Sugar-Borate Esters

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breast cancer cells, M.S. thesis, University of Nevada Las Vegas, ..... phosphorus, and urinary boron in athletic and sedentary women. ... Commission, 2010.

Send Orders of Reprints at [email protected] Anti-Cancer Agents in Medicinal Chemistry, 2013, 13, 000-000

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Sugar-Borate Esters – Potential Chemical Agents in Prostate Cancer Chemoprevention Romulus Ion Scorei1 and Radu Popa2,* 1

Department of Biochemistry, A.I. Cuza street, No. 13, University of Craiova, Craiova, Dolj, 200585, Romania; 2University Park Campus, ZHS 117, Mail Code 0740, University of Southern California, Los Angeles, 90089-0740 CA USA Abstract: The potential value of sugar-borate esters (SBEs) in the chemo-preventive therapy of prostate cancer has been reviewed. We propose that SBEs act as boron (B) vehicles, increasing the concentration of borate inside cancer cells relative to normal cells has been proposed. Increased intracellular concentration of borate activates borate transporters, but also leads to growth inhibition and apoptosis. The effects of SBEs on normal cells are less dramatic because SBEs are naturally-occurring biochemicals, common and abundant in some fruits and vegetables, and also because borate dissociated from SBEs in natural diet doses is easily exported from normal cells. Cancer cell lines that over-express sugar transporters or under-express borate export are potential targets for SBE-based therapy. With regard to efficiency against cancer cells and drug preparation requirements, trigonal cis-diol boric monoesters will be one of the most effective class of SBEs. Because negative correlation exists between borate intake and the incidence of prostate cancer, and because most cancer cells over-express sugar transporters, SBEs are proposed as a potential chemopreventive avenue in the fight against primary and recurrent prostate cancer.

Keywords: Boron, sugar-borate esters, prostate cancer, chemoprevention, diet, ribose, fructose, sugar transport. I. INTRODUCTION Chemoprevention is the use of chemical agents to reverse, suppress or prevent carcinogenic progression [1, 2]. Qualities sought in chemopreventing agents include efficiency against cancer progression, limited side effects, easiness of administration, known mechanisms of action and cost effectiveness in prolonged treatments [3]. The high incidence and extended latency of prostate cancers [4, 5], makes them better targets for chemopreventive therapy. The main strategies for prostate cancer chemoprevention include: anti-inflammatory agents such as aspirin [6], non-steroidal anti-inflammatory agents [7] and statins [8]; targeting sex steroid hormones [9]; lowering oxidation levels [10]; and changes in diet [11-15]. Diet-based chemoprevention is complex and includes a combination of changes in nutritional intake balance and antioxidants [16-19]. The most important markers for evaluating the efficiency of prostate cancer chemoprevention are: prostate inflammation, benign prostatic hypertrophy, prostatic intraepithelial neoplasia (PIN) and the prostate-specific antigen (PSA) [20, 21]. In cancerous prostates, oxidation levels are high and inflammation creates additional freeradicals, which eventually escalate the evolution toward the precancerous condition PIN [22, 23]. PIN is a useful marker for studying chemoprevention because it does not influence the PSA level, may appear long before prostate cancer has been diagnosed (e.g. sometimes more than ten years later), and because about 85% of all men with prostate cancer also have PIN [24, 25]. Elevated PSA levels may be an indication of prostate cancer, but may also be associated with a non-cancerous prostatitis (i.e. prostate inflammation). Men with prostate cancer often have >4 ng/mL PSA level, but prostate cancer is also possible at lower PSA levels as well [26]. The incidence of prostate cancer relative to PSA is 15% at 10 ng/mL PSA. This makes PSA a valuable tool for selecting human subjects for data mining and for studying chemoprevention [26].

