BORONMaintains BoneSy JointSy NeuronSy

and May Reduce Prostate Cancer Risk

by Stephen B. Strum, MD, FACPMedical Oncologist Specializing in Prostate Cancer

As our knowledge of biological systems has increased. over the past ten years, a greater understanding of

the importance of cellular communication and balancehas been reached. The integrative nature of medicine, socharacteristic of biological orchestration, has now cometo embrace the use of substances that a few decades agowere hardly recognized as important to human health.

Coenzyme QIO, acetyl L-carnitine, alpha lipoic acid,lycopene, selenium, and gamma tocopherol are a fewexamples of new players in the biologic symphonyBoron can now be added to our list of vital nutrientsin the orchestration of health.

While boron has long been known to promote healthybone density, new research shows that it can shrinkprostate tumor size, lower PSA, and may help to preventprostate cancer. Additional fmdings show that boronalleviates joint discomfort and preserves cognitivefunction. The good news is that this low-cost mineralhas been added to the most popular supplements thatFoundation members are already taking. > »

Collector's Edition 2004 LIFE EXTENSION 27

BORON^S EFFECTON CANCER

Boron reduces prostatecancer incidence by up to 64%

In a study by Zhang et al, menwho ingested the greatest amount ofboron were 64% less likely to developprostate cancer (PC) compared tomen who consumed the leastamount of boron (see Figure 1).This information was presented atthe annual Experimental Biologyconference in Florida in 2001.'The study, from the CancerEpidemiology Training Program atthe UCLA School of PublicHealth, compared dietary patternsof 76 men with prostate cancer tothat of 7,651 males without cancer.The greater the quantity of boron-rich foods consumed, the greaterthe reduction in risk of being diag-nosed with prostate cancer. Thosemen consuming the most boron(i.e., in the upper quartile of boronconsumption) had a 64% reductionin prostate cancer, while men in thesecond quartile had a 35% reduc-tion in risk and those in the third

quartile reduced their risk by 24%.Men in the lowest quartile of boronconsumption ate roughly one sliceof fruit per day, while those in thehighest quartile consumed 3.5 serv-ings of fruit per day plus oneserving of nuts. Boron-rich foodsinclude plums, grapes, prunes, avo-cados, and nuts such as almondsand peanuts. A serving of 100grams of prunes (12 dried prunes)has 2-3 mg of boron and 6.1 gramsof fiber.'

Boric acid acts to inhibitserine proteases—itdecreases PSA by 87% andreduces tumor size in aprostate cancer mouse m.odel

The mechanism of boron's effecton reducing prostate cancer inci-dence in the study by Zhang et alpreviously cited is not known.However, a preliminary report on theeffect of boric acid (boron) solutionsgiven to mice bearing the humanprostate cancer cell-line calledLNCaP may shed some light on thismechanism. In a study publishedin a 2002 Proceedings of the

-

BORON LOWERS RISK OF PROSTATE CANC

RiskReduction

100

80

60

40

20

0

64%

35%24%

Prostate CancerRisk Reduction

1st 2nd 3rd 4th

Quartiles Relating to Boron Intake

FIGURE 1. Lower Prostate Cancer Risk Associated with Boron Consumption.Those men consuming the most boron had the greatest protective effect against thedevelopment of prostate cancer. Sources of boron include non-citrus fruits like driedprunes, plums, grapes, raisins, nuts such as almonds and peanuts, red wine, and coffee.No protective effect of boron was noted against breast, colorectai, uterine, cervical, orskin cancers.'̂

FIGURE 2: Mitoses in ProstateCancer Biopsy. Mitoses (also calledmitotic figures) may be easily foundusing the light microscope. If mitosesare abundant in number, it can be pre-sumed that the proliferative rate of thetumor is high. High mitotic rates areseen with more aggressive histologicgrades of prostate cancer.

American Association of CancerResearch, Gallardo-Williams et alindicated that mice receiving 1.7 or9.0 mglkglday of boric acid sohitionorally had decreases in tumor size by38% and 25%, respectively.^ Thesame groups had drops in PSA(prostate-specific antigen) of 88.6%and 86.4%, respectively. The controlgroup receiving only water had nodrop in PSA or decrease in tumorsize.

Additional findings of interestincluded a decreased amount ofmitoses in the mice treated withboric acid compared to the controlgroup. Mitoses reflect chromo-somes or genetic material that arein the process of cell division.Mitotic figures can be seen usinga conventional microscope; thegreater the number of mitoses, thegreater the intensity of cell divisionand tumor growth (see Figure 2).The authors also found that thehistochemica! expression of IGF-1(insulin-like growth factor type 1)was markedly reduced by borontreatment. Circulating blood levelsof IGF-1 were not reduced in thetreated mice, however.

