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

Khan, Mohammad W. ; Saadalla, Abdulrahman ; Ewida, Ahmed H. ; Al-Katranji, Khalid ; Al-Saoudi, Ghadier ; Giaccone, Zachary T. ; Gounari, Fotini ; Zhang, Ming ; Frank, David A. ; Khazaie, Khashayarsha

Cancer Immunology, Immunotherapy, 2018-01, Vol.67 (1), p.13-23 [Peer Reviewed Journal]

Berlin/Heidelberg: Springer Berlin Heidelberg

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Title:
The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer
Author: Khan, Mohammad W. ; Saadalla, Abdulrahman ; Ewida, Ahmed H. ; Al-Katranji, Khalid ; Al-Saoudi, Ghadier ; Giaccone, Zachary T. ; Gounari, Fotini ; Zhang, Ming ; Frank, David A. ; Khazaie, Khashayarsha
Subjects: Activation ; Adjuvants, Immunologic - therapeutic use ; Animal models ; Animals ; Anti-Infective Agents - therapeutic use ; Antineoplastic Agents - therapeutic use ; Breast cancer ; Breast Neoplasms - drug therapy ; Cancer Research ; CD8 antigen ; CD8-Positive T-Lymphocytes - immunology ; Cell Line, Tumor ; Cell Proliferation ; Cytotoxicity ; Cytotoxicity, Immunologic ; Disease Models, Animal ; Female ; Humans ; Immunology ; Lymphocytes ; Lymphocytes T ; Lysosomal Membrane Proteins - genetics ; Lysosomal Membrane Proteins - metabolism ; Medicine ; Medicine & Public Health ; Metastases ; Mice ; Mice, Inbred BALB C ; Neoplasm Transplantation ; Oncology ; Original Article ; Pyrimethamine ; Pyrimethamine - pharmacology ; Pyrimethamine - therapeutic use ; Stat3 protein ; STAT3 Transcription Factor - antagonists & inhibitors ; STAT3 Transcription Factor - metabolism ; Tumor cells ; Tumor Escape ; United States
Is Part Of: Cancer Immunology, Immunotherapy, 2018-01, Vol.67 (1), p.13-23
Notes: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Description: 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.
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
Language: English

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

Khan, Mohammad W. ; Saadalla, Abdulrahman ; Ewida, Ahmed H. ; Al-Katranji, Khalid ; Al-Saoudi, Ghadier ; Giaccone, Zachary T. ; Gounari, Fotini ; Zhang, Ming ; Frank, David A. ; Khazaie, Khashayarsha

Berlin/Heidelberg: Springer Berlin Heidelberg

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