*Address correspondence to this author University Park Campus, ZHS 117, Mail Code 0740, University of Southern California, Los Angeles, 900890740 CA USA; Tel: 1 503 725 9503; Fax: 1 503 725 3888; E-mail: [email protected] 1871-5206/13 $58.00+.00

Many connections were reported to exist between boron (B) and cancer. Boron deficiency was shown to be positively correlated with increased incidence of prostate cancer [27], lung cancer [28] and cervix cancer [29]. Increased abundance of B in the environment and diet was negatively correlated with prostate hyperplasia [30], inhibited the activity of prostate and breast cancer cells [31-35], and lowered the incidence of prostate cancer and the mortality in prostate cancer [27] and lung cancer patients [28]. Boron-containing compounds with anti-cancer effects include boric acid, borates, borate esters, boranes, borinic esters, boronic esters and oxazaborolidines [35, 36]. The drug Bortezomib (Velcade, Millennium Pharmaceuticals) is a boronate ester. Bortezomib is a proteasome inhibitor; it slows down the growth of prostate and breast cancer cells [37-39] and induces apoptosis in prostate cancer cells [37, 40], myeloma cells [41-43] mantle cell lymphoma [44], cell lung cancer [45], ovarian cancer [43], pancreatic cancer [46] and head and neck squamous cell carcinoma [47]. In this study we review the potential of sugar-borate esters (another class of B compounds) as chemopreventive agents against prostate cancer. II. NATURAL B COMPOUNDS OF POTENTIAL VALUE IN PROSTATE CANCER CHEMOPREVENTION The microelement B is important to many types of organisms but its primary cellular function is unknown [34, 48, 49]. In many cases, the role of B seems to be related to its ability to form complexes with compounds having cis-diol configurations [50]. Presently, B-based anticancer therapies include the use of boronate esters [51], and 10-B neutron capture therapy [52-54]. In this section we review effects of three classes of natural B compounds on living cells and in prostate cancer chemoprevention: (a) boric acid/borate; (b) polyketide-borate esters; and (c) sugar-borate esters. (a) Boric Acid (BA) Boric acid (BA) is an inhibitor of peptidases, proteases, proteasomes, arginase, nitric oxide synthase and transpeptidases [55, 56]. Its capacity to bind OH groups from NAD and serine may explain its capacity to inhibit dehydrogenases and serine proteases

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[57]. BA has been proposed in the therapy of prostate carcinoma [32] partly because of its capacity to inhibit the activity of the PSA serine protease [57, 58]. The effect of BA on androgen-sensitive cancer cells may involve inhibition of PSA formation, but also effects on DNA polymerization, thymidilate synthesis, Sadenosylmethyltransferase activity, non-histone chromatin methylation, DNAse and RNAse [31, 59].” BA also inhibited androgen-independent cell lines (e.g. DU-145 and PC-3l) indicating that other (serine protease-independent mechanisms) may also exist [32]. BA can control and inhibit the cell cycle (as seen in the proliferation of DU-145 cells) by inhibiting an agonist-stimulated release of Ca2+ from ryanodine receptor sensitive cell stores [58]. In high doses (12.5 mM to 50 mM) BA slowed down cell replication or induced apoptosis in melanoma cells and some breast cancer cells [34, 60, 61]. (b) Polyketide-borate Esters Boromycin is a polyether-macrolide produced by Streptomyces antibioticus with antibiotic activity against Gram-positive bacteria [62]. It acts at the cell membrane level and results in loss in intracellular potassium [62]. It also selectively disrupts the cell cycle in some cancer cell types, making them sensitive to specific anticancer agents [63]. Borophycin, a polyketide extracted from species of Nostoc [64], was shown to have inhibitory effects on

Scorei and Popa

several cancer cell lines [65]. Tartrolons are macrolides with a chemical structure related to boromycin and aplasmomycin [66] and have antiviral and antineoplastic chemotherapeutic properties [65]. Aplasmomycin, secreted by Streptomyces griseus, with antibiotic effects against Gram positive bacteria and Plasmodium berghei, was not yet verified against cancer cells, but it is similar in structure with tetralons which have anticancer properties [64]. (c) Sugar-borate Esters BA, and its ionic form borate, produces esters with sugars called sugar-borate esters (SBEs). SBEs can be trigonal or tetragonal, and monoesters or diesters (Fig. 1) [67]. Equilibrium between various SBEs in solution and the rates of inter-conversion depend on factors such as concentration, the type of sugar, pH and temperature. Sugars with high abundance of furanosic isomers and cis-diol groups (such as ribose and fructose) have increased reactivity and form numerous SBEs. At circumneutral or alkaline pH, electrically neutral trigonal mono-esters convert into electrically charged tetragonal esters. This transformation is important because the transport and effect of various SBEs on cells is controlled by both their chemical structure and electrical state. Relative to pyranosic esters, furanosic esters have higher association constant [68], which increases their shelf-stability and their value for SBEbased therapy [69]. Calcium fructoborate (CF), one example of

