Disulfiram causes selective hypoxic cancer cell toxicity and radio-chemo-sensitization via redox cycling of copper.

Disulfiram causes selective hypoxic cancer cell toxicity and radio-chemo-sensitization via redox cycling of copper. Free Radic Biol Med. 2020 Feb 04;: Authors: Falls-Hubert KC, Butler AL, Gui K, Anderson M, Li M, Stolwijk JM, Rodman SN, Solst SR, Tomanek-Chalkley A, Searby CC, Sheffield VC, Sandfort V, Schmidt H, McCormick M, Wels BR, Allen BG, Buettner GR, Schultz MK, Spitz DR Abstract Therapies for lung cancer patients initially illicit 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 μM CuSO4) was selectively toxic to H292 NSCLC cells versus normal human bronchial epithelial cells (HBEC). Furthermore, cancer cell toxicity was exacerbated at 1% O2, relative to 4 or 21% O2. 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% O2vs. 21% O2. 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 pe...
Source: Free Radical Biology and Medicine - Category: Biology Authors: Tags: Free Radic Biol Med Source Type: research

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Source: American Journal of Translational Research - Category: Research Tags: Am J Transl Res Source Type: research
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