28 LIFE EXTENSION Collector's Edition 2004

This study by Gallardo-Williamsis of potentially great significanceand the rationale for such a studymerits further discussion. Theauthors' evaluation of boric acid wasbased on a hypothesis that relates tothe important finding that PSA isnot only a hlomarker of prostate can-cer activity but also a fimctionalenzyme produced by prostate cancercells that acts to promote its very owntumor growth.'" My interpretation oftheir hypothesis is as follows:• PSA is an enzyme (a serineprotease) that frees IGF-1 frominsulin-like growth factor bindingprc^tein.• IGF-1 has been shown to promotethe growth of prostate eancer.• A reduction in PSAs enzymaticactivity should decrease the amountof IGF-1. This in turn shoulddecrease prostate cancer growth.• Boric acid is a known inhibitor ofseveral serine proteases.• Blood boric acid levels as low as 8mcg/ml can inhibit the proteolyticactivity of PSA (authors'separate work).

• Boric acid administration shouldtherefore reduce PSA.• This reduction of PSA should beaccompanied by decreased expres-sion of IGF-1 and deereased tumorgrowth.

This report apparently has led tofurther clinical trials now inprogress.

The anti-cancer effect of boroncompounds has been the subject ofprior studies that involved tumorcell lines of human malignanciesgrown in culture. These studies aresummarized in Table 1 on the nextpage.

BORON'S EFFECT ONBONE METABOLISM

Calcium-Magnesium <=>Boron Interactions

A large number of experimentsconducted in humans involvingboron supplementation or depriva-tion show that boron is vitallyinvolved in bone metabolism. It iswell aceepted that calcium and mag-

nesium are important constituentsor building blocks of healthy bone.In situations of adequate calciumsupply but deficient magnesiumresources, boron appears to substi-tute or "pinch hit" for magnesiumduring the process of bone forma-tion. Under such conditions, theconcentration of boron within bonetissue increases.

Collector's Edition 2004 LIFE EXTENSION 29

Acute lymphocytic

leukemia

Chronic lymphocytic

leukemia

Ehrlich ascites tumor

Ehrlich ascites tumor

L1210 murine

leukemia cells

DU-145 prostate

cancer cells

A549 lung

carcinoma cells

MCF-7 breast

cancer cells

LNCaP prostate

cancer cells

Mouse and human

leukemias

Human uterine,

colon, and lung

adenocarcinomas

Human gliomas

Murine and human

leukemia

Uterine carcinoma

tumor cell lines

Growth inhibition after

treatment with boron

compounds

Significant anti-tumor

action that was further

increased by combining

with ultrasound therapy

Significantly increased

survival time

Dose-dependently

inhibited DNA synthesis

Reduced PSA by 86-89%and reduced tumor vol-ume by 25-38%; mitosesand IGF-1 decreased intissue studies

Inhibited growth

Potent in vivo antineo-

plastic activity and in

vitro cytotoxicity

dihydroxy (oxybiguanido) boron (iii) hydrochloridemonohydrate (HB)

guanidine biboric acid adduct (GB)

hydroxosalicyt hydroxomato boron (iii) (SHB)

dihydroxy (oxybiguanido) boron (111) hydrochloride

monohydrate

guanidine bibortc acid adduct (GB)

Borato-1,2-diaminocydohexane platinum (11) (BDP)

Boric acid solution

Amino-o-carborane-hydrochloride 7

Adenosine 5'[N,N-di-(gamma-o-carboranyl)propyl]

phosphorodiamldate 1

_ ^

4

5

6

7

3

8

9

TABLE 1. Anti-Cancer Activity of Boron. Studies of the anti-cancer efficacy of a number of boron compounds against a wide range oftumor cell lines (shown above) warrant clinical trials in humans.

Boron's effect on hone appears to hemediated hy its ahility to reduce theurinary excretion of calcium and alsomagnesium. In situations where ade-quate horon intake rather than borondepletion prevails, the net effect ofhoron is to raise ionized calciumlevels. This effect of boron—topreserve calcium and decrease uri-nary losses of calcium—is causedby its actions on the kidney.

