Selenium Biochemistry and Cancer: A Review of the … Biochemistry and Cancer: A...Selenium Biochemistry and Cancer: A Review of the Literature ... postgraduate Certification Course

Selenium and Cancer

Selenium Biochemistry and Cancer:A Review of the Literature

Lyn Patrick, ND

AbstractIn recent years, the role of selenium in theprevention of a number of degenerativeconditions including cancer, inflammatorydiseases, thyroid function, cardiovasculardisease, neurological diseases, aging,infertility, and infections, has been establishedby laboratory experiments, clinical trials, andepidemiological data. Most of the effects inthese conditions are related to the function ofselenium in antioxidant enzyme systems.Replenishing selenium in deficiency conditionsappears to have immune-stimulating effects,particularly in patients undergoingchemotherapy. However, increasing the levelsof selenoprotein antioxidant enzymes(glutathione peroxidase, thioredoxin reductase,etc.) appears to be only one of many ways inwhich selenium-based metabolites contributeto normal cellular growth and function. Animaldata, epidemiological data, and interventiontrials have shown a clear role for seleniumcompounds in both prevention of specificcancers and antitumorigenic effects in post-initiation phases of cancer.i/\ltern Med Rev 2004;9(3):239-258)

IntroductionSelenium's unique role in human physi-

ology has been found to include the prevention ofatherosclerosis, specific cancers, arthritis, diseasesof accelerated aging, central nervous system pa-thologies, male infenility. and altered immuno-logical function.' Selenium is active in a varietyof selenoproteins that include, but are not limitedto, the glutathione reductases.- Other.selenoproteins have roles that support immune

function and. through specific cellular pathways,may play a preventive role in both the initiationand promotion of specific cancers.'

Human Selenium BiochemistryAt least 25 selenoproteins have been iden-

tified in human biochemistry. The functions ofselenium are believed to be carried out byselenoproteins. in which selenium is specificallyincorporated as the amino acid selenocysteine.- Inaddition to incorporation as selenocysteine, sele-nium can replace sulfur in methionine. formingselenomethionine. This compound can be incor-porated non-specifically into proteins in place ofmethionine. Finally, selenium can be tightly boundby certain proteins, known as .selenium-bindingproteins, to distinguish them from trueselenoproteins.-

The first true selenoprotein identified wasglutathione peroxidase. which catalyzes the oxi-dation of reduced glutathione and allows for thereduetion of hydrogen peroxide to water, prevent-ing lipid peroxidation and eellular damage.^ Thereare basically five forms of glutathione peroxidase(GPx) that have been identified in human tissue:classical GPx (found only in the cell cytosol). gas-trointestinal GPx {found in the liver and gas-trointestinal tract), plasma glutathiotie peroxidase.phospholipid-hydroperoxide GPx (PHGPx). andsperm nuclei GPx.

Lyn Patrick, ND - Bastyr University graduate1984; privatepractice Durango. CO. specializing in HIV intection,environmental medicine and hepatitis C; faculty of thepostgraduate Certification Course in EnvironmentalMedicine at the Southwest College of NaturopathicMedicine; Contributing Editor, Alternative Medicine Review.Physician-member of the Hepatitis C Ambassadors Team.Correspondence address: 2530 Colorado Ave. Suite 2C,Durango. CO 81301Email: [email protected]

Alternative Medicine Review • Volume 9, Number 3 • 2004 Page 239

Selenium and Cancer

Table I. Seienium-containing Enzymes'-

Selenoenzyme

Glutathione peroxidase (GSHPx)

Gastrointestinal GSHPx

Location

plasma, thyroid

GI tract

Glutathione peroxidase (classic)

