Anticancer Agents Med Chem. 2009 Nov 16. [Epub ahead of print]
Boron-Containing Compounds as Preventive and Chemotherapeutic Agents for Cancer.
Scorei RI,
Popa R Jr.
Dept. Biochemistry, University of Craiova, A.I. Cuza Street, no.13, Craiova, 200585, Romania.
romulus_ion@yahoo.com.
In the last few years boron (B) compounds became increasingly frequent in the chemotherapy of some forms of cancer with high malignancy and of inoperable cancers. As more B-based therapy chemicals are developed it is necessary to review the correlation between B and the incidence of different forms of cancer, the biochemical and molecular mechanisms influenced by B and to explore the relevance of B in the chemoprevention of cancer. This minireview analyzes dietary and therapeuptic principles based on the chemistry of B compounds and B-based radiotheraphy. We summarize studies correlating B-rich diets or B-rich environments with regional risks of specific forms of cancers, and studies about the utilization of natural and synthetic B-containing compounds as anticancer agents. We review mechanisms where B-containing compounds interfere with the physiology and reproduction of cancer cells.
Types of cancers most frequently impacted by B-containing compounds include prostate, breast, cervical and lung cancer. Mechanisms involving B activity on cancer cells are based on the inhibition of a variety of enzymatic activities, including serine proteases, NAD-dehydrogenases, mRNA splicing and cell division, but also receptor binding mimicry, and the induction of apoptosis. Boron-enriched diets resulted in significant decrease in the risk for prostate and cervical cancer, and decrease in lung cancer in smoking women. Boron-based compounds show promising effects for the chemotheraphy of specific forms of cancer, but due to specific benefits should also be included in cancer chemopreventive strategies.
PMID: 19912103 [PubMed - as supplied by publisher]
Boric Acid Inhibits Cell Growth in Breast and Prostate Cancer Cell Lines
| ISBN | 978-1-4020-5381-8 (Print) 978-1-4020-5382-5 (Online) |
| Part | Part II |
| DOI | 10.1007/978-1-4020-5382-5_29 |
| Pages | 299-306 |
| Subject Collection | Biomedical and Life Sciences |
| SpringerLink Date | Thursday, June 07, 2007 |
Susan L. Meacham
9, 11, Kyler E. Elwell
10, Sarah Ziegler
11 and Stephen W. Carper
10, 11 
| (9) | Department of Nutrition Sciences,Division of Health Sciences, School of Health and Human Sciences, Las Vegas, NV, 454003, 89154-4003 |
| (10) | Department of Chemistry, College of Sciences, Las Vegas, NV, 454003, 89154-4003 |
| (11) | UNLV Cancer Research Center, University of Nevada Las Vegas, Las Vegas, NV, 454003, 89154-4003 |
http://www.springerlink.com/content/g5m1387331848237/
Abstract
Boron, an element ubiquitous in the earth’s crust can be found in most soil types as well as in fresh and salt water, consequently, boron is a natural constituent in the human diet (Nemodruk and Karalova, 1969, Meacham and Hunt, 1998). In a typical adult daily intakes of boron were measured to be approximately 1 mg/day (Meacham and Hunt, 1998, Rainey et al. 1999). Boron is considered an essential micronutrient for higher plants; however, the most recent US dietary recommendations concluded that insufficient evidence existed to consider boron an essential micronutrient for humans (Warrington, 1923, Loomis and Durst, 1992, IOM, 2001). However, evidence does exist that indicates boron plays a beneficial role in some physiological processes of various animal species and measurable responses to adjusted boron intakes in humans have been observed (Rowe and Echkert, 1999, Nielsen, 1998).
Toxicol Pathol. 2004 Jan-Feb;32(1):73-8.
Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice.
Gallardo-Williams MT,
Chapin RE,
King PE,
Moser GJ,
Goldsworthy TL,
Morrison JP,
Maronpot RR.
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
FULL TEXT
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.
PMID: 14713551 [PubMed - indexed for MEDLINE]
Quote:
The latency period and incidence rates were not different between control and treatment groups, indicating that boron supplementation did not affect the initial stages of tumor formation from the implanted cells. This early stages of tumor implantation are hardly relevant in terms of the development the human disease. However, later on, size differences indicate that the boron supplementation affected the growth
and development of the cells once the tumor was established. More importantly, there were morphologic characteristics indicating that the tumors in boron-supplemented animals were less aggressive than the tumors in control animals. Of special
interest if the effect of boron on the total number of observed mitotic figures, which can be considered a surrogate measure of cell proliferation. In boron-supplemented animals the number of mitotic figures per observed fieldwas significantly decreased as compared to control, indicating impaired cell proliferation.