Fig. (1). Chemical structures of main B-containing compounds, boric acid, borate and examples of common types of furanosic borate sugar esters (BSE) with ribose and fructose.

Sugar-Borate Esters – Potential Chemical Agents in Prostate Cancer

SBE used in the prevention and treatment of osteoporosis and osteoarthritis [70-72], is a natural plant-mineral complex found in plants, commercially available as nature-identical mineral complex produced by chemical synthesis [67]. CF has been shown to inhibit MDA-MB-231 breast cancer cells, a metastatic cancer cell line that is estrogen-insensitive. Inside cells, CF acts as an antioxidant, induces over-expression of apoptosis-related proteins and eventually leads to apoptosis in a dosage-dependent manner [61]. The ideal B-containing chemicals for chemotherapy should show low toxicity, high specificity in targeting cancer cells, and (once inside the cytoplasm) they should release toxic borate in solution for a long time. Healthy cells curb the toxicity of B by exporting borate. This, combined with the limited capacity of BA and borate to target cancer cells, significantly lowers the chemotherapeutic usefulness of BA and borate. Boronate esters show higher specificity for cancer cells than BA or borate [73], but they are also more toxic to normal cells [56]. SBEs are less toxic than BA, are similar in structure with natural B compounds commonly found in fruits and vegetables [67, 74] and are better for targeting cancer cells than BA and borate [61]. It was proposed that the capacity of SBEs to target cancer cells is also better than that of boronate esters [35]. This is because SBEs (in monoester forms) are transported into cells via sugar transporters [74, 76] but also because many cancer cells show increased expression of sugar transporters [77-79]. Due to their dissociative properties, SBEs release less borate in solution than BA (Eqs. 1-3). Thus, once in the cytoplasm of cells with diminished capacity to export borate, SBEs release borate in solution for a longer time. Bo + OH- = B- (Ko = 8.5·104) Eq. 1 2 4 B L = B + L (K1 = 6.6·10 for L = fructose; and K1 = 1.82·10 for L = ribose) Eq. 2 B-L2 = B-L + L (K2 = 9.1·104 for L = fructose; and K2 = 6.3·104 for L = ribose) Eq. 3 where: Bo = boric acid; B- = borate; L = ligand; B-L = tetragonal borate monoesters and B-L2 = tetragonal borate diesters. Ko values represent the concentration of borate (in Eq.1 and Eq.2) and of monoester (in Eq.3) at equilibrium at a concentration of the reagent of 1M. Association constants for trigonal B esters are difficult to determine with precision because they evolve rapidly into tetragonal forms [68, 79-81]. For these reasons SBEs are thought to be appropriate for cancer chemoprevention and chemotherapy. We propose that: • during SBE-based therapy B is introduced into cells masked as a derivatized sugar; • trigonal monoesters (which are not electrically charged) are better than tetragonal SBEs or sugar borate diesters; • ribose SBEs are better than fructose SBEs (because cancer cells show particularly active RNA synthesis which requires large amounts of ribose); and • furanose SBEs drugs are better than pyranose SBEs drugs due to differences in shelf stability. III. THE ACTIVITY OF SBES IN NORMAL CELLS AND EFFECTS ON PROSTATE CANCER CELLS (a) SBEs as Anti-inflammatory Agents The link between inflammation and cancer occurs through production of cytokines and growth factors favoring cancer cell growth, the induction of COX-2 (a protein controlling the synthesis of prostaglandines linked with tumor proliferation), and the generation of mutagenic reactive chemical species of oxygen and nitrogen [82-84]. Cytokines produced during inflammation increase the expression of 5-lipoxygenase (5-LOX) [85], which leads to the formation of metabolites favoring cancer development. Inhibiting