Phospholipid hydroperoxide glutathione peroxidase (PHGPx)

cytosol

cell membrane

Sperm nuclei glutathione peroxidase

Thioredoxin reductase

Selenoprotein P

sperm nuclei

tissues, skin, thyroid

blood, thyroid

Type I iodothyronine deiodinase

Type II iodothyronine deiodinase

liver, kidneys, thyroid

Phospholipid-hydroperoxide GPx isfound in cell nuclei, mitochondria, and ihe cyto-sol. and specifically acts to prevent lipidperoxidation in cell membranes. This is a uniquefunction of this antioxidant enzyme, as most anti-oxidant enzymes cannot reduce phospholipid hy-droperoxides inside cell membranes." This particu-lar form of GPx is found in high concentrations inspermatozoa, and is involved in sperm maturationand the prevention of cellular apoptosis. The ejacu-late of infertile men contain.s significantly loweramounts of PHGPx compared to men with nor-mal sperm counts and motility indexes.''As a cla.ssof enzymes, the PHGPx regulate eico.sanoid pro-duction and cell signaling hy reactive oxygen spe-cies. GPx levels in the blood and liver are respon-.sive to early dietary selenium deficiency: whereas,the phospholipid-rich tissue membranes that eon-tain PHGPx appear to be less affeeted by mildselenium deficiency.'̂

Selenoproiein P. the majority of the sele-nium found in the bloodstream, also acts as anantioxidant enzyme and a selenium-transporterand appears to be very sensitive to dietary sele-nium.'

brain

Thioredoxin reductase. anotherselenoenzyme that acts as an antioxidant. is foundin all tissues. As a major component of the anti-oxidant system, thioredoxin reduetase is respon-sible for degrading peroxides and hydroperoxidesoutside cell membranes. Peroxides and hydroper-oxides have been shown to cause cell death. DNAdamage, and tissue atrophy.'̂ Thioredoxin redue-tase also reeyeles lipoic acid and vitamin C. regu-lates the metabolism of vitamin K3. and acts toregulate cell growth and the activity of tumor-sup-pressing protein p53.''This selenocy.steine-encod-ing enzyme exists in large concentrations inkeratinocytes and melanocytes. where it is be-lieved to provide the initial line of defense againstultraviolet light-generated free radical damage.'"Thioredoxin reductase is responsive to increasedlevels of selenium in the cellular environment.Adding selenium at a low I microM concentra-tion, a level easily achievable in humans by supple-mentation, increases the antioxidant activity ofthioredoxin reductase by 40-tbld in epithelial celllines." Table I summarizes the selenium-eontain-ing enzymes.

Page 240 Alternative Medicine Review • Volume 9, Number 3 • 2004

Selenium and Cancer

Generalbody proteins

Selenomethionine

Selenocysteine

SeleniumBioavailability

Selenium is storedin the tissues in varying den-sity: 30 percent of tissue se-lenium is in the liver. 15 per-cent in the kidney. 30 per-cent in muscle, lOpereentinthe plasma, and the remain-ing 15 percent throughoutother organs." Because se-lenium binds to mercury andis deposited in tissue in aninert complex with a 1:1molar ratio, this selenium-mercury complex is unavail-able for metabolism. Whenfree non-mercury-bound se-lenium is determined in spe-cific tissues, tissue concen-trations are greatest in thekidney cortex and pituitarygland, followed by the thy-roid gland, liver, spleen, andeerebral eortex,'^

There is no homeo-static control meehanism forselenium absoiption and se-lenium is highly absorbable.Selenium occurs naturally inplants as selenomethionine. Se-methyl-selenomethionine. selenocysteine. andselenocystine.''^ Selenite (commercially availableas sodium selenite) is greater than 80-percentbioavailable and selenomethionine or selenate canbe greater than 90-percent bioavailabie.''^ Ab.sorp-tion from food is also efficient and adult humanexposure to selenium via diet ranges in differentparts of the world from 11-5.000 meg/day. Aver-age dietary intake usually falls within the rangeof 20-300 meg/day.'" This range is broad enoughto create a differenee between normal tissue glu-tathione peroxidase and subnormal levels. Sele-nium deficits, correlated with serum selenium con-centrations less than H5-90 mcg/L. are commonin parts of China where juvenile cardiomyopathy

Figure I. Selenium Metabolism-

Selenoproteins(as selenocysteine)

Selenite

GS-Se-SG

Selenophosphate

(Hydrogen selenide)

GS+SeH

(Methylselenide)

Dimethylselenide

1

breath

(Trimethylselenonium ion) • -

From: Ip C. Lessons from basic research in selenium and cancer prevention.JA/ufr1998;128:1845-1854.

