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Boron Supplementation Inhibits the Growth and Local Expression of IGF-1 in Human Prostate Adenocarcinoma (LNCaP) Tumors in Nude Mice
Maria T. Gallardo-Williams
Laboratory of Experimental Pathology
Robert E. Chapin
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC
Paula E. King
ILS, Inc., Research Triangle Park, NC
Glenda J. Moser
ILS, Inc., Research Triangle Park, NC
Thomas L. Goldsworthy
ILS, Inc., Research Triangle Park, NC
James P. Morrison
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
Robert R. Maronpot
Laboratory of Experimental Pathology, maronpot{at}niehs.nih.gov
Prostate-specific antigen (PSA) is a serine protease and one of the most abundant proteins secreted by the human prostate epithelium. PSA is used as a well-established marker of prostate cancer. The involvement of PSA in several early events leading to the development of malignant prostate tumors has made it a target for prevention and intervention. It is thought that PSA cleaves insulin-like growth factor binding protein-3 (IGFBP-3), providing increased local levels of IGF-1, leading to tumor growth. Separately, there are data that suggest an enzymatic regulatory role for dietary boron, which is a serine protease inhibitor. In this study we have addressed the use of boric acid as a PSA inhibitor in an animal study. We have previously reported that low concentrations (6 ug/mL) of boric acid can partially inhibit the proteolytic activity of purified PSA towards a synthetic fluorogenic substrate. Also, by Western blot we have followed the degradation of fibronectin by enzymatically active PSA and have found significant inhibition in the presence of boric acid. We proposed that dietary supplementation with boric acid would inhibit PSA and reduce the development and proliferation of prostate carcinomas in an animal model. We tested this hypothesis using nude mice implanted subcutaneously with LNCaP cells in Matrigel. Two groups (10 animals/group) were dosed with boric acid solutions (1.7, 9.0 mgB/kg/day) by gavage. Control group received only water. Tumor sizes were measured weekly for 8 weeks. Serum PSA and IGF-1 levels were determined at terminal sacrifice. The size of tumors was decreased in mice exposed to the low and high dose of boric acid by 38% and 25%, respectively. Serum PSA levels decreased by 88.6% and 86.4%, respectively, as compared to the control group. There were morphological differences between the tumors in control and boron-dosed animals, including a significantly lower incidence of mitotic figures in the boron-supplemented groups. Circulating IGF-1 levels were not different among groups, though expression of IGF-1 in the tumors was markedly reduced by boron treatment, which we have shown by immunohistochemistry. These data indicate that low-level dietary boron supplementation reduced tumor size and content of a tumor trophic factor, IGF-1.This promising model is being evaluated in further studies.
Key Words: Prostate cancer • LNCaP cell line • boron • dietary supplementation • serine protease • chemoprevention.
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Toxicologic Pathology, Vol. 32, No. 1,
73-78 (2004)
DOI: 10.1080/01926230490260899
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