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5-LOX-related metabolites triggers apoptosis in prostate cancer cells [86]. The anti-inflammatory activity of B may be an outcome of suppressing serine proteases released by inflammation-activated white blood cells, by inhibition of leukotriene synthesis, by reduction of reactive oxygen species generated during neutrophils’ respiratory burst, or by suppression of T-cell activity and antibody concentrations [87]. SBEs inhibit the synthesis of arachidonic acid (AA)-derived eicosanoids, a class of pro-inflammatory prostaglandins [67]. High B intake leads to its incorporation in membrane phospholipids, partly substituting AA-derived eicosanoids, and increases the abundance of the omega-3-derived eicosapentaenoic acid [88]. Treatments of LPS-stimulated RAW264.7 macrophages with CF inhibited the production of IL-1β and IL-6 cytokines and that of nitric oxide [89]. Because these chemicals are inflammation mediators, it was proposed that CF can be used as an antiinflammatory agent [90, 91]. Adding CF to the diet of farm animals led to higher abundance of omega-3 polyunsaturated fatty acids (omega-3 PUFA) in the meat of pigs and in the meat and eggs of chicken [91-93]. Increased abundance of omega-3 PUFA relative to omega-6 PUFA was shown to increase the cellular resistance to inflammatory stimuli associated with cancer progression [94]. (b) The Transport of B Into Cells In small amounts, B is needed by the cells, but excess BA and borate are toxic [95-97]. Cells regulate the internal concentration of borate via specialized transporters, though the mechanism of regulation is little understood [98, 99]. Electrically neutral B compounds cross the membrane passively [100-102]. The borate anion (Fig. 2) can be transported by aquaporins such as AQP9 [103] or specialized transporters such as NABC1 in humans [95], ATR1 in yeast [104, 105] and BOR1 in plants [103]. SBEs were shown to enter the blood stream at the intestine level [67], but how they cross the cell membrane remains unclear. Because borate and phosphate share many similarities in structure and chemical reactivity, they substitute for each other in many compounds and processes [106, 107]. They may also substitute each other during cross-membrane transport. SBE transport may occur via sugar transporters (most likely this applies to the SBEs that contain non-charged trigonal borate; Fig. 1), by facilitated diffusion, and by translocation in the case of SBEs containing electrically charged tetragonal borate (Fig. 1), [69]. Sugar transporters are one of the likeliest avenues for introducing CF mono and diesters into cells [67]. Putative candidates for this activity are the fructose transporter Glut5 and glucose-6-phospahte translocase. Differences in the expression of sugar transporters may explain why some cancer cells are more sensitive to SBEs than normal cells [108]. B transporters influence the practicality of using BA in cancer treatments [31]. Some cancer cells have impaired ability to eliminate excess borate and are about five times more prone to borate induced apoptosis than normal cells [32]. Partly because of their diffusive properties, boronates are more efficient anticancer agents than BA. It is hypothesized that SBEs is more difficult to eliminate from cells than borate, because no specialized SBE transporters exist, because SBEs are most likely transported via sugar transporters (which in cancer cells are more active inward), and because the intracellular concentration and need for sugars and phosphate is always higher than that for BA. In support of this hypothesis, CF has been shown to trigger apoptosis in MDA231 breast cancer cells at concentrations 4-5 times lower than BA [61]. (c) The Relationship Between B and Vitamin D3 The inverse correlation between exposure to solar radiation and the incidence and mortality of breast cancer was proposed to be associated with the production of vitamin D2 [109-110]. Vitamin D3 (calcitriol) is a derivative of D2, has important roles in regulating the prostatic cell growth and has demonstrated effects on the prostate cancer cell line LNCaP [111]. Vitamin D3 arrests the cell cycle, induces apoptosis and inhibits metastases and the

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Fig. (2). Known and putative mechanisms for the transport of common boron compounds (boric acid, borate, boronates, borate sugar esters and boric acid sugar monoesters) into cells.