(Keshan disease) and ehondrodystrophy (Kasehin-Beek disea.se) result from selenium deficiency.'În the United States, however, most soils are sele-nium replete, and whereas low serum seleniumlevels of I ! -20 mcg/l. in parts of China are com-mon, serum levels in South Dakota and Marylandhave been reported to be as high as 133-197 meg/

Metabolism of SeleniumCompounds

Selenomethionine is the major organicseleno-compound in cereal grains, grassland le-gumes, and soybeans, as well as in selenium-en-riched yeast used for selenium supplementation.'"In several animal studies measuring the distribu-


Selenium and Cancer

tion of .supplemental selenium, tissue storage ofselenium was shown to be higher withselenomethionine cotnpared to selenocysteine.selenate, and selenite. Selenomethionine is gen-erally thought to be the tiiost bioavailable form ofselenium.' Selenomethionine. however, may sub-stitute in tissue proteins for methionine, and chang-ing the methionine content of the diet will alterhow tnuch selenotnethionine is used to satisfymethionine requirements.--''

Selenoproteins can be produced in thebody from a variety of selenium sources (FigureI).-'' Selenomethionine competes with methion-ine for absorption on the gut surface, and is incor-porated and stored in body proteins that containmethionine. It may also be converted throughtransulfuration to seienocysteine and degraded tohydrogen selenide via the beta-lyase enzyme. Se-lenite is also metabolized to hydrogen selenide viaa pathway in which it is complexed with glu-tathione. Hydrogen selenide acts as a precursorfor selenoprotein synthesis and is also the form ofselenium excreted; it is methylated and excretedthrough urine and breath. This is why one of thesymptoms of selenium toxicity is referred to as'•garlic breath" - the odor of dimethylselenideexcreted through the lungs.- Mote than 90 per-cent of animal chcmoprevention studies have usedeither sodium selenite or selenomethionine as thetest agent.-

Selenium ToxicityThe U.S. Environmental Protection

Agency (EPA) limit for seleniutn based on pro-jected lifetime exposure is 5 mcg/kg body weight/day. The low adverse effect level (LOAEL). thelowest level of selenium at which any adverse ef-fect may be seen in humans, has been calculatedat 1540 ± 653 tiicg/day. The no adverse effect level(NOAEL). the level at which no adverse effectswill be expected, has been calculated at 819 ± 126mcg/day."

Combs, however, reports that human se-lenium toxicity states seen in China require dailyintakes on the order of 2 tng daily.'^ No evidenceof selenium toxicity was seen in the NutritionalPrevention of Cancer Trial at doses of 400 meg

selenium daily in 424 persons for 1.220 personyears of observation. None of the seven people inthe selenium group who withdrew from the studycomplained of symptoms of sclenosis {changes inhair, nails, or skin, or garlic breath).'^

A further trial of selenium in biopsy-proven prostate cancer in which patients wererandomized to 1.600 or 3.200 meg/day selenizedyeast for 12 months did not report any selenium-related toxicity signs or symptoms.•'''

Selenoproteins and the ThyroidGland

Although there is inconsistent data con-cerning the role of low selenium levels in thyroidcancer, the role of selenium in thyroid metabo-lism is complex, and an understanding ofselenium's free-radical protective effects ate cru-cial to understanding the role selenium may playin thyroid cancers.

