[Frontiers in Bioscience S3, 205-215, January 1, 2011]

Calcium fructoborate: plant-based dietary boron as potential medicine for cancer therapy

Ion Romulus Scorei

University of Craiova, Biochemistry Department, A.I.Cuza, street, no.13, Craiova, Romania, East Europe


1. Abstract
2. Introduction
3. Dietary boron and cancer risks
3.1. Dietary boron and prostate cancer
3.2. Dietary boron and lung cancer
3.3. Dietary boron and cervical cancer
4.Study on the mechanism of action of calcium fructoborate
4.1. Molecular Compositions
4.2. Calcium fructoborate and oxidative stress
4.3. Calcium fructoborate and anti-inflammatory processes
5. Fructoborate as potential anticancer agent
5.1. Breast cancer and calcium fructoborate
5.2. Fructoborate and 10B-Neutron Capture Therapy-a vision for future
6. Summary and perspective
7. Acknowledgements
8. References


It was predicted that more B-containing molecules will be discovered that will prove useful in applications involving cell surface signaling, but insufficient progress was made in this general direction. The main objective of this review is to reveal other promising research directions for B-chemoprevention and chemotherapy using Calcium Fructoborate (CF). Targets include breast cancer, prostate cancer, lung cancer and cervical cancer. CF has been identified as Ca ( (C6H10O6)2B)2o4H2O and is a natural product from plants (can be produced by chemical synthesis as well), and is efficient in the prevention and treatments (as adjuvant) of osteoporosis and osteoarthritis. CF showed inhibitory effects on MDA-MB-231 breast cancer cells as well, and enters the cell (most likely) by a co-transport mechanism via a sugar transporter. Inside cells CF acts as an antioxidant and induces the overexpression of apoptosis-related proteins and eventually apoptosis.


Numerous biological functions of B compounds are known. Boron is present in bacterial antibiotics such as tartrolon, borophycin, boromycin and aplasmomycin (1-3) and in the bacterial quorum sensing molecule auto-inducer AI-2 (4). Plants need B for growth, blooming, seed formation, and extract borate from soil using specialized transporters such as BOR1 (5). In plants the rigidity of the cell wall depends in part on the formation of a rhamnogalacturonan II complex (RG-II), a pectic polysaccharide covalently linked through cis-diol bonds to apiosil residues of borate esters (6, 7). Borate ions activate the mitogen-activated protein kinase pathway and stimulate the growth and proliferation of human embryonic kidney 293 cells (8, 9). The B-transporter NaBC1 controls plasma borate levels in human kidney cells (8). Whether cells can manage B independently of the expression and activity of B transporters remains unclear. The fact that B has such a broad spread of physiological functions is not surprising. The electronic structure of B and its position in the periodic table (adjacent to carbon) make B-containing molecules electrophilic with trigonal planar structures that are neutral yet isoelectronic relative to carbocations. The formation of additional bonds with B creates the formation of anionic tetravalent compounds with tetrahedral structure, which behave as nucleophiles (10). Various types of B-containing molecules exist or are presently investigated as therapeutic agents. They include B-containing analogues of natural biomolecules (11), the antibacterial and antimalarial agent diazaborine (12), antibacterial oxazaborolidines (13, 14), antibacterial diphenyl borinic esters (15), the antifungal agent benzoxaborole AN2690 (16), and a B-N bond containing estrogen receptor modulator (17). Except for the drug Bortezomib, the major current use of B-compounds in the treatment of cancer is in neutron capture therapy (BNCT), (18, 19). It was predicted that more B-containing molecules will be discovered that will prove useful in applications involving cell surface signaling (20, 21), but insufficient progress was made in this general direction. The main objective of this review is to reveal other promising research directions for B-chemoprevention, chemotherapy and 10Boron Neutron Capture Therapy (10BNCT) using CF. Targets include breast cancer, prostate cancer, lung cancer and cervical cancer.


3.1. Dietary boron and prostate cancer

Prostate cancer is the most common cancer in men in USA and it is one of the eight highest causes of mortality in men (22). Dietary B is inversely correlated with prostate cancer (23, 24), though the source of this correlation remains unclear. The risk of prostate cancer was one third smaller in men ingesting >1.8 mg B d-1 through food relative to 0.9 mg B d-1. High B content in food however, did no offer protection against other forms of cancers (24). High correlation (r = 0.63) was found between the concentration of B from subsurface water and the distribution of prostate cancer in Texas (25). Increased uptake of boric acid (BA) decreased the incidence of prostate tumors in mice, and reduced the levels of Immunoglobulin F (IgF) from tissue and prostate specific antigen (PSA) from plasma (26). Broader understanding of the cellular mechanisms involving B was gained form the work of Barranco et al. (27) who showed that BA inhibited the growth of prostate cancer cell through decreased expression of A-E cyclin, though B did not induce cell death. Furthermore, cells treated with BA showed decreased adhesion and migration, indicating lower metastatic potential. It was hypothesized that B produces effects on prostate cancers through its influence on steroid hormones (particularly androgens); androgens are putatively involved in prostate carcinogenesis (28, 29). The fact that high estradiol levels correlate with low prostate cancer risks is also known (28). The supplementation of food with 10 mg of B twice a week had effect on plasma testosterone levels in four weeks, but significant changes (from 52 to 74 pmol l-1) in estradiol levels (28). Increased dietary B in women led to increased levels of estrogen indicating a connection between B and estrogen expression (29, 30). Three research directions can be used to study the relationship between B and prostate cancer risks: regulation of steroid hormones, anticancer metabolites and cell proliferation. Several potential BA binding sites may be involved in prostate cancer. For example Prostate Serum Antigen (PSA), a serine protease, is a potential site for direct boration (31). BA decreased the expression of five major cyclin proteins (A, B1, C, D1 and E), which have significant roles in the cell cycle (32), and inhibited the release of Ca (II) stored by the NAD+ cADPR system, which may explain the effects of B on prostate cancer cells (33). No correlation with prostate cancer frequency was observed when the B consumption was maximum 1.17 mg d-1 (34).

3.2. Dietary boron and lung cancer

Along with many other factors, cigarette smoking is the highest risk factor in lung cancer. Higher lung cancer-related mortality was seen in man than women (35). Negative correlation was also found between the amount of B intake and the incidence of lung cancer, though the underlying mechanism remains unclear (36). Experimental evidence showed that nutrition with some B-compounds (such as BA, borax, and CF) had antioxidant or anti-inflammatory consequences (37-42). Correlation exists between some lung cancers and 17-beta -estradiol and treatments includes 17-beta-estradiol-based hormone replacement therapy (HRT) (43). It was shown that dietary supplementation with B increases the concentration of 17-beta-estradiol (44), mimics the effect of HRT and, in postmenopausal women may be used to decrease cancer risks associated with low estrogen levels. Low dietary B (alone or jointly with HRT) was correlated with increased lung cancer risks in women (43). It was proposed that reduction in lung cancer risks may be due to estrogen receptors binding substrates other than estrogen, including carcinogenic polycyclic aromatic hydrocarbons (PAHs) from the cigarette smoke condensate (44). Women with high dietary B intakes, as well as HRT users, may show higher hormone levels competing with cigarette smoke carcinogens for estrogen receptors (45). If this model is correct, then increasing the B intake during HRT will also limit the carcinogenic potential of PAHs from cigarette smoke. It was recently confirmed that the highest quartile of B intake was associated with the lowest lung cancer risks in smokers, while the highest risk existed in smokers with low dietary B and no HRT (45).

