Boron Abstracts 4

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Evaluation of ecological and in vitro effects of boron on prostate cancer risk (United States).
            (Barranco et al., 2007) Download
OBJECTIVE:  To determine: (1) the correlation of prostate cancer incidence and mortality with groundwater boron and selenium concentrations; and (2) the impact of boron on prostate cancer cell proliferation during co-treatment with alternative chemo-preventative agents, along with boron pre-treatment effects on cell sensitivity to ionizing radiation. METHODS:  For regression analysis, data on prostate cancer incidence and mortality were obtained from the Texas Cancer Registry, while groundwater boron and selenium concentrations were derived from the Texas Water Development Board. Cultured DU-145 prostate cancer cells were used to assess the impact of boric acid on cell proliferation when applied in combination with selenomethionine and genistein, or preceding radiation exposure. RESULTS:  Groundwater boron levels correlated with a decrease in prostate cancer incidence (R = 0.6) and mortality (R = 0.6) in state planning regions, whereas selenium did not (R = 0.1; R = 0.2). Growth inhibition was greater during combined treatments of boric acid and selenomethionine, or boric acid and genistein, versus singular treatments. 8-day boric acid pre-exposure enhanced the toxicity of ionizing radiation treatment, while dose-dependently decreasing the expression of anti-apoptotic protein Bcl-2. CONCLUSIONS:  Increased groundwater boron concentrations, across the state of Texas, correlate with reduced risk of prostate cancer incidence and mortality. Also, boric acid improves the anti-proliferative effectiveness of chemo-preventative agents, selenomethionine and genistein, while enhancing ionizing radiation cell kill.

Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice.
            (Gallardo-Williams et al., 2004) Download
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.

Receptor activated Ca(2+) release is inhibited by boric acid in prostate cancer cells.
            (Henderson et al., 2009) Download
BACKGROUND:  The global disparity in cancer incidence remains a major public health problem. We focused on prostate cancer since microscopic disease in men is common, but the incidence of clinical disease varies more than 100 fold worldwide. Ca(2+) signaling is a central regulator of cell proliferation, but has received little attention in cancer prevention. We and others have reported a strong dose-dependent reduction in the incidence of prostate and lung cancer within populations exposed to boron (B) in drinking water and food; and in tumor and cell proliferation in animal and cell culture models. METHODS/PRINCIPAL FINDINGS:  We examined the impact of B on Ca(2+) stores using cancer and non-cancer human prostate cell lines, Ca(2+) indicators Rhod-2 AM and Indo-1 AM and confocal microscopy. In DU-145 cells, inhibition of Ca(2+) release was apparent following treatment with Ringers containing RyR agonists cADPR, 4CmC or caffeine and respective levels of BA (50 microM), (1, 10 microM) or (10, 20, 50,150 microM). Less aggressive LNCaP cancer cells required 20 microM BA and the non-tumor cell line PWR1E required 150 microM BA to significantly inhibit caffeine stimulated Ca(2+) release. BA (10 microM) and the RyR antagonist dantroline (10 microM) were equivalent in their ability to inhibit ER Ca(2+) loss. Flow cytometry and confocal microscopy analysis showed exposure of DU-145 cells to 50 microM BA for 1 hr decreased stored [Ca(2+)] by 32%. CONCLUSION/SIGNIFICANCE:  We show B causes a dose dependent decrease of Ca(2+) release from ryanodine receptor sensitive stores. This occurred at BA concentrations present in blood of geographically disparate populations. Our results suggest higher BA blood levels lower the risk of prostate cancer by reducing intracellular Ca(2+) signals and storage.

Prostate-specific antigen: an overlooked candidate for the targeted treatment and selective imaging of prostate cancer.
            (LeBeau et al., 2010) Download
The role of prostate-specific antigen (PSA) or kallikrein-related peptidase 3 (KLK3) as a biomarker for prostate cancer is well known; however, the precise physiological role of it's serine protease activity in prostate cancer remains a mystery. PSA is produced at high levels by both androgen-dependent and -independent prostate cancers. Studies have documented high levels of active PSA in the milieu surrounding osseous and soft tissue metastases. This evidence, coupled with growing experimental evidence, suggests that PSA plays an important role in the pathobiology of prostate cancer. These observations support the development of PSA-selective inhibitors as useful tools for the targeted treatment and imaging of prostate cancer. Here, we review the research that has been conducted to date on developing selective inhibitors for PSA. The different approaches used to determine PSA substrate specificity and for creating inhibitors are discussed. In addition, the unique active site characteristics of PSA and how these motifs aided our research in developing PSA targeted agents are highlighted.

Nothing Boring About Boron.
            (Pizzorno, 2015) Download
The trace mineral boron is a micronutrient with diverse and vitally important roles in metabolism that render it necessary for plant, animal, and human health, and as recent research suggests, possibly for the evolution of life on Earth. As the current article shows, boron has been proven to be an important trace mineral because it (1) is essential for the growth and maintenance of bone; (2) greatly improves wound healing; (3) beneficially impacts the body's use of estrogen, testosterone, and vitamin D; (4) boosts magnesium absorption; (5) reduces levels of inflammatory biomarkers, such as high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor α (TNF-α); (6) raises levels of antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase; (7) protects against pesticide-induced oxidative stress and heavy-metal toxicity; (8) improves the brains electrical activity, cognitive performance, and short-term memory for elders; (9) influences the formation and activity of key biomolecules, such as S-adenosyl methionine (SAM-e) and nicotinamide adenine dinucleotide (NAD(+)); (10) has demonstrated preventive and therapeutic effects in a number of cancers, such as prostate, cervical, and lung cancers, and multiple and non-Hodgkin's lymphoma; and (11) may help ameliorate the adverse effects of traditional chemotherapeutic agents. In none of the numerous studies conducted to date, however, do boron's beneficial effects appear at intakes > 3 mg/d. No estimated average requirements (EARs) or dietary reference intakes (DRIs) have been set for boron-only an upper intake level (UL) of 20 mg/d for individuals aged ≥ 18 y. The absence of studies showing harm in conjunction with the substantial number of articles showing benefits support the consideration of boron supplementation of 3 mg/d for any individual who is consuming a diet lacking in fruits and vegetables or who is at risk for or has osteopenia; osteoporosis; osteoarthritis (OA); or breast, prostate, or lung cancer.

 


 

References

Barranco, WT, PF Hudak, and CD Eckhert (2007), ‘Evaluation of ecological and in vitro effects of boron on prostate cancer risk (United States).’, Cancer Causes Control, 18 (1), 71-77. PubMed: 17186423
Gallardo-Williams, MT, et al. (2004), ‘Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice.’, Toxicol Pathol, 32 (1), 73-78. PubMed: 14713551
Henderson, K, et al. (2009), ‘Receptor activated Ca(2+) release is inhibited by boric acid in prostate cancer cells.’, PLoS One, 4 (6), e6009. PubMed: 19554099
LeBeau, AM, et al. (2010), ‘Prostate-specific antigen: an overlooked candidate for the targeted treatment and selective imaging of prostate cancer.’, Biol Chem, 391 (4), 333-43. PubMed: 20180648
Pizzorno, L (2015), ‘Nothing Boring About Boron.’, Integr Med (Encinitas), 14 (4), 35-48. PubMed: 26770156