The human thyroid gland contains one ofthe highest selenium contents of any tissue in thebody.-"* Selenium is present in thyrocytes and fol-licular tissue in the fortii of glutathione peroxi-dase, selenoprotein P. and thioredoxin. Abundantamounts of extracellular glutathione peroxidascare present in thyroid tissue to act as an antioxi-dant defense system against significant amountsof hydiogen peroxide resulting from thyroid hor-mone ptoduction.-" Glutathione peroxidasc in thy-roid tissue also controls thyroglobulin iodination.Type I iodothyronine deiodinase. a selenium en-zyme that tequires selenocysteine. catalyzes theconversion of thyroxine (T4) to triiodothyronine(T3) in the Hver.-̂ and type II iodothyroninedeiodinase catalyzes the same reaction in thebrain.-'' These enzymes are not found in thyroidtissue in large amounts, but have effects on circu-lating thyroid hormone levels due to their role inT3 production.-' The deiodinase selenoenzymcsalso catalyze the breakdown of T4 to reverse T3.degrade T4 to T2, inactivate T3. and regulate thepituitary-hypothalamic-thyroid axis.-^

Thyroid metabolism is sensitive to theselenium content in the diet. Significantdepressions in T3/T4 ratios have been observedin elderly subjects on low-selenium diets.-''


Selenium and Cancer

A depression in selenoenzyme activity, withsubsequent lowering of T3/T4 ratios, has also beendocumented in a population previously receivingselenium-rich wheat from Canada and switchedto selenium-poor grain from Europe.'~" In areas ofChina where both soil selenium and iodine differsignificantly depending on the region, inhabitantswith subclinical hyperthyroidism had lower levelsof serum selenium (S2.6 mcg/L) compared tocontrols (87.3 mcg/L).^' Normal controls alsodemonstrated an inverse relationship between TSHand serum selenium: when serum levels werebelow 80 mcg/L. TSH levels were correlated at2.1 mU/L. significantly higher than in those withserum selenium above 80 mcg/L whodemonstrated median TSH levels of 1.28-1.29 mU/L. Serum selenium was also inversely correlatedwith thyroid autoantibody levels. Those witbthyroperoxidase antibody (TPO Ab) levels > 600lU/mL had a mean serum selenium of 83.6 lU/L,while those with TPO Ab levels lower than 600had mean serum selenium levels between 92.9 and9.*i.6 mcg/L."

Selenium Replacement inHypothyroidism

Selenium replacement studies in hypothy-roidism have focused on areas of the world whereboth selenium and iodine deficiencies are endemic.Studies using 50 meg selenium daily in goiter-endemic areas in Zaire have resulted in signifi-cant improvement of symptoms, while serum lev-els of T4 and reverse T3 dropped to normal range,serum total T3 improved, and serum TSH levelsstayed within normal ranges.'- Because of the in-teraction of iodine and selenium in thyroid me-tabolism, and the fact that iodine replacement in-creases oxidative metabolism in thyroid tissue, itis recommended that in situations where both se-lenium and iodine are deficient, replacement ofboth minerals is necessary for the normalizationof thyroid function."

The results of rat studies have led to theassumption that selenium supplementation inhumans will invariably lead to increased serumT3 levels. Human studies, however, show that maynot always be the case.^' Short-term effects of

selenium supplementation on thyroid functionreveal a more complex picture of thyroid/selenoprotein interactions. Studies of iodine-replete men given either dally doses of 300 megselenium from high-selenium foods or kept on aselenium-deficient diet of 14 meg daily haveshown responses that illustrate the unique effectof selenium on human thyroid metabolism.-'* After99 days, the high selenium group had a significantdrop in serum total T3 levels and a compensatoryincrease in TSH levels. The low-selenium grouphad a rise in serum total T3 levels. Becauseselenium can be stored in thyroid tissue, even in astate of selenium deficiency, it is not clear if thelow-selenium diet had a direct effect on thyroidtissue levels of selenoproteins or whetherdeiodinase enzyme levels were affected. Thisstudy is important because it indicates seleniumsupplementation is more complex than has beenpresumed, and longer trials will indicate whetherthese alterations in hormone levels with seleniumsupplementation are temporary or long-term.