3.3. Dietary boron and cervical cancer

Cervical cancer is the second most frequent cancer in women worldwide, yet in countries such as Turkey it only ranks the 7th (46). The cause of this discrepancy is unclear and may involve a combination of environmental, genetic, social and infectious factors. For example, Human papillomaviruses (HPV) are the main cause of cervical cancer; HPV 16 and HPV 18 cause ~95% of all cervical cancers. Many other factors are also correlated with the incidence of cervical cancer (47-49). According to one hypothesis the low incidence of cervical cancer in Turkey is correlated with its B-enriched soil (50, 51). Indeed, the ingestion of B via drinking water is negatively correlated with risks of cervical cancer (52). It was suggested that this effect may be due to the interference of B chemistry in the life cycle of HPVs, but no such correlation was found with the incidence of oral cancers also induced by HPVs (52). It was found that serine protease inhibitors reduce the immortalizing and transforming capacity of the HPV E7 oncogene (53), and that the plasminogen activator inhibitor-1 (also a serine protease inhibitor) reduces the invasive capacity of cancer cells (54). Because B exists in the human body mostly in the form of BA, (which is an inhibitor of serine proteases), it was hypothesized that ingestion of higher amounts of B through drinking water will inhibit HPV transformation, thus reducing the incidence of cervical cancer (52).


4.1. Molecular compositions

CF, dietary supplement produced by the FutureCeuticals Company (proprietary name, FruiteX-B®), with potential use in chemotherapy of diseases, was investigated by thermal analysis and by X-ray diffraction (55, 56). Results of measurements performed in air show that FruiteX-B® is identical with the natural CF. FruitexB loses water of crystallization up to 150oC and then degrades in six stages, more exactly one endothermic and five exothermic. By thermal analysis (TA), the molecular formula Ca ( (C6H10O6)2B)2.4H2O has been established (56). X-rays diffraction (XRD) indicates a weak crystallinity of CF. Thermal analysis of FruitexB and of BA and calcium carbonate showed that there are no similarities between their thermo analytical curves. Only with fructose, similarities appear, but shifted to higher temperatures as a result of the bonding influences in the calcium fructoborate complex. Mass loss is of 8.5 % up to 152oC, when the experiment is performed in air. This loss is due to the crystallization water of the compound. By correlation of the results of thermo gravimetric analysis with the elemental analysis, no precursors traces were found and the molecular formula of FruitexB has been identified as Ca ( (C6H10O6)2B)2o4H2O. Above 152 oC, the decomposition in air occurs in six stages: first stage is weakly endothermic, the second is weakly exothermic, and the following four are exothermic. For the last 4 stages, the exchanged heat was determined as well. Gravimetric effects of the last six stages are due to decomposition of fructose from the complex with a mass loss of 77.8 �1 %, compared to the 76.6 % (calculated on the basis of the proposed formula). Residue of 13.7�1 % is calcium borate (theoretical 14.8 %). XRD results show a weak crystallinity of calcium fructoborate and confirmed the thermal analysis results when no evidence of fructose, boric acid and calcium carbonate were found (56). FruitexB comes therefore as the calcium fructoborate found in natural products.

4.2. Calcium Fructoborate and Oxidativ stress

Despite the fact that there has been remarkable progress regarding the beneficial effects of supplementing human and animal diet with B compounds, especially in their natural forms, their mechanisms of action have not been elucidated yet. Our studies were inspired by research that showed that borate protects the skin and facilitates the healing of profound wounds through its action on some compounds of the extracellular matrix of the conjunctive tissue (57). Keratinocyte cultures have been chosen as the study model because these cells are the major constituents of the epidermis, actively involved in skin wound healing by their capacity to proliferate and differentiate into cells forming the skin barrier. The response of keratinocytes to different agents is of particular interest because these cells take part in cutaneous immunological reactions that involve the release of pro-inflammatory cytokines (58). There is evidence to support the hypothesis that dietary B helps control the normal inflammatory process by serving as a suppressive signal that down regulates specific enzymatic activities at the inflammation site that are typically elevated during inflammation (59,60). Our studies demonstrated that the incubation of keratinocytes with CF did not generate an oxidative stress and its antioxidant effect after the exogenous exposure of the cells to H2O2. The inhibiting effect of the CF on pyrogallol auto-oxidation suggests its possible role as a scavenger for superoxide radicals. The antioxidant effect of a soluble carbohydrate compound of B (CF), represents a new challenge for the natural antioxidant world and shows a very important physiological role of B in life processes. Based on our results, we support the hypothesis that the soluble carbohydrate compounds of B, formed by the complexation of boric acid with free sugars , glycolipids, and glycoproteins, buffer the reactive species of oxygen by developing organic peroxyborates. Our results suggest a hypothetical mechanism of influence of the CF as scavenger for the reactive species of oxygen. In this paper (40) we have taken into account the balance between the actively metabolic mono-dentate carbohydrate complex and the bi-dentate carbohydrate complex of CF. We suppose that the mono-dentate complex is capable of react with the superoxide radical , generating a organic peroxyborate radical , accompanied by the release of hydrogen peroxide. The peroxyborate radical might have a longer lifetime than the common oxygen reactive species, being able to react with a hydrogen donor (DH2) which it oxidized with the reconstruction of the mnon-dentate complex. This path can be catalyzed by an enzyme with peroxidase capacity. The fact that CF in high concentrations increases the intracellular oxidant power of the keratinocites might suggest that at higher organic peroxyborate radical concentration, the capacity of the cellular peroxidase activity is exceeded. The validity of this mechanism might explain several effects of B and its derivates, (e.g., CF) as well as the implication of these compounds in the cellular signalization mechanisms, supplementing the types of reactive species with derivates of B (40).

