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Cited by 74Cancer Cells and MetastasisImmunotherapy and Immune ResponsesCell death mechanisms and regulation

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

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Sun, Ting, Yang, Wei, Toprani, Sneh M., Guo, Wei, He, Lile, DeLeo, Albert B., Ferrone, Soldano, Zhang, Gong +4 more·2020·Cell Communication and Signaling
DOI 10.1186/s12964-019-0507-3PMC PMC7057578
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Abstract

Background: The current successful clinical use of agents promoting robust anti-tumor immunity in cancer patients warrants noting that radiation therapy (RT) induces immunogenic cell death (ICD) of tumor cells, which can generate anti-tumor immune responses. However, breast cancer stem cells (BCSCs) are resistant to RT and RT alone usually failed to mount an anti-tumor immune response. Methods: High aldehyde dehydrogenase activity (ALDH)bright and CD44+/CD24−/ESA+ cancer cells, previously shown to have BCSC properties, were isolated from human MDA-MB-231 and UACC-812 breast cancer cell lines by flow cytometer. Flow sorted BCSCs and non-BCSCs were further tested for their characteristic of stemness by mammosphere formation assay. Induction of ICD in BCSCs vs. non-BCSCs in response to different in vitro treatments was determined by assessing cell apoptosis and a panel of damage-associated molecular pattern molecules (DAMPs) by flow and enzyme-linked immunosorbent assay (ELISA). Results: We found that ionizing radiation (IR) triggered a lower level of ICD in BCSCs than non-BCSCs. We then investigated the ability of disulfiram/cooper (DSF/Cu) which is known to preferentially induce cancer stem cells (CSCs) apoptosis to enhance IR-induced ICD of BCSCs. The results indicate that DSF/Cu induced a similar extent of IDC in both BCSCs and non-BCSCs and rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. IR and DSF/Cu induced ICD of BCSCs could be partly reversed by pre-treatment of BCSCs with a reactive oxygen species (ROS) scavenger and XBP1s inhibitors. Conclusion: DSF/Cu rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. Our data demonstrate the potential of IR and DSF/Cu to induce ICD in BCSCs and non-BCSCs leading to robust immune responses against not only differentiated/differentiating breast cancer cells but also BCSCs, the root cause of cancer formation, progression and metastasis. Graphical abstract:

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  • DIS combined with copper sensitizes ionizing radiation-resistant cancer stem cells due to elevated ROS level, amplifying radiation damage, and by activation of the IRE1α/XBP1 signaling axis.

    “DIS combined with copper sensitizes ionizing radiation-resistant cancer stem cells, due to elevated ROS level, amplifying radiation damage, and by the activation of the IRE1α/XBP1 signaling axis.78”

    From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [78]

    The Results section ('DSF/Cu rendered BCSCs as sensitive as non-BCSCs to IR-induced ICD') reports that disulfiram/copper increased radiation-induced immunogenic cell death in breast cancer stem cells. The Results section on ROS and IRE1α/XBP1, together with the Discussion, says these pathways are partially involved. The passages do not establish that elevated ROS amplified radiation damage itself, and the finding is specific to immunogenic cell death in breast cancer stem cells. (LLM, conf=0.84)

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References 49 · Cited by 74

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Authors
Sun, T., Yang, W., Toprani, S. M., Guo, W., He, L., DeLeo, A. B., Ferrone, S., Zhang, G., Wang, E., Lin, Z., Hu, P., & Wang, X.
Affiliations
Harvard University (US)
Corresponding author
Wang, Xinhui
ORCID
Venue
Cell Communication and Signaling
Publisher
Springer Science and Business Media LLC
Published
2020-03-05
Volume
18
Issue
1
Pages
36-36
ISSN
1478-811X (ISSN-L)
DOI
10.1186/s12964-019-0507-3
PMC
PMC7057578
OpenAlex
W3011949533
Cited by
74
References
49
Citations by year
2026: 3 · 2025: 6 · 2024: 13 · 2023: 14 · 2022: 11 · 2021: 18 · 2020: 9
FWCI
4.70
Type
journal article
Language
en
Update notices
correction (2020-04-02)
Open access
Licence
Locations
  • Cell Communication and Signaling (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Massachusetts General Hospital (R01CA226981-01A1)
  • U.S. Department of Defense (W81XWH-16-1-0500)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
immunogenic cell death, breast cancer stem cells, disulfiram, radioresistance (biology), ionizing radiation, copper, drug repurposing, damage-associated molecular patterns, reactive oxygen species, XBP1, apoptosis, antitumor immunity, mammosphere formation
MeSH terms
Immunogenic Cell Death, Antineoplastic Agents, Breast Neoplasms, Disulfiram, Female, Humans, Radiation Tolerance, Neoplastic Stem Cells, Cell Line, Tumor, Drug Repositioning

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