Selenium and Thyroid CancersStudios of selenium tissue levels in thy-

roid tumors are not consistent. One study of tis-sue samples from 135 patients found a slightlylower level of selenium in both benign and malig-nant tumors compared to normal tissue, but alsofound significantelevationsof silver, cobalt, mer-cury, and rubidium in both benign and malignantthyroid tissue compared to normal tissue.'^

Another study sampled 43 persons whodeveloped thyroid cancer an average of 4.8 yearsafter blood samples were taken."^ Compared tomatched controls, cases were significantly lowerin serum selenium than controls. Those with can-cer who had serum levels less than or equal to1.25 microM/L had a 7.7-times greater risk forthyroid cancer compared to controls. Those withhigher levels of serum selenium - 1.26-1.64microM/L - had a 6.1-times greater chance ofhaving thyroid cancer. Levels greater than or equalto 1.65 microM/L were associated with no in-creased risk of thyroid cancer.


Selenium and Cancer Review

Other studies, however, have failed to findlinks between selenium and thyroid carcinogen-esis. A study investigating tissue selenium foundno difference in selenium, tissue selenoenzymelevels, tumor levels of selenium, glutathione per-oxidase, or other seienoproteins compared to thosein normal thyroid tissue.'^

On the other hand, low selenium levelsand lower selenoenzyme activity levels have beendocumented in parathyroid adenoma tissue and C-cell carcinoma tissue - medullary thyroid carci-noma - when compared to goiter, autoimmunedisease, or differentiated thyroid cancer.'** Meanzinc and selenium levels in thyroid tissue of pa-tients with thyroid carcinoma were found to besignificantly lower than that of patients with non-cancerous thyroid disorders.''' The ratios of cop-per/zinc, copper/selenium, and /inc/selenium weresignificantly higher in those w ith thyroid carcino-mas than controls or those with other thyroid dis-orders.

Epidemiological Studies of Seleniumand Cancer Risk

Erythrocyte. serum, plusma, and urineselenium levels have been found to be lower in avariety of cancer diagnoses compared to bothmatched and unmatched controls.^" ^̂ The major-ity of epidemiological studies also provide evi-dence for selenium as a chemopreventive agentfor specific cancers: prostate."'"'"*'' *̂colorectal.'"'' stomach.'̂ - and multiplecaThe study of plasma selenium and non-melanomaskin cancers that led to the Nutritional Preventionof Cancer Trial, a 10-year prospective study of1.738 Americans detailed below, found initialplasma selenium levels inversely con-elated to bothnon-melanoma skin cancer and colonicadenomatous polyps.̂ ^ Those with plasma levelsbelow the U.S. population median of 128 ng/mLplasma were four times more likely to have oneor more polyps than those with levels above 128ng/mL.

In a prospective study of 39.268 men andwomen in Finland, risk for several cancers wassignificantly elevated in men who had the lowest

level of serum selenium-for cancers of the stom-ach, pancreas, and lung specifically.'" The meanlevels of serum selenium found in those who de-veloped cancer - 53-63 mcg/L - would be con-sidered low in the United States.'^

A prospective study of 4.857 Japanesepatients followed serum selenium levels in thosewho developed cancers of all types over a 36-month period.̂ ^ Those who developed cancer dur-ing the trial period had significantly lower serumselenium levels at baseline than those who werecancer free. Studies in China's Qidong Provincedemonstrated a significant inverse associationbetween the incidence of primary hepatocellularcarcinoma and plasma selenium levels.^'' In aneight-year retrospective trial in WashingtonCounty. Maryland, those with low plasma sele-nium had a two-fold increased risk for bladdercancer.''" A U.S. study of 11.000 hypertensivesfollowed for five years showed a two-fold increasein risk for all cancers in those in the lowest (< 115ng/mL) quintile compared to those in the highestquintile (> 154 ng/mL) of plasma selenium."*-

