Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation,angiogenesis and protection against oxidative stress |
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Authors: | Koichi Ito Stacy A. Scott Samuel Cutler Lan-Feng Dong Jiri Neuzil Helen Blanchard Stephen J. Ralph |
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Affiliation: | (1) School of Medical Science, Griffith Health Institute, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia;(2) Institute for Glycomics, Griffith University, Southport, QLD, Australia;(3) Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic; |
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Abstract: | Cancer cells produce galectin-1 as a tumor promoting protein. Thiodigalactoside (TDG) as a non-metabolised small drug, is shown to suppress tumor growth by inhibiting multiple cancer enhancing activities of galectin-1, including immune cell dysregulation, angiogenesis and protection against oxidative stress. Thus, using B16F10 melanoma and 4T1 orthotopic breast cancer models, intratumoral injection of TDG significantly raised the levels of tumor-infiltrating CD8+ lymphocytes and reduced CD31+ endothelial cell content, reducing tumor growth. TDG treatment of tumors in Balb/c nude mice (defective in T cell immunity) reduced angiogenesis and slowed tumor growth by a third less than in immunocompetent mice. Knocking down galectin-1 expression (G1KD) in both cancer cell types significantly impeded tumor growth and the sensitivity of the G1KD tumors to TDG was severely reduced, highlighting a specific role for galectin-1. Endothelial cells were protected by galectin-1 from oxidative stress-induced apoptosis induced by H2O2, but TDG inhibited this antioxidant protective effect of galectin-1 and reduced tube forming activity in angiogenic assays. We show for the first time that the single agent, TDG, concurrently prevents many tumor promoting effects of galectin-1 on angiogenesis, immune dysregulation and protection against oxidative stress, providing a potent and novel small molecule as an anti-cancer drug. |
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