Tumors from control animals, in general, consisted of tightly packed cells, with many blood sinuses and vascular structures within the tumor. In contrast, tumors from treated
animals were not only smaller, but less densely packed, and presented large necrotic areas. The presence of a more developed vascular network in the control tumors indicates a more aggressive potential, since the growth of tumors in boron supplemented
animals would be limited due to lack of oxygen as a consequence of poor development of blood vessels.
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J Nutr. 2003 Nov;133(11):3577-83.
Dietary boron decreases peak pancreatic in situ insulin release in chicks and plasma insulin concentrations in rats regardless of vitamin D or magnesium status.
Bakken NA,
Hunt CD.
U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, USA.
Because dietary boron deprivation induces hyperinsulinemia in vitamin D-deprived rats, the influence of dietary boron on insulin metabolism as modified by nutritional stressors was examined in two animal models. Male weanling Sprague-Dawley rats were assigned to each of four (Experiment 1) or 8 (Experiment 2) dietary groups for 35 d: the basal diet (< 0.2 mg B; <1.0 mg Mg/kg) was supplemented with boron (as orthoboric acid) to contain <0.2 or 2.0 (a physiologic amount) mg B/kg; with magnesium (as magnesium acetate), at 100 (inadequate) or 360-400 (adequate) mg/kg; and with cholecalciferol [vitamin D-3; 25 microg/kg for study length (Experiment 2), or, depleted for 16-17 d then repleted until end of experiment (Experiments 1 and 2)]. In the rat model, boron reduced plasma insulin (Experiment 1, P < 0.002; Experiment 2, P < 0.03), but did not change glucose concentrations regardless of vitamin D-3 or magnesium status. Cockerels (1 d old) were fed a ground corn, high protein casein and corn oil-based basal diet (low boron; 0.3 mg B/kg) supplemented with boron as orthoboric acid to contain 0.3 or 1.65 mg/kg (a physiologic amount) and vitamin D-3 at 3.13 (inadequate) or 15.60 (adequate) microg/kg. In the chick model, boron decreased (P < 0.045) in situ peak pancreatic insulin release at 26-37 d of age regardless of vitamin D-3 nutriture. These results suggest that physiologic amounts of boron may help reduce the amount of insulin required to maintain plasma glucose.
PMID: 14608076 [PubMed - indexed for MEDLINE]
J Bone Miner Res. 1994 Feb;9(2):171-82.
Dietary boron modifies the effects of vitamin D3 nutrition on indices of energy substrate utilization and mineral metabolism in the chick.
Hunt CD,
Herbel JL,
Idso JP.
United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, North Dakota.
An experiment was designed to test part of the hypothesis that physiologic amounts of dietary boron enhance utilization of or, alternatively, compensate for, inadequate concentrations of active vitamin D metabolites to normalize energy substrate utilization and mineral metabolism. Day-old cockerel chicks were fed a ground corn, high-protein casein, corn oil-based diet (< or = 0.18 mg B/kg) supplemented with physiologic amounts of boron (as orthoboric acid) at 0 (non-PSB) or 1.4 (PSB) mg/kg and vitamin D3 (as vitamin D3 powder in corn endosperm carrier) at 3.13 (inadequate, IVD) or 15.6 (adequate, AVD) micrograms/kg. After 26 days, IVD decreased food consumption and plasma calcium concentrations and increased plasma concentrations of glucose, beta-hydroxybutyrate, triglycerides, triiodothyronine, cholesterol, and alkaline phosphatase activity. In the IVD chicks, PSB returned plasma glucose and triglycerides to concentrations exhibited by the AVD chicks and increased food consumption in both IVD and AVD chicks. Histologic findings suggested that PSB enhanced maturation of the growth plate. A ninefold increase in dietary boron yielded only a two-fold increase in plasma boron concentration and no increase in femur boron concentration, which suggests that boron is under homeostatic control. The findings suggest that boron acts on at least three separate metabolic sites because it compensates for perturbations in energy substrate utilization induced by vitamin D3 deficiency, enhances major mineral content in bone, and, independently of vitamin D3, enhances some indices of growth cartilage maturation.