As stated above, this calcium-preserving effect of boron becomespronounced in circumstances inwhich dietary magnesium is low.With this biologic effect, horon isacting as a hackup system to preservecalcium in the hlood and reduce uri-nary calcium loss. In effect, boronacts literally and figuratively as a"bodyguard" to preserve calciumand magnesium in situations ofnutritional stress that would other-wise adversely affect metabohcprocesses involved with these sub-stances."

The effect of boron intake wasanalyzed in a human study involv-ing 12 post-menopausal women noton estrogen replacement therapy.Patients were first given a boron-deficient diet consisting of 0.25 mg

of boron daily for 119 days. Thiswas followed by a 48-day period inwhich the same patients receivedboron supplementation at a dose of3 mg per day. Patients were alsostudied during periods of adequatemagnesium intake versus magne-sium deficiency. Deprivationof boron and/or magnesiumcaused changes that are similar tothose seen in women withpost-menopausal osteoporosis,including increased loss of urinarycalcium. However, in womenreceiving 3 mg of boron per day,urinary losses of both calcium andmagnesium were significantlydiminished, especially if dietarymagnesium was low. Also notedwere increased levels of plasmaionized calcium, beta estradiol, andtestosterone.'-

Vitamin D <=>Boron Interactions

Boron manifests additional inte-grative effects on bone metabolismin its actions relating to vitamin D(cholecalciferol). Vitamin D affectsabsorption and utilization of calci-um and also has major anti-cancer

effects relating to slowing tumorcell proliferation.'- Vitamin Denhances calcium absorptionthrough the stomach and smallintestine. The effect of boron onraising plasma calcium levels may,in part, be due to its enhancingeffect on vitamin D.'^ Agaia horonis acting as a helper, haekup agent,and/or facilitator to maintain honeintegrity in its actions on vitamin Dand calcium.

BORON'S EFFECT ONARTHRITIS

The inhibition of enzymes suchas serine proteases (e.g., PSA) wasmentioned in relation to the anti-cancer effects of boron. In a reviewof the literature on boron'smetabolic activities. Hunt et al alsoemphasized the down-regulation ofother enzyme activities by boron.''For example, boron has beenshown to inhibit cyclooxygenase(COX) and lipoxygenase (LOX).These two enzymes mediate theinflammatory cascade and are per-tinent to therapies directed againstinflammatory conditions. Suchanti-inflammatory capabilities of

Collector's Edition 2004 LIFE EXTENSION 31

boron are clearly pertinent to itsanti-cancer effect, because thereduction of COX II and LOXenzymes leads to a decrease inprostaglandin E2 (PGE2) andother unfavorable eicosanoids suchas leukotrienes. These hormonalbreakdown products of arachidonicacid were discussed and illustratedin an article on prostate cancer inthe June 2003 Life Extension maga-zine. We now know that omega-6fatty acid metabolism that isallowed to continue down thispathway represents a vital stimulusfor angiogenesis and cancergrowth.

The very same prostaglandinsand leukotrienes are mediatorsof inflammatory conditions suchas degenerative joint diseaseand osteoarthritis. PGE2 andleukotrienes have been implicatedin causing problems with jointswelling, restricted joint motion,and other arthritic complaints.Anti-arthritic agents like glu-cosamine sulfate work throughinhibition of COX II and PGE2 bysuppressing nuclear factor kappabeta (NfkappaB)—a proinflamma-tory cytokine.'*'" There is alsoevidence that boron has similarmodes of action in reducing arthrit-ic conditions.'** -" These findings areclinically supported by evidenceshowing that areas of the worldwith low levels of boron in the soilhave a higher percentage of peoplesuffering from arthritis in compari-son to regions with higher soillevels of boron. There is also epi-demiologic evidence that in areas

of the world where boron intake is 1mg or less per day, the estimatedincidence of arthritis ranges from20% to 70%, whereas in areas ofthe world where boron intake isusually 3-10 mg, the estimated inci-dence of arthritis ranges from 0 to10%.-' In a study of 20 patientswith osteoarthritis, the 50% whoreceived a daily supplement of 6 mgof boron noted subjective improve-ment (less pain on movement),while only 10% of those who hadreceived placebo improved over thesame time interval.'̂

In another study, bone adjacentto joints with osteoarthritis tends tobe less mineralized than controlbone and bone from fracturepatients. Interestingly, bonesamples in such instances have sig-nificantly lower concentrations of

Lastly, there have been studiesthat show the anti-arthritic effectsof S-adenosylmethionine (SAMe)are equivalent to those seen withnon-steroidal anti-inflammatoryagents (NSAIDs) but without thetoxicity seen with NSAIDs."'*-̂Also interesting is a reportindicating a very high affinity ofSAMe for boron.-^ An interestingconsideration would be to evaluatethe efficacy of SAMe in reducingarthritic symptoms in relationshipto boron consumption and boronbiood levels.

