title: Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer.
abstract: Cancer cells often have increased levels of reactive oxygen species (ROS); however, acquisition of redox adaptive mechanisms allows for evasion of ROS-mediated death. Inflammatory breast cancer (IBC) is a distinct, advanced BC subtype characterized by high rates of residual disease and recurrence despite advances in multimodality treatment. Using a cellular model of IBC, we identified an oxidative stress response (OSR) signature in surviving IBC cells after administration of an acute dose of an ROS inducer. Metagene analysis of patient samples revealed significantly higher OSR scores in IBC tumor samples compared to normal or non-IBC tissues, which may contribute to the poor response of IBC tumors to common treatment strategies, which often rely heavily on ROS induction. To combat this adaptation, we utilized a potent redox modulator, the FDA-approved small molecule Disulfiram (DSF), alone and in combination with copper. DSF forms a complex with copper (DSF-Cu) increasing intracellular copper concentration both in vitro and in vivo, bypassing the need for membrane transporters. DSF-Cu antagonized NFκB signaling, aldehyde dehydrogenase activity and antioxidant levels, inducing oxidative stress-mediated apoptosis in multiple IBC cellular models. In vivo, DSF-Cu significantly inhibited tumor growth without significant toxicity, causing apoptosis only in tumor cells. These results indicate that IBC tumors are highly redox adapted, which may render them resistant to ROS-inducing therapies. DSF, through redox modulation, may be a useful approach to enhance chemo- and/or radio-sensitivity for advanced BC subtypes where therapeutic resistance is an impediment to durable responses to current standard of care.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA; Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Allensworth
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA; Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Myron K
authors.initials: MK
authors.lastname: Evans
authors.affiliation: Department of Medical Oncology and Molecular Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Aldrich
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Festa
authors.affiliation: Department of Medical Oncology and Molecular Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, USA.
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Rachid
authors.initials: R
authors.lastname: Safi
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
authors.affiliation: Translational Cancer Research Unit, Oncology Center, General Hospital Sint-Augustinus, Antwerp, Wilrijk, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Van Laere
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA; Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; Department of Pathology, Duke University Medical Center, Durham, NC, USA. Electronic address: gayathri.devi@duke.edu.
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism*; D004221:Disulfiram / Q000494:pharmacology*; D005260:Female; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D007476:Ionophores; D003300:Copper; D004221:Disulfiram
keywords: ALDH; Antioxidant; Apoptosis; NFκB; SUM149; XIAP