Dissertation
Repurposing Disulfiram for targeting of hypoxic cancer cells through redox cycling of copper
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2021
DOI: 10.17077/etd.006105
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 versus 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 non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells versus normal bronchial epithelial cells. 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 significantly increased total cellular Cu levels, with higher Cu present in tumor versus normal cells and in cancer cells at 1% O2 versus 21% O2. Additionally, elevated Cu levels in hypoxia remained elevated 48 h after treatment. DSF toxicity was shown to be dependent on Cu retention by inhibiting toxicity with a Cu chelator, bathocuproinedisulfonic acid (BCS), and with overexpression of a Cu export protein, ATP7B. Toxicity was also shown to be partially dependent on oxidative stress mechanisms initiated by Cu, including production of superoxide and hydrogen peroxide, which were inhibited by a superoxide dismutase (SOD) mimetic, GC4419, and overexpression of catalase. DSF/Cu treatment also induced lipid peroxidation, increased mitochondrial superoxide production, and decreased mitochondrial membrane potential. In addition to its selective toxicity to hypoxic cancer cells, DSF also caused radio-chemo-sensitization and reduced radiation and chemotherapy resistance at hypoxia. Finally, DSF decreased xenograft tumor growth in vivo when combined with radiation and platinum-based chemotherapy in both NSCLC and SCLC. 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.
Details
- Title: Subtitle
- Repurposing Disulfiram for targeting of hypoxic cancer cells through redox cycling of copper
- Creators
- Kelly C Falls-Hubert
- Contributors
- Douglas R Spitz (Advisor)Garry R Buettner (Committee Member)Bryan G Allen (Committee Member)Michael K Schultz (Committee Member)Eric B Taylor (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Free Radical and Radiation Biology
- Date degree season
- Spring 2021
- Publisher
- University of Iowa
- DOI
- 10.17077/etd.006105
- Number of pages
- xii, 122 pages
- Copyright
- Copyright 2020 Kelly C Falls-Hubert
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 103-113).
- Public Abstract (ETD)
Lung cancer is one of the most deadly cancers in the United States, and despite multiple modalities of treatment, the 5-year survival rate remains below 20% for non-small cell lung cancer (NSCLC) patients and below 6% for small cell lung cancer (SCLC) patients. Given these outcome, new treatment options that can selectively kill cancer cells, as well as hypoxic cells that are responsible for drug resistance and metastasis, are urgently needed. Disulfiram (DSF) is an FDA approved drug that may be repurposed for targeting these cells. Results show that DSF causes selective toxicity to cancer cells and enhances the effects of radiation and chemotherapy in cancer cells. Furthermore, DSF is well tolerated by normal cells and does not enhance the effects of standard of care therapeutic agents in normal tissue. Results show that this selective toxicity of DSF is caused by delivery of copper into cancer cells, which is a reactive metal ion that produces reactive oxygen species and causes damage to multiple cell components. These effects are also enhanced in cancer cells treated in hypoxia. Given that hypoxic regions of tumors are resistant to most anti-cancer therapies, this finding identifies DSF as a promising drug to repurpose as an adjuvant to standard of care.
- Academic Unit
- Free Radical and Radiation Biology Program
- Record Identifier
- 9984096977702771
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