proliferation of prostate cancer cells [112-115]. Its tumor inhibition activity may be due to the induction of the cyclin dependent kinase inhibitor p21 and G1-G0 cell cycle arrest. This activity may explain the regression of cancer cell growth in rats treated with vitamin D3 [116]. Vitamin D3 also initiates its own inactivation because it also induces the expression of CYP24, a protein that initiates the Vitamin D3 catabolism, a mechanism present in prostate cells [117]. B in general and CF in particular, increase the intracellular concentration of vitamin D3 [70, 118]. This effect may be due to the fact that B up-regulates the 25-hydroxylation step or suppresses the vitamin D3 catabolic pathway [119]. Because B readily forms covalent complexes with cis-vicinal dihydroxy compounds, it is reasonable to assume that B also forms complexes with 24,25dihydroxyvitamin D, the final product of the 25-OH-D reaction with 24-OH-hydroxylase (a vitamin D3 regulator). This complex acts as a competitive inhibitor for the 24-OH- hydroxylase reaction, or, as a down regulator of this enzyme. B may also be an inhibitor of microsomal enzymes (24-hydroxylase and estradiol hydroxylases) which catalyze the insertion of the hydroxyl group vicinal to the existing hydroxyl groups of steroids [119]. For these reasons, combinations of vitamin D3 with chemical B compounds that are easy to assimilate and tend to accumulate into cells, are a potential strategy for hormonal cancer chemoprevention and chemotherapy [118]. (d) B and Proteasome Inhibition Proteasomes are large protein complexes recycling ubiquitinated proteins. Several anti-apoptotic and proliferative signaling pathways require proteasomal activity. In the prooncogenic NF-κB pathway, which is activated and prevalent in the regulation of many types of tumors, NF-κB proteins are kept in inactive state by the IκB proteins [51, 118]. In order to remove this inhibition, IκBs have to be phosphorylated, poly-ubiquitylated and then recycled. Correct functioning of proteasomes appears to require that B exists in the cells within a specific concentration range. Both, too little or too much B inhibit proteasome activity [120, 121]. In high concentration, BA and boronic acid slow down the carcinogenic progression, because they block the degradation of IκBs, which in turn down-regulates the NF-κB signalling. The drug Bortezomib inhibits proteasomes, possibly through the formation of complexes with their active site(s) [122]. The ensuing inhibition of the NF-κB signaling pathway reduces the expression of pro-

inflammatory response genes and up-regulates the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1. In turn, this increases the frequency of apoptosis in tumor cells. This mechanism may be part of the Bortezomib-based treatment of multiple myeloma, relapsed mantle-cell lymphoma [123] and prostate cancer [124,125]. The relationship between Bortezomib and apoptosis is complex and may be influenced by numerous factors. For example, over-expression of the anti-apoptotic protein Bcl-2 in H460 cells did not affect proteasomal activity, but decreased the effect of Bortezomib on apoptosis [126]. BA, which dissociates in borate, inhibits the effect of Bortezomib on cancer cells. This may be due to competition between borate and boronate-esters for proteasome active site(s) [127]. Understanding this interference is important in future studies of the efficiency of Bortezomib on proteasomes, in the presence of natural and artificial SBEs. This is particularly important in the case of neutral monoester SBEs, which release less borate by dissociation than BA. How will for example, a diet of fruits rich in SBEs (such as plums) or treatments with CF will influence the therapeutic efficiency of Bortezomib? (e) Effects on B Compounds on Enzymatic Activity Borates, borate esters and boronic esters interfere with the activity of many enzymes, including NADH-cytochrome b5 (cyt. b5) reductase [EC 1.6.2.2] [128], phosphorylases [129], alcohol dehydrogenas, xanthine oxidase, glutamyl transpeptidase and cytochromes [130]. The mechanisms involved, albeit not fully clear, often include interactions with OH and cis-diol groups. Borate forms complexes with amino and hydroxy groups of proteins, targeting residues of lysine, glutamine, serine, hystidine and proline [131]. It also binds polyhydroxy compounds such as sugars (mannitol, xylitol, sorbitol, glucose and fructose) [74] and ribose from NAD and FAD, phenols (catechol and pyrogallol) and α-hydroxy acids (2-hydroxyisobutyric acid, salicylic acid, and cis2-hydroxycyclopentanecarboxyric acid) [132]. Borate stabilizes the tertiary structure and activity of alkaline phosphatase, protecting it from oxidative stress [133]. This was attributed to borate creating a chemical bridge between carbohydrate residues and protecting 1,2diols and 1,3-diols. B was also shown to increases the resistance of heme-containing proteins (such as cyt c and metmyoglobin) to thermal stress [134]. At biochemical and therapeutic levels, the main usefulness of B may be to protect heme proteins (Cyt c and metMb) from oxidative stress [135]. Similar to proteasome-level

