TY - JOUR
T1 - Inhibition of prostate cancer bone metastasis by synthetic TF antigen mimic/galectin-3 inhibitor lactulose-L-leucine
AU - Glinskii, Olga V.
AU - Sud, Sudha
AU - Mossine, Valeri V.
AU - Mawhinney, Thomas P.
AU - Anthony, Douglas C.
AU - Glinsky, Gennadi V.
AU - Pienta, Kenneth J.
AU - Glinsky, Vladislav V.
N1 - Funding Information:
Address all correspondence to: Vladislav V. Glinsky, MD, Department of Pathology and Anatomical Sciences, M263 Medical Science Building, University of Missouri, Columbia, MO 65212. E-mail: glinskiivl@missouri.edu; or Kenneth J. Pienta, MD, 1500 E Medical Center Dr, University of Michigan Ann Arbor, Comprehensive Cancer Center, Ann Arbor, MI 48109-0946. E-mail: kpienta@med.umich.edu 1This work was supported in parts by award number 1I01BX000609 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (V.V. Glinsky), American Heart Association National SDG 0830287N (O.V. Glinskii), and National Institutes of Health SPORE 2 P50 CA69568 and 1 PO1 CA093900 (K.J. Pienta). K.J. Pienta receives support from the Prostate Cancer Foundation and as an American Cancer Society Clinical Research Professor. The authors disclose no potential conflicts of interest. 2V.V. Glinsky and K.J. Pienta share senior authorship. Received 1 November 2011; Revised 19 December 2011; Accepted 19 December 2011 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.111544
PY - 2012/1
Y1 - 2012/1
N2 - 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-LLeu 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 smallmolecular-weight carbohydrate-based compounds targeting β-galactoside-mediated interactions could provide valuable means for controlling and preventing metastatic prostate cancer spread to the skeleton.
AB - 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-LLeu 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 smallmolecular-weight carbohydrate-based compounds targeting β-galactoside-mediated interactions could provide valuable means for controlling and preventing metastatic prostate cancer spread to the skeleton.
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U2 - 10.1593/neo.111544
DO - 10.1593/neo.111544
M3 - Article
C2 - 22355275
AN - SCOPUS:84857024314
SN - 1522-8002
VL - 14
SP - 65
EP - 73
JO - Neoplasia
JF - Neoplasia
IS - 1
ER -