4.3. Calcium fructoborate and anti-inflammatory processes

Our in vitro studies show that CF has profound effects on human PMN cells related to its concentration (41). Thus, the treatment with CF of fMLP-stimulated PMN, for 24 h, resulted in a decrease of respiratory burst, in a dose-dependent manner. The decrease of ROS level was evident even when non-cytotoxic doses were used (for example, by 50% at 450 μM CF), which underlies the fact that CF is a superoxide anion scavenger and may have anti-inflammatory effects. These data must be interpreted considering the previous observations that neutrophils stimulation with fMLP results in an increase of superoxide anion generation and apoptosis level (61). It is possible that CF inhibits activation of the enzymatic complex NADPH-oxidase that directly reduces molecular oxygen to generate superoxide anion, which is later converted into other reactive intermediates. It is worth mentioning that this action is due to CF and not to calcium ions or borate residue from its composition). Actually, Granfeldt et al. (62) showed that an increase in (Ca2+) mediated through binding of fMLF to its receptor is part of a signaling cascade that activates the plasma membrane-localized oxidase. At this moment, it is difficult to propose a mechanism by which CF inhibits NADPH-oxidase function because this membrane-bound enzyme complex is comprised of both integral membrane and cytosolic proteins, and it is subjected to a complex control. A better understanding of the mechanisms used by the CF to inhibit the NADPH-oxydase will allow developing a new therapeutic approach to deal with the phenomenon. Hunt (63) proposed an essential role of boron as a regulator of respiratory burst by suppression of serine proteases released by inflammation-activated white blood cells, inhibition of leukotriene synthesis, reduction of reactive oxygen species generated during the neutrophil's respiratory burst, and suppression of T-cell activity and antibody concentrations. Investigation of CF effects on the intracellular level of superoxide anions in unstimulated PMN cells strengthens the idea of the antioxidant activity exerted by CF, previously proposed by us (40), according to which CF is a scavenger for superoxide anions. The superoxide dismutase (SOD) protects the PMN contents against oxidizing activity by destroying superoxide anions (O-2); SOD reduces both the oxidative stress and the activation of mediators of inflammatory response (64). In our study, we pointed out a low level of superoxide anions at the cytotoxic dose of CF as a result of an increase in SOD activity. Low superoxide dismutase activity in PMN cells may explain the small discrepancies between the data regarding the superoxide anions and SOD activity. These data suggest that PMN cells apoptosis and CF-induced cytotoxicity is not mediated by the superoxide release.

In a recent study (65), we showed that treatment of LPS-stimulated RAW264.7macrophage cells with CF induced an inhibition of the IL-1β, IL-6 and NO release in the culture media, an increase of TNF-α production, and had no effects on LPS-induced COX-2 protein expression. The pro-inflammatory cytokine IL-1β is synthesized by activated monocytes and macrophages as a 31-kDa, biologically inactive precursor that is proteolytically processed to the biologically active 17-kDa mature molecule by the IL-1β converting enzyme. Studies on LPS-stimulated cultured macrophages, showed that induction of apoptosis but not necrosis effectively induced conversion of the IL-1β precursor to its mature form and resulted in the concomitant release of the mature cytokine from the cell (66). Our data suggest that CF affects the post-translational activation of biologically inactive IL-1β precursor. Considering the absence of pro-apoptotic effects of CF treatment (data not shown) we came to the conclusion that this compound could uncouple IL-1 β processing and apoptosis. The effects of CF treatment on IL-6 synthesis by RAW 264.7 macrophages might be explained by the fact that IL-6 is a secondary cytokine whose expression can be stimulated by primary cytokines like IL-1, whose post-translational activation seems to be inhibited by this borate derivative. These studies provide evidence to support the view that CF can be an effective, safe anti-inflammatory agent. Our results regarding CF effects on LPS-stimulated macrophage TNF-α production are contradictory because TNF-α plays a major role in regulating inflammation, mostly through the induction of inflammatory cytokines, including IL-1β and IL-6. Cao et al. (67) studied LPS-induced TNF-α formation in THP-1 cells and noticed the inhibitory effect exhibited by boric acid. Interestingly, when Armstrong and Spears (68) examined the effect of boron supplementation of pig diets they found a decreased inflammatory response following a phytohemmaglutinin intradermal injection. They also noticed an increased level of TNF-α in serum as well as in peripheral blood monocytes isolated from pigs that received the B-supplemented diet and cultured in the presence of LPS. These data could not explain the reduction in localized inflammation following an antigen challenge in pigs. Other studies showed that boron increased TNF-α release by cultured human fibroblasts and chick embryo cartilage (69,70). The complex regulation of TNF-α synthesis, at the level of transcription, translation, and secretion, makes difficult to explain the high levels of this cytokine at the same time with the decrease in other inflammatory mediators (71-73) In addition, the signaling pathways involved in cytokine release from RAW 264.7 macrophages are now under investigation (74). Moreover, the involvement of different pro- and anti-inflammatory mediators in a sequential and concerted manner and regulation of cytokine induction can occur after a variable pattern in different cell types and depends on the nature of the stimulatory ligand. These mediators can act at the level of cell surface, cell membrane, cytosol, or nucleus. There is continuing interest in the effects of long-chain n-3 polyunsaturated fatty acids (PUFAs) on human immune function and inflammatory processes (75, 76). In previous studies (77, 78) it was shown that increasing dietary (n-3) to (n-6) fatty acid ratio from 0 to 1 resulted in a dose-response increase in TNF production by LPS-stimulated resident peritoneal macrophages. On the other hand, some experimental data suggested that boron had essential function similar to (n-3) fatty acids (79). Consequently, macrophage CF treatment might induce a replacement of n-6 PUFA with n-3 PUFA in cell membranes generating a decreased cellular response to inflammatory stimuli.

Nitric oxide is synthesized from L-arginine by L-arginine NO pathway and is converted to nitrite and nitrate in oxygenated solutions. A family of enzymes, termed the NO synthases (NOS), catalyze the formation of NO and citrulline from L-arginine, O2, and NADPH. The constitutive NOS isoforms (NOS-1 and NOS-3) produce low levels of NO as a consequence of increased intracellular Ca2+. By contrast, the inducible isoform of NOS (NOS-2 or iNOS) generates large amounts of NO through a Ca2+-independent pathway (80). Some pro-inflammatory agents, such as endotoxin, TNF-α and IL-1 induce NOS-2 activity. High levels of NO induce changes suggestive of apoptosis in RAW 264.7 mouse macrophage cell line (81). It is possible for CF to inhibit NO production by blocking iNOS expression in RAW 264.7 macrophages. Due to the critical role that NO release plays in mediating inflammatory responses, our data suggest that CF could represent a useful anti-inflammatory agent. Jeon et al. (82) showed that the p38 MAPK pathway is specifically involved in LPS-induced iNOS expression in LPS-stimulated RAW 264.7 cells. The p38 MAPK also regulates LPS-induced TNF-α and IL-1 production by monocytes (83, 84). In a study focused on the effects of NO on TNF synthesis in the RAW 264.7 cell line (85) a suppression of LPS-induced TNF synthesis by exogenous addition of NO-releasing agents was found. The finding of an increased TNF production in the presence of two NO synthase inhibitors, indicated a negative feedback by endogenous NO on TNF synthesis in vitro. Cyclooxygenase-2, the enzyme primarily responsible for induced prostaglandin synthesis, represents the product of an immediate early gene induced by endotoxin in macrophages. Secreted prostaglandins promote inflammation by increasing vascular permeability and vasodilatation and by directing cellular migration into the site of inflammation through the production and release of pro-inflammatory cytokines such as interleukin-6 (86). Our data suggest that CF does not affect COX-2 protein expression level in LPS-stimulated macrophages and, consequently, neither the prostaglandin synthesis, which might sustain the anti-inflammatory properties of this boron derivative. Since CF complex is characterized by a high boron-fructose association constant (about 6,000) (87) we consider that in vitro response of LPS-stimulated macrophages is due to the entire molecule. There are studies demonstrating that various boron-containing compounds displayed anti-inflammatory properties (88, 89). In a comparative study concerning the effects of CF and sodium borate on fMLP-stimulated PMN we found that CF exhibited superior anti-inflammatory and antioxidant properties (40). Moreover, we demonstrated that while both boric acid and CF inhibited the growth of MDA-MB-231 breast tumor cells, only CF induced the apoptosis (90). This study demonstrated that CF treatment of LPS-stimulated RAW 264.7 macrophages induced an up-regulation of TNF-α protein level in culture medium, no significant changes in the level of LPS-induced COX-2 protein expression and a decrease in NO production as well as in IL-1β and IL-6 release. Although we can conclude that CF might affect macrophage production of inflammatory mediators, these studies have to be completed with further research aiming to establish whether CF treatment can be beneficial for suppression of pro-inflammatory cytokine production and against progression of endotoxin-associated diseases. We also intend to elucidate the mechanism of CF effects and its efficacy as an anti-inflammatory agent comparing to drugs with well established anti-inflammatory action.