Sugar-Borate Esters – Potential Chemical Agents in Prostate Cancer

effects the activity of cytochrome c is regulated by the concentration of B and inhibited when B is either above or below some optimal thresholds [136, 137]. Inorganic additives enhancing the effect of B compounds on enzymes include calcium, magnesium and phosphorus [138]. (f) Effects of Borate/phosphate Similarities Negative correlation has been reported to exist between the concentration of phosphate and borate in plants cells [139] and in normal and osteoporotic bones [140]. Borate was shown to enhance phosphorylation and, in humans, was proposed to affect living cells via a mediator (putatively TNF-alpha) whose transduction signal involves a phosphorylation cascade [141]. Though many similarities exist in structure and activity between borate and phosphate the borate:phosphate substitution is little studied. Phosphate esters are important in cellular energetics, biochemical activation, signal transduction and conformational switching. The borate:phosphate similarity, combined with borate’s ability to spontaneously esterify hydroxyl groups, suggests that phosphate ester recognition sites on proteins might exhibit significant affinity for non-enzymatically formed borate esters [106]. For example, the complex between RNase A and 3′-deoxycytidine-2′-borate was shown to mimic the structure of the complex between RNase A and 2′-cytidine monophosphate inhibitor. The RNase A capacity to bind cyclic cytidine-2′,3′-borate ester, a structural homolog of the cytidine2′,3′-cyclic phosphate substrate, was also seen. In normal cells the borate:phosphate competition is little important, probably because in cells phosphate is thousands of times more abundant than borate, but also because in complexes such cytidine-2′,3′ - RNAse the affinity for phosphate is higher than the affinity for borate [106]. Based on earlier evidence we expect that the effect of borate:phosphate similarity should increase in phosphate-starved cells treated with SBEs.

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IV. SBE-BASED TREATMENTS AND B TRANSPORT DEFICIENCY AS AN POTENTIAL AVENUE IN THE FIGHT AGAINST CANCER The recommended daily intake of B in humans is between 0.14 and 0.28 mg / day kg body weight (bw) [142, 143]. Increased exposure to about 2.5 and 24.8 mg borate / kg bw (used in the past to treat epilepsy), has has been shown to have non-lethal secondary effects such as alopecia, and some reversible effects such as dermatitis, anorexia and indigestion [144]. The lethal daily dose of B is in the range 400–900 mg / kg bw [145]. The genotoxicity of B was studied by Moore [146]. The 50% lethal dose of B, as boric acid, for one time administration is very high (2.6 g per kg bw), close to that of table salt (3 g per kg bw) [147]. In borax treatments of cultured lympohocites no effects were seen at 0.1 mg/ml, inhibition of proliferation occurred between 0.15 and 0.6 mg/ml, sister chromatin exchange increased at 0.6 mg/ml and the 50% inhibitory concentration was 0.9 mg/ml [148]. We found no references linking B exposure with carcinogenesis. B sensitivity varies between normal and cancer cells, not all cancer cells are sensitive to B and the response to B vary among Bsensitive cancer cells. In cell cultures, cancer cells died at concentrations between 1 and 50 mM BA, and non-cancer cells were about 5 times more resistant to B [31]. SBEs are appealing for therapy because they are less toxic to healthy cells than BA [67]. In one study (Perry Scientific Inc, 2001, unpublished) the highesst dose of CF and B citrate administered to rats (by oral gavage) was 37.5 mg/kg at single dose administration. No toxicity was noted at this dosage equivalent to 2,250 mg CF (60 mg elemental B) for a 60-kg human [67]. The median lethal dose (LD50) for CF is 18.75 g/kg (=0.525 g B), higher than that of BA (2.6 g/kg (=0.462 g B) (Perry scientific Inc. 2001). Thus, CF intake levels equivalent to single digits milligrams B per day are safe, and are close to BSE

