant to cancer therapy. Clonogenic survival assays showed that DSF (50-150 nM) combined with physiological levels of Cu (15 mu M CuSO4) was selectively toxic to H292 NSCLC cells vs. normal human bronchial epithelial cells (HBEC). Furthermore, cancer cell toxicity was exacerbated at 1% O-2, relative to 4 or 21% O-2. This selective toxicity of DSF/Cu was associated with differential Cu ionophore capabilities. DSF/Cu treatment caused a> 20-fold increase in cellular Cu in NSCLCs, with nearly two-fold higher Cu present in NSCLCs vs. HBECs and in cancer cells at 1% O-2 vs. 21% O-2. DSF toxicity was shown to be dependent on the retention of Cu as well as oxidative stress mechanisms, including the production of superoxide, peroxide, lipid peroxidation, and mitochondrial damage. DSF was also shown to selectively (relative to HBECs) enhance radiation and chemotherapy-induced NSCLC killing and reduce radiation and chemotherapy resistance in hypoxia. Finally, DSF decreased xenograft tumor growth in vivo when combined with radiation and carboplatin. These results support the hypothesis that DSF could be a promising adjuvant to enhance cancer therapy based on its apparent ability to selectively target fundamental differences in cancer cell oxidative metabolism.
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