A meta-analysis of large prospective stud-ies has shown a consistent relationship betweenlow prediagnostic levels of senim selenium in can-cer patients compared to cancer-free controls.'''The meta-analysis examined nine studies that as-sessed prediagnostic levels of antioxidants and 10specific types of cancer. The levels of serum sele-nium in those who developed cancer of the stom-ach, pancreas, lung, and bladder were significantlylower than controls. The difference was most pro-nounced for pancreatic cancer.

Several studies have demonstrated no pro-tective association between selenium and cancerlisk.''-*'̂ Some studies that found no relationshipbetween selenium and cancer risk used toenailselenium as a marker for selenium intake."" Thismethod of assessing dietary selenium exposure andassuming toenail selenium as a reflection of tis-sue stores has been questioned by Schrauzer''"*when there is insufficient difference amongquintiles of toenail selenium, raising concernsabout toenail selenium being an imprecise tool indetermining selenium status.


Selenium and Cancer

The NutritionalPrevention ofCancer Trial

In 1985. Clarkpublished geographicaldata on the selenium con-tent of food crops by U.S.county, showing an inverseassociation of total cancertnortality with local forageplant selenium levels.'''^''''An inverse a.s.sociation wasfound with the incidence oflung, rectal, bladder,esophageal. and cervicalcancer in rural counties,and lung, breast, rectal,bladder, esophageal. anduterine cancers in all coun-ties. Clark also publisheddata showing that in case-control studies in NorthCarolina, those with squa-nuuis cell carcinoma orbasal cell epithclioma hadsignificantly lower plasmaselenium levels compared to controls/'' When com-pared to cancer-free controls, those with the lowestlevels of plasma selenium were .'S.H times more likelyto have either cancer.

These data encouraged a study of the effectsof selenium supplementation in cancer preventionand led to the now well-known Nutritional Preven-tion of Caticer Trial (NPCTrial)."^The NPCTrial isthe only prospective double-blind, placebo-con-trolled, randomi/ed trial in the Western world (o testa selenium supplement on a large population andmeasure eancer incidence.

The study originally attempted to assess theability of selenized yeast containing 200 meg ofelemental selenium to pievent recurrences of non-melanoma skin cancer in 1.312 residents of thesoutheastern United States, where soil seleniumlevels are the lowest in the nation. Because ofunexpected results, the ti iai was unblinded early; i.e..selenium suppletnentation significantly decreased thetotal cancer ineidence by 50 percent, and specifically

Figure 2, Plastna Levels of Selenium on Entry in NPC Trial^

100 140 180plasma Se, ng/mL

220

From: Combs GF. Impact of selenium and cancer prevention findings on thenutrition-health paradigm. Nutr Cancer 2001 ;40;6-11.

dropped the incidence of lung eaneer by 48percent, prostate cancer by 63 percent, andcolorectal cancer by 58 percent.''" Analysis of moreextended data from the original trial found theprotective effect of selenium, although stillimpressive, deereased to a statistically significant25-percent reduction in total cancer incidence, a42-pereent reduction in prostate cancer incidence,and a 51-percent reduction in total eancermortality. In this follow-up report the decrease inlung eaneer incidence was no longer statistieallysignificant, while a 54-percent reduction incolorectal cancer incidence was marginallysignificant (p=O.O57).̂ " Because 75 percent of thetrial group was male, the effects were confined tomales and were most prominent in smokers andthose with baseline plasma selenium levels below121.6 ng/mL. Those who entered the trial withplasma selenium levels less than 106 ng/mLshowed both the greatest protection from seleniumand the highest rates of subsequent cancer in thecontrol group (Figures 2. 3. and 4).'



