title: Inhibition of prostate cancer bone metastasis by synthetic TF antigen mimic/galectin-3 inhibitor lactulose-L-leucine.
abstract: Currently incurable, prostate cancer metastasis has a remarkable ability to spread to the skeleton. Previous studies demonstrated that interactions mediated by the cancer-associated Thomsen-Friedenreich glycoantigen (TF-Ag) and the carbohydrate-binding protein galectin-3 play an important role in several rate-limiting steps of cancer metastasis such as metastatic cell adhesion to bone marrow endothelium, homotypic tumor cell aggregation, and clonogenic survival and growth. This study investigated the ability of a synthetic small-molecular-weight nontoxic carbohydrate-based TF-Ag mimic lactulose-L-leucine (Lac-L-Leu) to inhibit these processes in vitro and, ultimately, prostate cancer bone metastasis in vivo. Using an in vivo mouse model, based on intracardiac injection of human PC-3 prostate carcinoma cells stably expressing luciferase, we investigated the ability of Lac-L-Leu to impede the establishment and growth of bone metastasis. Parallel-flow chamber assay, homotypic aggregation assay, modified Boyden chamber assay, and clonogenic growth assay were used to assess the effects of Lac-L-Leu on tumor cell adhesion to the endothelium, homotypic tumor cell aggregation, transendothelial migration, and clonogenic survival and growth, respectively. We report that daily intraperitoneal administration of Lac-L-Leu resulted in a three-fold (P < .05) decrease in metastatic tumor burden compared with the untreated control. Mechanistically, the effect of Lac-L-Leu, which binds and inhibits galectins by mimicking essential structural features of the TF-Ag, was associated with a dose-dependent inhibition of prostate cancer cell adhesion to bone marrow endothelium, homotypic aggregation, transendothelial migration, and clonogenic growth. We conclude that small-molecular-weight carbohydrate-based compounds targeting β-galactoside-mediated interactions could provide valuable means for controlling and preventing metastatic prostate cancer spread to the skeleton.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Glinskii
authors.forename: Sudha
authors.initials: S
authors.lastname: Sud
authors.forename: Valeri V
authors.initials: VV
authors.lastname: Mossine
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Mawhinney
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Anthony
authors.forename: Gennadi V
authors.initials: GV
authors.lastname: Glinsky
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Glinsky
mesh_terms: D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate; D000970:Antineoplastic Agents / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D037502:Galectin 3 / Q000037:antagonists & inhibitors; D006801:Humans; D007792:Lactulose / Q000031:analogs & derivatives* / Q000494:pharmacology; D007930:Leucine / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D023041:Xenograft Model Antitumor Assays
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D000970:Antineoplastic Agents; D037502:Galectin 3; C016467:Thomsen-Friedenreich antigen; D007792:Lactulose; D007930:Leucine