Disulfiram causes Selective Hypoxic Cancer Cell Toxicity and Radio-chemo-sensitization via Redox Cycling of Copper and O 2 •‒ mediated Oxidative Stress

Lung cancer is one of the most deadly cancers in the USA, and despite multiple modalities of treatment, the 5 year survival rate remains 4 ) are selectively toxic to lung cancer cells versus normal bronchial epithelial cells. Furthermore, the cancer cell toxicity of DSF is exacerbated at 1% O 2 , relative to 4 or 21% O 2 . DSF acts as a copper ionophore, and DSF treatment significantly increased total Cu levels, with higher Cu levels present in tumor versus normal cells and in cancer cells at 1% O 2 versus 21% O 2 . Treatment of cancer cells with a copper chelator [bathocuproinedisulfonic acid (BCS)] as well as a superoxide dismutase (SOD) mimetic (GC4419) was shown to inhibit DSF toxicity, suggesting that redox cycling of Cu contributed to toxicity. DSF was also shown to enhance radiation and chemotherapy-induced cancer cell killing and reduce chemotherapy resistance under hypoxia. DSF also inhibited increases in %ALDH+ cancer stem cells in bulk populations exposed to radiation and enhanced radiation toxicity in both ALDH+ and ALDH- cells. Finally, DSF caused decreased lung cancer xenograft growth and protected mice from weight loss during treatment with carboplatin and radiation. These results suggest that DSF is a promising adjuvant for cancer therapy based on its ability to selectively target fundamental differences in oxidative metabolism of Cu in cancer versus normal cells.