Journal article
Disulfiram causes selective hypoxic cancer cell toxicity and radio-chemo-sensitization via redox cycling of copper
Free radical biology & medicine, Vol.150, pp.1-11
04/2020
DOI: 10.1016/j.freeradbiomed.2020.01.186
PMID: 32032663
Abstract
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 μM CuSO4) was selectively toxic to H292 NSCLC cells vs. 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 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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•Disulfiram causes selective toxicity in cancer cells vs. normal cells.•Disulfiram toxicity is enhanced at hypoxia.•Disulfiram causes selective radio-chemo-sensitization in cancer cells and hypoxia.•O2•-, H2O2, lipid oxidation, and Cu retention/efflux (via ATP7B) govern toxicity.
Details
- Title: Subtitle
- Disulfiram causes selective hypoxic cancer cell toxicity and radio-chemo-sensitization via redox cycling of copper
- Creators
- Kelly C Falls-Hubert - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAAimee L Butler - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAKai Gui - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAMichael Anderson - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAMengshi Li - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAJeffrey M Stolwijk - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USASamuel N Rodman - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAShane R Solst - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAAnn Tomanek-Chalkley - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USACharles C Searby - Department Pediatrics, University of Iowa, Iowa City, IA, 52242, USAVal C Sheffield - Department Pediatrics, University of Iowa, Iowa City, IA, 52242, USAVanessa Sandfort - Gastroenterology and Hepatology, Münster University Hospital (UKM), Münster, GermanyHartmut Schmidt - Gastroenterology and Hepatology, Münster University Hospital (UKM), Münster, GermanyMichael L McCormick - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USABrian R Wels - State Hygienic Lab, University of Iowa, Ankeny, IA, 50023, USABryan G Allen - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAGarry R Buettner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAMichael K Schultz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USADouglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
- Resource Type
- Journal article
- Publication Details
- Free radical biology & medicine, Vol.150, pp.1-11
- DOI
- 10.1016/j.freeradbiomed.2020.01.186
- PMID
- 32032663
- NLM abbreviation
- Free Radic Biol Med
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Publisher
- Elsevier Inc
- Grant note
- name: DSF; name: BCS; name: DSF; name: DSF; DOI: 10.13039/100000002, name: National Institutes of Health, United States, , award: F30 CA213817, R01 CA182804, T32 GM007337, T32 CA078586, P30 CA086862, P01 CA217797, P50 CA174521
- Language
- English
- Date published
- 04/2020
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Medical Genetics and Genomics; Radiation Oncology; Radiation Research Laboratory; Ophthalmology and Visual Sciences
- Record Identifier
- 9984070799102771
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