Boron Supplementation Inhibits the Growth and Local Expression of IGF-1 in Human Prostate Adenocarcinoma (LNCaP) Tumors in Nude Mice

Abstract

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.

Cellular changes in boric acid-treated DU-145 prostate cancer cells

“…In culture, BA has been shown to inhibit the proliferation of LNCaP and the androgen-independent prostate cancer cell lines DU-145 and PC-3, in a dose-dependent manner (Barranco and Eckhert, 2004). Since DU-145 cells do not synthesise PSA, BA's mode of inhibiting proliferation is likely not to occur by inhibiting the conversion of IGFBP-3 to IGF-1, as proposed in LNCaP tumours (Gallardo-Williams et al, 2004;Sobel and Sadar, 2005). The present investigation was initiated to define morphological and molecular responses of DU-145 prostate cancer cells to BA, which might lead to an explanation of its antiproliferative properties.…”

“…The biological plausibility of this observation has been supported by cell culture and animal studies. Treatment of nude mice, injected with androgen-sensitive LNCaP prostate cancer cells, with BA caused a reduction in tumour growth of 25 -38%, along with a reduction in plasma PSA levels of 88% (Gallardo-Williams et al, 2004). BA inhibits the activity of serine proteases, including prostate-specific antigen (PSA), presumably by binding to its active site (Bone et al, 1987;Gallardo-Williams et al, 2003).…”

Phenylboronic acid selectively inhibits human prostate and breast cancer cell migration and decreases viability

“…16,[32][33][34] Recent epidemiological, in vitro, and animal studies reveal a possible role for boric acid (BA), the most abundant physiological form of boron in the plasma, as a chemotherapeutic agent. [16][17][18][19][20][21] In a nude mouse model of prostate cancer, BA decreases tumor size, IGF-1 serum levels and PSA levels and proteolytic activity. 20,21 Barranco et al also demonstrate that 1 mM of boric acid significantly decreases migration and proliferation of the prostate cancer cell line DU-145 in vitro.…”

“…[16][17][18][19][20][21] In a nude mouse model of prostate cancer, BA decreases tumor size, IGF-1 serum levels and PSA levels and proteolytic activity. 20,21 Barranco et al also demonstrate that 1 mM of boric acid significantly decreases migration and proliferation of the prostate cancer cell line DU-145 in vitro. 17,18 These studies motivate our search for additional derivatives of BA that may be effective at selectively inhibiting the metastatic properties of tumor cells.…”

Genotoxicity and Cytotoxicity of novel 10B carrier ((2R)-4,5,6-trihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)boronic acid

“…According to several studies, the supplementation of food with boron reduces the risk of some cancers [29,30]. Moreover, Gallardo-Williams et al showed that additional boron taken with food reduces the size of tumors and the level of IGF-I in rats [31]. Acerbo and Miller reported that boron prevents the proliferation of cancer cells in melanoma [32].…”