5.1. Breast cancer and calcium fructoborate

CF is a natural product from plants (can be produced by chemical synthesis as well), and is efficient in the prevention and treatments (as adjuvant) of osteoporosis and osteoarthritis (40, 41, 42). CF showed inhibitory effects on MDA-MB-231 breast cancer cells as well (90, 91), and enters the cell (most likely) by a co-transport mechanism via a sugar transporter (42). Inside cells CF acts as an antioxidant and induces the overexpression of apoptosis-related proteins and eventually apoptosis (40, 90). In the recent study, we demonstrated that CF and BA inhibited the proliferation of breast cancer cells MDA-MB-231 in a dose-dependent manner (90). As revealed by different experiments (TUNEL, Bcl-2 and pro-caspase-3 protein expression, and cytochrome c caspase-3 activities), it appeared that the anti-proliferative effect of CF in breast cancer cells MDA-MB-231 is mediated by induction of apoptosis. On the other hand, BA induced a cell death-independent proliferative inhibition of breast cancer cells. In a previous study, Barranco and Eckhert (92), using DU-145 prostate cancer cells, showed that BA inhibited cell proliferation without inducing apoptosis. They demonstrated that BA induces conversion to a senescent-like cellular phenotype and also causes a dose-dependent reduction in cyclins A-E, as well as mitogen-activated protein kinase proteins, suggesting their contribution to proliferative inhibition (93). Unlike BA, the mechanism underlying the antiproliferative activity of CF has not been elucidated. When MDA-MB-231 cells were treated with 0.45 mM CF, for 24 h, no effects on cell viability, Bcl-2, caspase-3, and p53 protein expression were observed. Cytotoxic effects and an increase in caspase-3 activity were seen in MDA-MB-231 cells treated with CF doses higher than 2.25 mM. Therefore, the treatment of tumor cells with CF resulted in a rapid release of cytochrome c from the mitochondria, which preceded caspase 3 activation. At CF concentrations greater than or equal to 5 mM CF, the cytotoxic effects became stronger, and repression of Bcl-2 protein expression was seen. The mechanism of the noticed downregulation of Bcl-2 by CF remains to be delineated. This may occur at the transcription level and/or post-transcription level and may also involve reduced Bcl-2 messenger ribonucleic acid stability, leading to a decrease in Bcl-2 expression. Taking into account the central role of p53 in the regulation of apoptosis, it is of great interest to study p53 involvement in the apoptosis induction by different potential chemotherapeutic agents. In this context, we investigated the relationship between p53 tumor suppressor protein immunoreactivity and CF action upon MDA-MB-231 cells and found out a down regulation of p53 protein expression at doses greater than or equal to 5 mM. An explanation of this finding might be that higher doses of CF stimulated degradation of p53 mediated by cytoplasmic 26S proteasomes (94, 95) and that in MDA-MB-231 cells the apoptotic process is p53 independent. Based on these results, we conclude that while both BA and CF inhibit the growth of breast cancer cells, only CF induces apoptosis. Further studies will be needed to determine if BA and CF will be suitable for clinical application in breast cancer patients.

5.2. Fructoborate and 10B-Neutron Capture Therapy-a vision for future

10BNCT was initially proposed as a means to selectively kill cancer cells without affecting normal cells (96). The present days BNCT uses a number of 10B-containing compounds that preferentially concentrate in tumor cells. The tumor area is then irradiated by a neutron beam; neutrons interact with 10B and yield highly energetic 2He4 and recoiling 3Li7 nuclei along with kinetic energy and γ-radiation (97).

This allows delivering high radiation dosage to the cancer cells with limited effects on normal cells. Modern BNCT is actually a combination of chemo- and radiotherapy and is used in the treatment of high grade glioma. In order for BNCT to be therapeutically useful 10B-chemicals have to show some specific properties: i) Good water solubility so they can be administered intravenously; ii) Low toxicity; iii) High selectivity by tumor cells; and iv) Accumulation in large concentrations in cancer cells. The larger challenge of BNCT was and remains biasing the retention of B toward cancer cells.

The small intestine regulates fructose absorption from dietary sources and, therefore, the availability of fructose to other tissues. It is also the organ system expressing the greatest amount of GLUT5 in human (98). After apical transport mediated by GLUT5, fructose is transported across the basolateral membrane by GLUT2. Recent work proposes that GLUT2 is also involved in the apical transport of fructose (99). After the small intestine, the kidney skeletal muscle and adipocytes expresses the most GLUT5 in human (100). In brain, GLUT5 has been identified in different cell types such as human microglia (101), cerebellar Purkinje cells in human fetus (102), mouse cerebellum (103), human blood-brain barrier (104), and rat hippocampus (105). Because the GLUT5 transporter is commonly found in tissues that metabolize fructose (106), these brain cells may be capable of utilizing fructose. GLUT5 mRNA and protein expression are affected by the development of tumors in certain organ systems. In general, oncogene-transformed cells that portray cancerous characteristics will also exhibit an increase in glucose transport by over expressing specifically sugar transporters like GLUT1 in breast, colorectal, lung, and ovarian carcinoma GLUT12 in breast cancer, or GLUT3 in lung, ovarian, and gastric cancers (100). This increase in glucose transport and metabolism may reflect a requirement by these rapidly growing cells for more sources of energy (107). Although GLUT5 is poorly expressed in normal mammary epithelial cells, the breast carcinoma cell lines MCF-7 and MDA-MB- 231 possess high amounts of GLUT5 mRNA and protein and exhibit high rates of fructose transport (108). In fact, GLUT5 knockdown by antisense oligonucleotide decreases rates of fructose uptake, thereby inhibiting the proliferation and the growth of MCF-7 and MDA-MB-231 cells, which are, respectively, models of early and late-stage breast cancer (109). A large-scale screening of the GLUT family of transporters in malignant vs. normal human tissues and cells showed that GLUT5 was highly over expressed in 27% of cancerous tissues tested, including tumors in brain, breast, colon, liver, lung, testis, and uterus (110). In situ RT-PCR and ultra structural immunohistochemistry confirmed GLUT5 expression in breast cancer. The extensive expression of the glucose/fructose transporter GLUT2, and the fact that in most of the tumor cells over expressing GLUT5 the rate of fructose uptake is exacerbated, indicate that fructose may be a preferred substrate providing energy required for the growth and proliferation of tumor cells. This increase of GLUT5 could indicate preferential utilization of fructose by cancer cells (100). In Caco2 cells and in highly proliferative cancer cells, GLUT5 expression is significant enough that it appears to be a good marker of malignancy or high proliferation rate. This suggests that cancerous cells lose the inhibitory factor (s) that blocks intensive GLUT5 expression in normal cells (100) and enriched 10-Boron-Fructoborate (EBF) may become an important chemical challenger in the fight against some cancers. EBF transport inside cancerous cells induces a pro-apoptosis effect, as shown in our research (90), enhancing the BNCT effect.


