Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress.

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 H(2)O(2), 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.

• Authors: Koichi Ito, Stacy A Scott, Samuel Cutler, Lan-Feng Dong, Jiri Neuzil, Helen Blanchard, Stephen J Ralph
• Journal: Angiogenesis (Angiogenesis) Vol. 14 Issue 3 Pg. 293-307 (Sep 2011) ISSN: 1573-7209 [Electronic] Germany
• PMID: 21523436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Galectin 1
• Thiogalactosides
• thiodigalactoside

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics)
• CD8-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics, immunology)
• Endothelial Cells (metabolism, pathology)
• Female
• Galectin 1 (antagonists & inhibitors, genetics, immunology, metabolism)
• Gene Knockdown Techniques
• Immunity, Cellular (drug effects)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms, Experimental (drug therapy, genetics, immunology, metabolism, pathology)
• Neovascularization, Pathologic (drug therapy, genetics, immunology, metabolism)
• Oxidative Stress (drug effects)
• Thiogalactosides (pharmacology)