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: Olga V Glinskii, Sudha Sud, Valeri V Mossine, Thomas P Mawhinney, Douglas C Anthony, Gennadi V Glinsky, Kenneth J Pienta, Vladislav V Glinsky
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 14 Issue 1 Pg. 65-73 (Jan 2012) ISSN: 1476-5586 [Electronic] United States
• PMID: 22355275 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, Tumor-Associated, Carbohydrate
• Antineoplastic Agents
• Galectin 3
• Thomsen-Friedenreich antigen
• Lactulose
• Leucine

Topics

• Animals
• Antigens, Tumor-Associated, Carbohydrate
• Antineoplastic Agents (pharmacology)
• Biomimetic Materials (pharmacology)
• Bone Neoplasms (prevention & control, secondary)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Galectin 3 (antagonists & inhibitors)
• Humans
• Lactulose (analogs & derivatives, pharmacology)
• Leucine (pharmacology)
• Male
• Mice
• Mice, SCID
• Prostatic Neoplasms (pathology, prevention & control)
• Xenograft Model Antitumor Assays