title: 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.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, QLD, Australia.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ito
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Scott
authors.forename: Samuel
authors.initials: S
authors.lastname: Cutler
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Dong
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
authors.forename: Helen
authors.initials: H
authors.lastname: Blanchard
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ralph
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D037483:Galectin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007111:Immunity, Cellular / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D013862:Thiogalactosides / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D037483:Galectin 1; D013862:Thiogalactosides; C031803:thiodigalactoside