Three avenues with specific methodology exist when using B chemistry against cancer cells: diet-based chemoprevention, chemotherapy and 10B-BNTC. Negative correlation was found to exist between B-supplemented nutrition and the incidence of some forms of cancer. Potential mechanisms regarding the activity of B-containing chemicals against cancer cells include the inhibition of numerous enzymatic processes, such as serine proteases, NAD-dehydrogenases, mRNA splicing, DNA polymerization, thymidilate synthesis, S-adenosylmethyltransferase, non-histone chromatin methylation, DNAse, RNAse, catepsin and others. Boron-containing chemicals also act by influencing Ca2+ receptors, by inhibiting cell division, nuclear receptor binding mimicry, and the induction of apoptosis. Because B has a small atomic mass and its chemistry includes neutrophilic and electrophilic reactivity, a wide array of B-based chemicals can be created and tested for chemoprevention and chemotherapy.

CF is a natural product that can be very efficiently used as a boron food supplement in prevention and adjuvant treatment of osteoporosis and osteoarthritis. Our opinion is that more boron should be added to multivitamins especially in the organic form of these (CF). The CF form of boron is being found in some vegetables like celery and broccoli and fruits like grapes and plumes. At the same time, CF may also become a pharmaceutical ingredient with effects in oxidative metabolism and cell apoptosis. CF enters the cell by a "masked" transport and for cells with great affinity for sugars in physiological pathogenic states, CF could induce cell apoptosis. The prooxidant and antioxidant mechanisms are directly correlated to the molecular structure of CF. Compared to CF, the boric acid is transported into the cells using boron-specific transporter, NaBC1, while CF is transported using probably a sugar transporter. We believe that CF is highly reactive only toward the cells with over expressed sugar transporters, such as intestinal cells, adipose cells, muscle cells, and some cancerous cells.


This work was supported by the University of Craiova, Faculty of Horticulture, Romania and FutureCeuticals, USA.


1. B Austin: Novel pharmaceutical compounds from marine bacteria. J Appl Bacteriol 67, 461-470 (1989)

2. H Irschik, D Schummer, K Gerth, G Hofle and H Reichenbach: The tartrolons, new boron-containing antibiotics from a myxobacterium, Sorangium cellulosum. J Antibiot 48, 26-30 (1995)

3. K Gademann and C Portmann: Secondary metabolites from Cyanobacteria: Complex structures and powerful bioactivities. Curr Org Chem 12, 326-341 (2008)

4. X Chen, S Schauder, N Potier, A van Dorsselaer, I Pelczer, BL Bassler and FM Hughson: Structural identification of a bacterial quorum-sensing signal containing boron. Nature 415, 545-549 (2002)

5. J Takano, KL Miwa, N Yua, T von Wire'n, and T Fujiwara: Endocytosis and degradation of BOR1, a boron transporter of Arabidopsis thaliana, regulated by boron availability. Proc Natl Acad Sci USA 102, 12276-12281 (2005)
PMid:16103374    PMCid:1189310

6. T Ishii and T Matsunaga: Isolation and characterization of a boronrhamnogalacturonan II complex from cell walls of sugar beet pulp. Carbohydr Res 284, 1-9 (1996)

7. M Kobayashi, T Matoh and J Azuma: Two chains of rhamnogalacturonan II are cross-linked by borate-diol ester bonds in higher plant cell walls. Plant Phys 110, 1017-1020 (1996)
PMid:12226238    PMCid:157802

8. M Park, Q Li, N Shcheynikov, W Zeng and S Muallem: NaBC1 is a ubiquitous electrogenic Na+-coupled borate transporter essential for cellular boron homeostasis and cell growth and proliferation. Mol Cell 16, 331-341 (2004)

9. M Tanaka and T Fujiwara: Physiological roles and transport mechanisms of boron: perspectives from plants. Pflug Archiv-Eur J Phys 456, 671-677 (2008)

10. NA Petasis: Expanding roles for organoboron compounds versatile and valuable molecules for synthetic, biological and medicinal chemistry. Aust J Chem 60, 795-798 (2007)

11. C Morin: The chemistry of boron analogues of biomolecules. Tetrahedron 50, 12521-12569 (1994)

12. C Baldock, GJD Boer, JB. Rafferty, AR Stuitje and DV Rice: Mechanism of action of diazaborines. Biochem Pharm 55, 1541-1549 (1998)

13. A Jabbour, D Steinberg, VM Dembitsky, A Moussaieff, B Zaks and M Srebnik: Synthesis and evaluation of oxazaborolidines for antibacterial activity against Streptococcus mutans. J Med Chem 47, 2409-2410 (2004)

14. A Jabbour, R Smoum, K Takrouri, E Shalom, B Zaks, D Steinberg, A Rubinstein, I Goldberg, J Katzhendler and M Srebnik: Pharmacologically active boranes. Pure Appl Chem 78, 1425-1453 (2006)

15. SJ Benkovic, SJ Baker, MRK Alley, YH Woo, YK Zhang, T Akama, W Mao, J Baboval, PT Ravi-Rajagopalan, M Wall, LS Kahng, A Tavassoli and L Shapiro: Identification of boronic esters as inhibitors of bacterial cell growth and bacterial methyltransferases, CcrM and MenH. J Med Chem 48, 7468-7476 (2005)

16. SJ Baker, YK Zhang, T Akama, A Lau, H Zhou, V Hernandez, W Mao, MRK Alley, V Sanders and JJ Plattner: Discovery of a new boron - containing antifungal agent, 5-fluoro-1,3- dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the potential treatment of onychomycosis. J Med Chem 49, 4447-4450 (2006)

17. HB Zhou, KW Nettles, JB Bruning, Y Kim, A Joachimiak, S Sharma, KE Carlson, F Stossi, JA Katzenellenbogen, GL Greene and JA Katzenellenbogen: Elemental isomerism: a boron- nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands. Chem Biol 14, 659-669 (2007)

18. AH Beddoe: Boron neutron capture therapy. Br J Radiol 70, 665-667 (1997)

19. Y Endo, T Yoshimi and C Miyaura: Boron clusters for medicinal drug design: Selective estrogen receptor modulators bearing carborane. Pure Appl Chem 75, 1197-1205 (2003)