PMID: 8140930 [PubMed - indexed for MEDLINE]
Environ Health Perspect. 1994 Nov;102 Suppl 7:35-43.
The biochemical effects of physiologic amounts of dietary boron in animal nutrition models.
Hunt CD.
United States Department of Agriculture, Agricultural Research Service, Grand Forks, North Dakota 58202-9034.
This review summarizes evidence that supports working hypotheses for the roles of boron in animal model systems. It is well established that vascular plants, diatoms, and some species of marine algal flagellates have acquired an absolute requirement for boron, although the primary role of boron in plants remains unknown. Recent research findings suggest that physiologic amounts of supplemental
dietary boron (PSB) affect a wide range of metabolic parameters in the chick and rat model systems. Much of the current interest in boron animal nutrition began with the initial finding that PSB stimulates growth in cholecalciferol (vitamin D3)-deficient chicks, but does not markedly affect growth in chicks receiving adequate vitamin D3 nutriture. The finding suggests that boron affects some aspect of vitamin D3 metabolism or is synergistic with vitamin D3 in influencing growth. Vitamin D3 regulates energy substrate utilization, and current research findings indicate that dietary boron modifies that regulatory function. The concentration of circulating glucose, the most thoroughly investigated metabolite to date, responds to PSB, especially during concomitant vitamin D3 deficiency. In chicks, PSB substantially alleviated or corrected vitamin D3 deficiency-induced elevations in plasma glucose concentrations. The influence of vitamin D3 on cartilage and bone mineralization is mediated in part through its role as a regulator of energy substrate utilization; calcification is an energy-intensive process.
There is considerable evidence that dietary boron alleviates perturbations in mineral metabolism that are characteristic of vitamin D3 deficiency. In rachitic chicks, PSB alleviated distortion of the marrow sprouts of the proximal tibial epiphysial plate, a distortion characteristic of vitamin D3 deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 7889878 [PubMed - indexed for MEDLINE]
Biol Trace Elem Res. 2008 Jun;122(3):197-205. Epub 2008 Jan 5.
Comparative effects of boric acid and calcium fructoborate on breast cancer cells.
Scorei R,
Ciubar R,
Ciofrangeanu CM,
Mitran V,
Cimpean A,
Iordachescu D.
Department of Biochemistry, University of Craiova, 13 A.I. Cuza, 200585, Craiova, Romania.
romulus_ion@yahoo.com
Recent studies suggested that boron has a chemo-preventive role in prostate cancer. In the present report, we investigated the effects of calcium fructoborate (CF) and boric acid (BA) on activation of the apoptotic pathway in MDA-MB-231 human breast cancer cells. Exposure to BA and CF inhibited the proliferation of breast cancer cells in a dose-dependent manner. Treatment with CF but not BA resulted in a decrease in p53 and bcl-2 protein levels. Furthermore, after the treatment with CF, augmentation of pro-caspase-3 protein expression, cytosolic cytochrome c level, and caspase-3 activity were observed, indicating apoptotic cell death induction. This was also demonstrated by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end-labeling assay. In conclusion, our data provide arguments to the fact that both BA and CF inhibited the growth of breast cancer cells, while only CF induced apoptosis. Additional studies will be needed to identify the underlying mechanism responsible for the observed cellular responses to these compounds and to determine if BA and CF may be further evaluated as chemotherapeutic agents for human cancer.
PMID: 18176783 [PubMed - indexed for MEDLINE]
Cell Adh Migr. 2008 Jul;2(3):153-60. Epub 2008 Jul 23.
Phenylboronic acid selectively inhibits human prostate and breast cancer cell migration and decreases viability.
Bradke TM,
Hall C,
Carper SW,
Plopper GE.
Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180-3596, USA.
Abstract
We compared the in vitro effect of boric acid (BA) versus phenylboronic acid (PBA) on the migration of prostate and breast cancer cell lines and non-tumorigenic cells from the same tissues.
Treatment at 24 hours with BA (< or =500 microM) did not inhibit chemotaxis on fibronectin in any cell line. However, treatment over the same time course with concentrations of PBA as low as 1 muM significantly inhibited cancer cell migration without effecting non-tumorigenic cell lines. The compounds did not affect cell adhesion or viability at 24 hours but did alter morphology;
both decreased cancer cell viability at eight days. These results suggest that PBA is more potent than BA in targeting the metastatic and proliferative properties of
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