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01-01-2018 | Original Article

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

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

Published in: Cancer Immunology, Immunotherapy | Issue 1/2018

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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Title: The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer
Authors: Mohammad W. Khan
Abdulrahman Saadalla
Ahmed H. Ewida
Khalid Al-Katranji
Ghadier Al-Saoudi
Zachary T. Giaccone
Fotini Gounari
Ming Zhang
David A. Frank
Khashayarsha Khazaie
Publication date: 01-01-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 1/2018
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-017-2057-0

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