Fig. (3). Diagram of proposed differences in cell transport between various types of SBEs. It is proposed that the most actively transported form of SBEs are trigonal boric monoesters (Fig. 1). Their transport is proposed to occur mainly via sugar transporters. As a result of this biased transport and subsequent hydrolysis in the cytoplasm the cell’s interrior is acidified and the tetragonal borate esters accumulate inside the cells. Cells with higher expression of sugar transporters (such as most cancer cells) and cells with impaired borate export are more vulnerable to SBE-based treatmetns using trigonal boric monoesters.

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intake via food. Based on apoptosis measurements, some cancer cells were shown to be more sensitive to B than normal cells [31, 61]. Mecham (2007) has shown that the sensitivity of cultured cancer cells was negatively correlated with the expression of the NaBC1 borate transporter, indicating that apart from its borate import function NaBC1 may also be used to regulate the level of intracellular borate through export. [149]. Based on the fact that during treatments in the range 1-50 mM BA about 90 % of B was eliminated from the human body within 22-24 hours, the exposure treatments shown above, leading to the apoptosis of cancer cells, correspond with an approximate daily intake between 4.4 mg and 220 mg BA equivalent per kg bw. This is considered relatively safe to normal cells because it is below the toxic levels of B (see above), and close to the B exposure levels used in past for epilepsy treatments. For these reasons, B is a promising avenue for inducing apoptosis in some forms of cancer, including prostate. We propose that such treatments will be most efficient against cancers cell lines with under-expressed NaBC1 and when B is administered as SBE. The trigonal SBE would be particularly more efficient against cancer cells which unlike normal cells also show over-expression of sugar transporters (glucose and fructose channels), (Fig. 3) and against cancer forms with very slow progression (such as prostate cancer). V. CONCLUSIONS B is more toxic, and induces apoptosis, in some types of cancer cells (including prostate cancer) compared to non-cancer cells. SBEs are common in fruits and vegetables and are naturally absorbed by animal cells and are less toxic to normal cells than other B compounds such as inorganic borates, boric acid, boronates and boranes. The mechanism of transport for SBEs in animal cells is little understood. One putative avenue is via sugar transporters, in which case B enters the cells masked by a sugar. We propose that trigonal cis-diol isomers are some of the most effective SBEs against cancer cells. The effect of B on various forms of cancer cells varies, influenced by factors such as the level of expression of transport systems and the availability of phosphorus (relative to cellular needs for phosphorus). The involvement of B transporters in controlling cell proliferation is a novel research avenue in the fight against cancer. Some cancer cell lines will be more SBEs sensitive than others, because of higher expression of sugar transporters or diminished borate export capacity (Fig. 3). Because SBEs dissociate less than boric acid, they can be delivered discontinuously (e.g. through pelleted drugs), yet once inside target cells they will act as chronic releasers of toxic borate. This puts those cells having more active sugar import and diminished borate export at greater apoptosis risk. If SBEs prove to be beneficial in the fight against prostate cancer, the dietary strategy of persons belonging to age groups with increased prostate cancer risk and persons using anti-recurrence chemopreventive treatments should also include increase preponderance of foods and juices naturally rich in SBEs such as plums, avocado, nettle, walnuts, peaches, peanuts, honey and milk. CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS We thank the BioBoron Research Institute (Romania) for supporting this work. The authors contributed equally to this work. ABBREVIATIONS B = Boron BA = Boric Acid CF = Calcium Fructoborate

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omega-3 PUFA PIN PSA SBEs 5-LOX

=

omega-3 PolyUnsaturated Fatty Acids

= = = =

Prostatic Intraepithelial Neoplasia Prostate-Specific Antigen Sugar-Borate Esters 5-LipOXygenase

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Received: August 03, 2012

Revised: December 05, 2012

Accepted: December 06, 2012

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