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Cited by 103Cytokine Signaling Pathways and InteractionsCancer Immunotherapy and BiomarkersImmune cells in cancer

The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer

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Khan, Mohammad W., Saadalla, Abdulrahman, Ewida, Ahmed H., Al-Katranji, Khalid, Al-Saoudi, Ghadier, Giaccone, Zachary T., Gounari, Fotini, Zhang, Ming +2 more·2018·Cancer Immunology, Immunotherapy
DOI 10.1007/s00262-017-2057-0PMC PMC5783191
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Abstract

The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8+ T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.

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  • Subsequent studies by Khan et al. (2018) showed that GLG-801 has direct antitumor activity in two breast cancer mouse models.

    “Subsequent studies published recently by Khan et al. (2018) showed that GLG-801 has direct antitumor activity in two breast cancer mouse models.”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Khan et al., 2018

    The Discussion (page unavailable) reports that pyrimethamine (PYR) inhibited tumor growth in mouse models of transplanted and spontaneous breast cancer, including a direct effect on cancer cells. The paper does not identify PYR as GLG-801, so our copy cannot verify the claim under that drug name. (LLM, conf=0.84)

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Authors
Khan, M. W., Saadalla, A., Ewida, A. H., Al-Katranji, K., Al-Saoudi, G., Giaccone, Z. T., Gounari, F., Zhang, M., Frank, D. A., & Khazaie, K.
Affiliations
  • San Diego State University (US)
  • Mayo Clinic (US)
  • Northwestern University (US)
  • Dana-Farber Cancer Institute (US)
  • University of Chicago (US)
Corresponding author
Khazaie, Khashayarsha
ORCID
Venue
Cancer Immunology, Immunotherapy
Publisher
Springer Science and Business Media LLC
Published
2017-09-05
Volume
67
Issue
1
Pages
13-23
ISSN
  • 0340-7004 (ISSN-L)
  • 1432-0851
DOI
10.1007/s00262-017-2057-0
PMC
PMC5783191
OpenAlex
W2753005915
Cited by
103
References
1
Citations by year
2026: 4 · 2025: 8 · 2024: 9 · 2023: 13 · 2022: 17 · 2021: 16 · 2020: 23 · 2019: 9 · 2018: 4
FWCI
4.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Immunology Immunotherapy (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
National Institutes of Health (R01CA160436-05, R01 AA023417-03, R01 AI 108682-02)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
pyrimethamine, STAT3 inhibition, breast cancer, tumor immunosuppression, tumor microenvironment, tumor inflammation, CD8+ T cells, metastatic breast cancer, tumor cell proliferation, tumor invasion
MeSH terms
Adjuvants, Immunologic, Animals, Anti-Infective Agents, Antineoplastic Agents, Breast Neoplasms, Cytotoxicity, Immunologic, Disease Models, Animal, Female, Humans, Mice, Inbred BALB C, Neoplasm Transplantation, Pyrimethamine, United States, CD8-Positive T-Lymphocytes, Tumor Escape, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor, Mice, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 1

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