20. L Bolanos, K Lukaszewski, I Bonilla and D Blevins: Why boron? Plant Phys Biochem 42, 907-912 (2004)

21. M Redondo-Nieto, M Reguera, I Bonilla and L Bola: Boron dependent membrane glycoproteins in symbiosome development and nodule organogenesis. A model for a common role of boron in organogenesis. Plant Signal Behav 3, 298-300 (2008)
PMid:19841651    PMCid:2634263

22. S Collin, R Martin, C Metcalfe, D Gunnell, P Albertsen, D Neal, F Hamdy, P Stephens, J Lane and R Moore: Prostate cancer mortality in the USA and UK in 1975-2004: an ecological study. Lancet Oncol 9, 445-452 (2008)

23. Y Cui, MI Winton, ZF Zhang, C Rainey, J Marshall, JB De Kernion and CD Eckhert: Dietary boron intake and prostate cancer risk. Oncol Rep 11, 887-892 (2004)

24. H Adlercreutz: Phytoestrogens: Epidemiology and a possible role in cancer protection. Environ Health Perspect 103(7), 103-112 (1995)
PMid:8593855    PMCid:1518863

25. WT Barranco, P Hudak and CD Eckhert: Evaluation of ecological and in vitro effects of boron on prostate cancer risk (United States) Cancer Cause Control 18, 71-77 (2007)

26. MT Gallardo-Williams, RE Chapin, PE King, GJ Moser, TL Goldworthy, JP Morrison and RR Maronpot: Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice. Toxic Pathol 32, 73-78 (2004)

27. WT Barranco, HT Kim, SL Stella Jr., C.D. Eckhert: Boric acid inhibits stored Ca2+ release in DU-145 prostate cancer cells. Cell Biol Toxicol 25, 309-320 (2009)

28. PH Gann, CH Hennekens, J Ma, C Longcope and MJ Stampfer: Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst 88, 1116-1126 (1996)

29. MR Naghi and S Samman: The effect of boron supplementation on its urinary excretion and selected cardiovascular risk factors in healthy male subjects. Biol Trace Elem Res 56, 273-286 (1997)

30. FH Nielsen, CD Hunt, LM Mullen and JR Hunt: Effect of dietary boron on mineral, estrogen, and testosterone metabolism in postmenopausal women. FASEB J 1, 394-397 (1987)

31. MT Gallardo-Williams, RR Maronpot, RN Wine, SH Brunssen and RE Chapin: Inhibition of the enzymatic activity of prostate specific antigen by boric acid and 3-nitrophenyl boronic acid. The Prostate 54, 44-49 (2003)

32. WT Barranco and CD Eckhert: Cellular changes in boric acidtreated DU-145 prostate cancer cells. Br J Cancer 94, 884-890 (2006)

33. C Eckert, W Barranco and D Kim: Boron and prostate cancer a model for understanding boron biology. In Advances in Plant and Animal Boron Nutrition Proceedings of the 3rd International Symposium on all Aspects of Plant and Animal Boron Nutrition Eds: F Xu, HE Goldbach, PH Brown, RW Bell, T Fujiwara, CD Hunt, S Goldberg, L Shi, Springer: New York, 291-297 (2007)

34. A Gonzalez, U Peters, JW Lampe and E White: Boron intake and prostate cancer risk. Cancer Cause Control 18, 1131-1140 (2007)

35. DK Espey, XC Wu, J Swan, C Wiggins, AM Jim, E Ward, PA Wingo, HL Howe, LAG Ries, BA Miller, A Jemal, F Ahmed, N Cobb, JS Kaur and BK Edwards: Annual report to the nation on the status of cancer, 1975-2004, featuring cancer inAmerican indians and Alaska natives. Cancer 110, 2119- 2152 (2007)

36. SL Meacham, KE Elwell, S Ziegler and SW Carper: Boric acid inhibits cell growth in breast and prostate cancer cell lines.In: Advances in Plant and Animal Boron Nutrition Proceedings of the 3rd International Symposium on all Aspects of Plant and Animal Boron Nutrition Eds: F Xu, HE Goldbach, PH Brown, RW Bell, T Fujiwara, CD Hunt, S Goldberg, L Shi, Springer: New York, 299-306 (2007)

37. FH Nielsen: Biochemical and physiologic consequences of boron deprivation in humans. Environ Health Perspect 102, 7-59 (1994)
PMid:7889883    PMCid:1566640

38. FH Nielsen: The emergence of boron as nutritionally important throughout the life cycle. Nutrition 16, 512-514 (2000)

39. CD Hunt: Regulation of enzymatic activity: one possible role of dietary boron in higher animals and humans. Biol Trace Elem Res 66, 205-225 (1998)

40. R Scorei, VM Cimpoiasu and D Iordachescu: In vitro evaluation of the antioxidant activity of calcium fructoborate. Biol Trace Elem Res 107, 127-134 (2005)

41. R Scorei, R Ciubar, C Iancu, V Mitran, A Cimpean and D Iordachescu: In vitro effects of calcium fructoborate on fMLPstimulated human neutrophil granulocytes. Biol Trace Elem Res 118, 27-37 (2007)

42. D Miljkovic, IR Scorei, VM Cimpoiasu and ID Scorei: Calcium fructoborate: plant-based dietary boron for human nutrition. J Diet Suppl 6, 211-226 (2009)

43. MB Schabath, X Wu, R Vassilopoulou-Sellin, AA Vaporciyan and M R Spitz: Hormone replacement therapy and lung cancer risk. A case-control analysis clinical. Cancer Res 10, 113- 123 (2004)

44. Y Wang, Y Zhao and X Chen: Experimental study on the estrogen like effect of boric acid. Biol Trace Elem Res 121, 160- 170 (2008)

45. S Mahabir, MR Spitz, SL Barrera, YQ Dong, C Eastham and MR Forman: Dietary boron and hormone replacement therapy as risk factors for lung cancer in American women. J Epidemol 167, 1070-1080 (2008)

46. DG Hoel, DL Davis, AB Miller, EJ Sondik, AJ Swerdlow: Trends in cancer mortality in 15 industrialized countries, 1969-1986. J Natl Cancer Inst 84(5), 313-320 (1992)

47. G Ursin, MC Pike, S Preston-Martin, G d'Ablaing and RK Peters: Sexual, reproductive and other risk factors for adenocarcinoma of the cervix: results from a population-based case control study (California, United States) Cancer Cause. Control 7, 391-401 (1996)

48. N Ylitalo, P Sorensen, A Josefsson, M Frisch, P Sparen, J Ponten, U Gyllensten, M Melbye and HO. Adami: Smoking and oral contraceptives as risk factors for cervical carcinoma in situ. Int J Cancer 81, 357-365 (1999)


49. X Castellsague, XF Bosch and N Munoz: Environmental cofactors in HPV carcinogenesis. Virus Res 89, 191-199 (2002)

50. BS Sayli, E Tuccar and AH Ellan: An assessment of fertility and infertility in boron-exposed Turkish subpopulations, Part 3: Evaluation of fertility among sibs and in borate families. Biol Trace Elem Res 81, 255-267 (2001)

51. A Simsek, SY Velioglu, LA Coskun and BS Sayl: Boron concentrations in selected foods from borate-producing regions in Turkey. J Sci Food Agric 83, 586-592 (2003)