BORON'S EFEECTON BRAINFUNCTION

There are many parallels betweenthe medical applications of NSAIDsand the biological properties ofboron. These shared benefits may bedue to the common mechanismsinvolved in the down-regulation ofpro-inflammatory cytokines and thesubsequent reduction in COX II andLOX enzymes. These mechanismsprovide some explanation for the

Sources of BoronBoron is a trace mineral that isfound in non-citrus fruits such asplums, red grapes, apples, pears,and avocados, as well as inlegumes and nuts. It is also presentin significant amounts in coffeeand red wine. Dried fruits contain amuch higher amount of boron thanfresh fruit. For example, freshplums contain 0.45 mg of boronper 100 grams (g), but the sameweight of dried prunes (about 12prunes) contains 2.15 mg ofboron.̂ Although boron currently isnot considered an essential ele-ment in the diet of humans, manyscientists believe it merits the sta-tus as an essential "ultratrace"element.̂ ^ The usual dietary boronconsumption in humans is 1-2mg/day for adults. But boronrequirements may be as high as 9-12 mg per day.

positive clinical benefits of boronsuch as those seen in patients witharthritis and boron's relation to thereduction in the incidence ofprostate cancer, and hopefully inthe use of boron in prostate cancertreatment. Since it is now common-ly accepted that the routine use ofNSAIDs significantly reduces theincidence of Alzheimer's dis-ease,-'"" it is not surprising thatpapers have been published onboron's positive effect on cognitivefunction."

32 LIFE EXTENSION Collector's Edition 2004

Penland et al conductedexperiments in men and womento investigate the functional roleof boron in relation to brainelectrophysiology and cognitiveper formance (see Table 2).Findings were compared inhealthy older men and womenwhile on a diet deprived of boronversus a diet with ample boron(approximately 0.25 mg boron/2000kcal/day versus approximately 3.25mg boron/2000 kcal/day). The abili-ty of patients to perform skillsinvolving cognition and psychomo-tor tasks were assessed and showedsignificant impairment during theboron-deprived diet. Brain-wavepatterns were evaluated using anelectroencephalogram (EEG) andshowed an increased proportion oflow-frequency activity in patientson the boron-deprived diet. Similarfindings are often observed inresponse to general malnutritionand heavy metal toxicity. Theauthors concluded from such datathat boron appears to play a signifi-

cant role in human brain functionand cognitive performance, andthat boron is an essential nutrientfor humans."^

BORON:OTHER FUNCTIONS

Boric acid solution (3%) dramat-ically improves wound healingthrough action on the extracellularmatrix, a finding that has beenobtained in vitro."

BORON TOXICITY

In the 1870s, it was determinedthat sodium borate (borax, a form ofboron) had the ability to preservefoods. Over the next 50 years,borates were valued as preservativesand used to extend the palatabilityof fish, meat, cream, and butter."The first evidence of the potentialfor toxicity associated with borateconsumption occurred in 1904.Human volunteers, consuming over

500 mg per day of boric acid, hadsymptoms of decreased appetite,nausea, abdominal discomfort,and diarrhea. After this wasreported, the use of boron as afood preservative and tasteenhancer greatly declined, and bythe mid-1950s boron was essen-tially banned worldwide in thefood industry. Ironically, boronhas been replaced with monosodi-um glutamate that has beenshown to be neurotoxic'^ yetremain in widespread use.

Boron compounds are toxic toall species tested at high doses,but they are not carcinogenic ormutagenic." A rat developmentaltoxicity study of boron deter-mined a "no observed adverseeffect level (NOAEL) of 9.6 mgof boron per kg per day.Toxicology studies of boron inhumans have shown safety up to amaximal daily intake of 0.3 mg/kgof boron, which equates with adaily intake of 18 mg of boron fora 60-kg (132-pound)individual.'''

Function Studied

Manual dexterityEye-hand coordinationAttentionPerceptionEncoding and short-term memoryLong-term memory

Electroencephalogram (EEG)spectral analysis

Low-frequency activity

High-frequency activity

Boron-deprived Diet

Decreased

Higher

Lower

Boron-ample Diet

Normal

Lower

Higher

p value

<0.05

<0.05

TABLE 2: Effects of Boron Deprivation on Cognitive Performance and Brain Activity. In multiple studies, older men and womenshowed statistically significant impairment in cognitive function on a low-boron diet in comparison to a diet ample in boron. EEGactivity was also abnormal in patients on the low-boron diet."