52. M Korkmaz, E Uzgo, S Bakırdere, F Aydın and Y Ataman: Effects of dietary boron on cervical cytopathology and on micronucleus frequency in exfoliated buccal cells. Environ Toxicol 22, 17-25 (2007)

53. H Stoppler, D Koval and R Schlegel: The serine protease inhibitors TLCK and TPCK inhibit the in vitro immortalization of primary human keratinocytes by HPV-18 DNA. Oncogene 13, 1545- 1548 (1996)

54. BR Whitley, D Palmieri, CD Twerdi and FC Church: Expression of active plasminogen activator inhibitor-1 reduces cell migration and invasion in breast and gynecological cancer cells. Exp Cell Res 296, 151-162 (2004)

55. C Wagner, CF Curotto, RP Diez and EJ Bara: Experimental and theoretical studies of calcium fructoborate. Biol Trace Elem Res 122, 64-72 (2008)

56. P Rotaru, R Scorei, A Harabor and MD Dumitru: Thermal analysis of a calcium fructoborate sample. Thermochimica Acta 506, 8-13 (2010)

57. M Benderdour, T Van Bui, K Hess, A Dicko, F Belleville, and B Dousset: Effects of boron derivatives on extracellular matrix formation. J Trace Element Med Biol 14, 168-173 (2000)

58. CP Turner, A M Toye, and OTG Jones: Keratinocyte superoxide generation. Free Radical Biol Med 24, 401-407 (1998)

59. DC Hunt and PJ Idso: Dietary boron as a physiological regulator of the normal inflammatory response: a review and current research progress. J Trace Elements Exp Med 12, 221-233 (1999)

60. DC Hunt: Dietary boron: an overview of the evidence for its role in immune function. J Trace Elements Exp Med 16, 291-306 (2003)

61. R Kettritz, RJ Falk, JC Jennette and ML Gaido: Neutrophil superoxide release is required for spontaneous and FMLP- mediated but not for TNF alpha-mediated apoptosis. J Am Soc Nephrol 8, 1091-1100 (1997)

62. D Granfeldt, M Samuelsson and A Karlsson: Capacitative Ca2+ influx and activation of the neutrophil respiratory burst. Different regulation of plasma membrane-and granule-localized NADPH-oxidase. J Leukoc Biol 71, 611-617 (2002)

63. CD Hunt: Regulation of enzymatic activity: one possible role of dietary boron in higher animals and humans. Biol Trace Elem Res 66, 205-225 (1998)

64. K Uchimura, A Nagasaka, R Hayashi, M Makino, M Nagata, H Kakizawa, T Kobayashi, K Fujiwara, T Kato, K Iwase, R Shinohara, K Kato and M Itoh: Changes in superoxide dismutase activities and concentrations and myeloperoxidase activities in leukocytes from patients with diabetes mellitus. J Diabet Comp 13, 264-270 (1999)

65. RI Scorei, C Ciofrangeanu, R Ion, A Cimpean, B Galateanu, V Mitran and D Iordachescu: In vitro effects of calcium fructoborate upon production of inflammatory mediators by LPS-stimulated RAW 264.7 macrophages. Biol Trace Elem Res 135, 334-344 (2010),

66. A Zychlinsky, C Fitting, JM Cavaillon and PJ Sansonetti: Interleukin 1 is released by murine macrophages during apoptosis induced by Shigella flexneri. J Clin Invest 94, 1328-1332 (1994)
PMid:8083373    PMCid:295219

67. J Cao, L Jiang, X Zhang, X Yao, C Geng, X Xue and L Zhong : Boric acid inhibits LPS-induced TNF-alpha formation through a thiol-dependent mechanism in THP-1 cells. J Trace Elem Med Biol 22, 189-195 (2008)

68. TA Armstrong and JW Spears: Effect of boron supplementation of pig diets on the production of tumor necrosis factor-alpha and interferon-gamma. J Anim Sci 81, 2552-2561 (2003)

69. M Benderdour, K Hess, M Dzondo-Gadet, B Dousset, P Nabet and F Belleville: Effect of boric acid solution on cartilage metabolism. Biochem Biophys Res Commun 234, 263-268 (1997)

70. M Benderdour, K Hess, M Dzondo-Gadet, P Nabet, F Belleville and B Dousset: Boron modulates extracellular matrix and TNFα sythesis in human fibroblasts. Biochem Biophys Res Commun 246, 746- 751 (1998)

71. J Yao, N Mackman, TS Edgington and ST Fan: Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by egr-1, c-jun and NF-kappaB transcription factors. J Biol Chem 272, 17795-17801 (1997)

72. TK Means, RP Pavlovich, D Roca, MW Vermeulen and MJ Fenton: (2000) Activation of TNF-alpha transcription utilizes distinct MAP kinase pathways in different macrophage populations. J Leukocyte Biol 67, 885-893 (2000)

73. EY Tsai, JV Falvo, AV Tsytsykova, AK Barczak, AM Reimold, LH Glimcher, MJ Fenton, DC Gordon, IF Dunn and AE Goldfeld: A lipopolysaccharide-specific enhancer complex involving Ets, Elk-1, Sp1 and CREB binding protein and p300 is recruited to the tumor necrosis factor alpha promoter in vivo. Mol Cell Biol 20, 6084-6094 (2000)
PMid:10913190    PMCid:86084

74. S Pradervand, MR Maurya and S Subramaniam: Identification of signaling components required for the prediction of cytokine release in RAW 264.7 macrophages. Genome Biol 7, R11 (2006)
PMid:16507166    PMCid:1431720

PMid:16925833    PMCid:1810548

75. PC Calder: N−3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids 38, 343-352 (2003)

76. D. Rees, E.A. Miles, T. Banerjee, S.J. Wells, C.E. Roynette, K.W. Wahle and P.C. Calder: Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr 83, 331-342 (2006)

77. I Hardardóttir and JE Kinsella: Increasing the dietary (n−3) to (n−6) polyunsaturated fatty acid ratio increases tumor necrosis factor production by murine resident peritoneal macrophages without an effect on elicited peritoneal macrophages. J Nutr 122, 1942-1951 (1992)

78. L Ferrucci, A Cherubini, S Bandinelli, B Bartali, A Corsi, F Lauretani, A Martin, C Andres-Lacueva, U Senin and JM Guralnik: Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab 91, 439-446 (2006)

79. FH Nielsen and BJ Stoecker: Boron and fish oil have different beneficial effects on strength and trabecular microarchitecture of bone, J Trace Elem Med Biol 23(3), 195-203 (2009)

80. C Nathan and QW Xie: Nitric oxide synthases. Roles, tolls, and controls. Cell 78, 915-918 (1994)

81.JE Albina, S Cui, RB Mateo and JS Reichner: Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol 150, 5080-5085 (1993)

82. Y.J. Jeon, K.K. Young, M. Lee, S.M. Park, S.B. Han and H.M. Kim: Radicicol suppresses expression of inducible nitric-oxide synthase by blocking p38 kinase and Nuclear Factor-kB/Rel in lipopolysaccharidestimulated macrophages. J Pharmacol Exp Ther 294, 548-554 (2000)

83. R Beyaert, A Cuenda, W Vanden Berghe, S Plaisance, JC Lee, G Haegeman, P Cohen and W Fiers: The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J 15, 1914-1923 (1996)
PMid:8617238    PMCid:450110

84. AD Foey, SL Parry, LM Williams, M Feldmann, BM Foxwell and FM Brennan: Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-α: Role of the p38 and p42/44 mitogen activated protein kinases. J Immunol 160, 920-928 (1998)

85. A Eigler, J Moeller and S Endres S: Exogenous and endogenous nitric oxide attenuates tumor necrosis factor synthesis in the murine macrophage cell line RAW 264.7. J Immunol 154, 4048-4054 (1995)

86. JA Williams and E Shacter: Regulation of macrophage cytokine production by prostaglandin E2. Distinct roles of cyclooxygenase -1 and -2. J Biol Chem 272, 25693-25699 (1997)

87. R van den Berg, JA Peters and H van Bekkum: The structure and (local) stability constants of borate esters of mono- and di-saccharides as studied by 11B and 13C NMR spectroscopy. Carbohydr Res 253, 1-12 (1994)

88. Q Luan, T Desta, L Chehab, VJ Sanders, J Plattner and DT Graves: Inhibition of experimental periodontitis by a topical boron-based antimicrobial. J Dent Res 87, 148 (2008)

89. LH Mattingly, AR Gault and WJ Murphy: Use of systemic proteasome inhibition as an immunemodulating agent in disease. Endocr Metab Immune Disord Drug Targets 7, 29-3 (2007)

90. R Scorei, R Ciubar, CM Ciofrangeanu, V Mitran, A Cimpean and D Iordachescu: Comparative effects of boric acid and calcium fructoborate on breast cancer cells. Biol. Trace Elem. Res 122, 197-205 (2008)

91. R. Scorei and R. Popa: Boron-containing Compounds as Preventive and Chemotherapeutic Agents for Cancer, Anti-Cancer Agents in Medicinal Chemistry 10(4), 346-51 (2010)

92. WT Barranco and CD Eckhert: Boric acid inhibits humane prostate cancer cell proliferation. Cancer Lett 216, 21-29 (2004)

93. WT Barranco and CD Eckhert: Cellular changes in boric acid-treated DU-145 prostate cancer cells. Br J Cancer 94, 884-890 (2006)

94. F Chen, D Chang, M Goh, SA Klibanov and M Ljungman: Role of p53 in cell cycle regulation and apoptosis following exposure to proteasome inhibitors. Cell Growth Differ 11, 239-246 (2000)

95. TR. Shirangi, A Zaika and UM Moll: Nuclear degradation of p53 occurs during down-regulation of the p53 response after DNA damage. FASEB J 16 (3), 420-422 (2002)

96. GL Locher: Biological effects and therapeutic possibilities of neutrons, Am J Roentgenol Radium Ther Nucl Med 36, 1-13 (1936)

97. F Rolf, JA Barth, M Coderre, HV Graça and TE Blue : Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects. Clin Cancer Res 11 (11), 3987-4002 (2005)

98. GI Bell, T Kayano, JB Buse, CF Burant, J Takeda, D Lin, H Fukumoto and S Seino: Molecular biology of mammalian glucose transporters. Diabetes Care 13, 198-208 (1990)

99. G Boudry, CI. Cheeseman and MH Perdue. Psychological stress impairs Na_-dependent glucose absorption and increases GLUT2 expression in the rat jejunal brush-border membrane. Am J Physiol Regul Integr Comp Physiol 292, R862-R867 (2007)

100. V Douard and RP Ferraris: Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab 295, E227-E237 (2008)
PMid:18398011    PMCid:2652499

101. J Payne, F Maher, I Simpson, L Mattice, P Davies:Glucose transporter glut 5 expression in microglial cells. Glia 21(3), 327-331(1997)

102. F Nualart, A Godoy and K Reinicke: Expression of the hexose transporters GLUT1 and GLUT2 during the early development of the human brain. Brain Res 824, 97-104 (1999)

103. VA Funari, VL Herrera, D Freeman and DR Tolan: Genes required for fructose metabolism are expressed in Purkinje cells in the cerebellum. Brain Res Mol Brain Res 142: 115-122, (2005)

104. GJ Mantych, DE James and SU Devaskar: Jejunal/kidney glucose transporter isoform (Glut-5) is expressed in the human blood-brain barrier. Endocrinology 132, 35-40 (1993)

105. HJ Shu, K Isenberg, RJ Cormier, A Benz and CF Zorumski: Expression of fructose sensitive glucose transporter in the brains of fructose-fed rats. Neuroscience 140, 889-895 (2006)

106. Burant CF, Takeda J, Brot-Laroche E, Bell GI, Davidson NO. Fructose transporter in human spermatozoa and small intestine is GLUT5. J Biol Chem. 1992 Jul 25;267(21):14523-14526.

107. J Chesney: 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase and tumor cell glycolysis. Curr Opin Clin Nutr Metab Care 9, 535-539 (2006)

108. SP Zamora-Leon, DW Golde, II Concha, CI Rivas, F Delgado-Lopez, J Baselga, F Nualart and JC Vera: Expression of the fructose transporter GLUT5 in human breast cancer. Proc Natl Acad Sci USA 93, 1847-1852 (1996)

109. KK Chan, JY Chan, KK Chung and KP Fung: Inhibition of cell proliferation in human breast tumor cells by antisense oligonucleotides against facilitative glucose transporter 5. J Cell Biochem 93, 1134-1142 (2004)

110. A Godoy, V Ulloa, F Rodriguez, K Reinicke, AJ Yanez, L Garcia Mde, RA Medina, M Carrasco, S Barberis, T Castro, F Martinez, X Koch, JC Vera, MT Poblete, CD Figueroa, B Peruzzo, F Perez and F Nualart: Differential subcellular distribution of glucose transporters GLUT1-6 and GLUT9 in human cancer: ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues. J Cell Physiol 207, 614-627 (2006)

Abbreviations: CF: Calcium Fructoborate; MDA-MB-231: breast cancer cells; RG-II: rhamnogalacturonan II complex; NaBC1: Boron transporter; 10BNCT: 10-boron neutron capture therapy; BA: boric acid; IgF: Imunoglobuline F; PSA: prostate specific antigene; HRT: hormone replacement therapy; PAHs: polycyclic aromatic hydrocarbons; HPV: Human papilloma viruses ; PMN; polymorfonuclear cells; SOD: superoxide dismutase; PUFAs: polyunsaturated fatty acids; EBF: 10-Boron-Fructoborate.

Key Words: Calcium Fructoborate, Dietary Supplement, Prostate Cancer, Lung Cancer, Cervical Cancer, Breast Cancer, Apoptosis, Boron, GLUT-5, 10BNCT. Enriched 10-Boron-Fructoborate, Review

Send correspondence to: Ion Romulus Scorei, Address: Biochemistry Department, University of Craiova, AI Cuza street, no.13, Craiova, Romania,Tel: + 40 251 415690, Fax: + 40 251 415690, E-mail:romulus_ion@yahoo.com