Collector's Edition 2004 LIFE EXTENSION 33

Four patients with elevatedserum boric acid levels after single,acute ingestions of 10-297 gramswere reported to the RockyMountain Poison and Drug Center(RMPDC) between January 1983and August 1985. In these cases,systemic effects were absent. In1983-4, 364 cases of boric acidexposure were reported to theRMPDC. with only one fatalityfrom a probable chronic ingestion.In this case, vomiting, nausea, diar-rhea, and abdominal cramps werepresent. These observations sug-gest that significant poisoning isunlikely to result from a single,

34 LIFE EXTENSION Collector's Edition 2004

acute ingestion of boric acid.''A report by Pinto et al showed

that boric acid ingestion can induceurinary losses of vitamin B2(riboflavin)." Patients taking boronsupplements may wish to also con-sider B vitamin supplementation.Gordon et al reported a case of twoinfants using pacifiers dipped in ahoney-borax solution over a periodof several weeks in 1973. Theseinfants had findings of hair loss,anemia, and seizures. All signs andsymptoms disappeared after dis-continuation of the borax andhoney preparation."'

The critical effects of boron inseveral species involve male repro-ductive toxicity and developmentaltoxicity. Testicular effects occurredat approximately 26 milligrams ofboron equivalents per kilogram ofbody weight per day. Data onendocrine toxicity include alteredfollicle stimulating hormone andtestosterone levels within 14 daysof treatment.'' It is important toemphasize that the doses thatcause these effects are far higherthan the levels to which the humanpopulation could be exposed.Humans would need to consumedaily approximately 3.3 grams ofboric acid (or 5.0 grams of borax)to ingest the same dose level as thelowest animal NOAEL. No effectson fertility were seen in a popula-tion of workers exposed to boratesor to a population exposed to highenvironmental borate levels.^"Therefore, the likelihood of borontoxicity caused by boric acid andinorganic borates is remote.

CONCLUSIONS ONBORON'S ROLE INHEALTHAND DISEASE

Boron, the fifth element in theperiodic table of elements, has anumber of important functions that

are worthy of intense clinical atten-tion. Boron is an integrativeclement supporting the functionsof calcium, magnesium, and vita-min D. Boron enhances bone andjoint integrity and brain function.The results of a recent studyindicate that boron is the most sig-nificant element in the preventionof prostate cancer. This findingcomplements an exciting basicresearch study showing that boron,an inhibitor of serine proteasessuch as PSA, lowered PSA andprostate cancer volume significant-ly. This simple and relatively inex-pensive element deserves a majorfocus of funding in the world ofresearch and clinical medicine. I

Stephen B. Strum, MD has been aboard-certified medical oncologistsince ]975. In 2000 he became thefirs! medical direclor of the ProstateCancer Research Institute in LosAngeles. Dr. Stnim has publishedwidely about prostate cancer as wellas other areas to optimize outcomesfor those with cancer.

GLOSSARY

ACRONYM: A word formed fromthe initial letters of a name, such asBNCT for Boron Neutron CaptureTherapy.ADJUNCT: Something added toanother for embellishment or com-pletion.ADJUVANT: An additional therapythat is added to a primary treat-ment to increase or aid its effect.Adjuvant therapy is usually givenonce the primary therapy is com-pleted, e.g., radiation therapy afterprimary surgery. Neoadjuvant ther-apy indicates that the additivetherapy is given prior to the so-calledprimary therapy. For example,neoadjuvant androgen deprivationtherapy is often used prior to radi-ation therapy.

COCKEREL: A young rooster.KILOGRAM (kg): A unit of massequaling one thousand grams or 2.2pounds.MICROGRAM (meg or mg): A unitof mass equaling one millionth of agram.MICRON: A unit of length equal toone millionth of a meter or approx-imately 1/25,000 of an inch.MILLIGRAM (mg): A unit of massequaling one thousandth of a gram.NOAEL: No-Observed-Adverse-Effect Level. This is an acronymused to categorize toxicity ofvarious drugs, vitamins, and sup-plements.PROTEOLYTIC: Having the abilityto break down proteins by enzymeactions.QUARTILE: The value of theboundary at the 25th, 50th, or 75thpercentiles of a frequency distribu-tion; this is divided into four parts,each containing a quarter of thepopulation. In a class of 100 stu-dents, those 25 students with thehighest grades are in the upperquartile of the class, while the 25with the lowest grades are in thelowest quartile.

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