Figure 3. Ptotectivc Effect of Selenium on Subjects iti NPC Trial in Lowest Tertile of Selenium^

1.2

total cancers

total carcinomas

lung cancer

prostate cancer

colorectal cancer

<106 106-121

baseline plasma Se level ng/mL

From: Combs GF. Impact of selenium and cancer prevention findings on the nutrition-health paradigm.Nutr Cancer 2001 ;40:6-11.

Figure 4. Cancer Incidence in Placebo Group by Baseline Selenium

total cancers

total carcinomas

tung cancer

prostate cancer

colorectal cancer

<106 106-121

baseline plasma Se level ng/mLFrom: Combs GF. Impact of selenium and cancer prevention findings on the nutrition-health paradigm.Nutr Cancer 2001 ;40:6-11.


Selenium and Cancer

Those in the highest tertile of baseline se-lenium - over 121.6 ng/mL - actually had a non-significant increased total cancer incidence anddid not appear to benefit from selenium supple-mentation at 200 meg daily. The breast cancer in-cidence data in this trial demonstrated that the te-male subjects in the study taking selenium actu-ally experienced an increase in the incidence ofbreast cancer, but as authors of the NPC Trial datapoint out. the incidence is not significant and maybe irrelevant due to an inadequate numbers of fe-males7"The same insigniUcant increase was truefor other sites, including melanoma, esophagus,bladder, brain, leukemias. and lympbomas.™ Fi-nally, an evaluation by one of the principal inves-tigators in the NPC Trial reported that, derivedfrom the data. 96-300 meg of elemental seleniumdaily as selenomethionine is indicated for bothadequate antioxidant defense and tumor inhibi-tion.'

The Qidong and Linxian StudiesThe other large clinical intervention tri-

als involved two Chinese provinces where sele-nium deficiency and chronic hepatitis B are en-demic. The first, a trial giving 30-50 meg of dailyelemental selenium from sodium selenite to 20.847inhabitants of Qidong Province, resulted in a sta-tistically significant 5()-percent drop in the inci-dence of primary liver cancer.^' In a subset of thispopulation at high risk for primary liver cancer,2.474 families received 200 meg elemental sele-nium daily from a high-selenium yeast or placebo.At the end of the two-year study, those receivingselenium had a statistically significant 35-percentreduction in the incidence of primary liver can-cer."

In Linxian Province, the mortality fromesophageal caneer is the highest in the world. Anantioxidant intervention trial followed differentgroups taking antioxidant supplements for fiveyears, during whieh time cancer mortality fromstomach and esophageal cancer accounted for 32percent of all caneer deaths in the controlpopulation. In the group supplemented daily withbeta-carotene, vitamin E. and 50 meg elementalselenium from high-selenium yeast, total caneer

mortality was reduced by 13 percent, a statisticallysignificant drop.'- Follow-up data found asignificant inverse association between baselineserum selenium and mortality from esophagealsquamous cell carcinoma and gastric cardiacancer." The effect of selenium in this trial may.in large part, have resulted from the treatment ofselenium deficiency and normalization ofselenoprotein levels, including glutathioneperoxidase. The mean serum seleniumconcentration in the study population was 73 meg/L; deficiency in this study was defined as any levelbelow 78 mcg/L.

Animal Chemoprevention Studies:The Search for Active Metabolitesof Selenium

In the NPC Trial, only six of the 1,312subjects had initial plasma selenium levels below80 ng/mL.'"This is considered the minimum levelof plasma selenium necessary in the bloodstreamfor maximum production of selenoproteins (glu-tathione peroxidases. thioredoxin reductase, etc.).''̂In other words, tbe chemoprevention observed inthe NPC Trial was not the result of increased lev-els of the glutathione peroxidases or otherselenoproteins. This hypothesis, that theantitumorigenic effect of selenium works via path-ways other than selenoprotein pn)duction. has beensupported in more than 100 studies of animalmodels of selenium chemoprevention.'""

Animal studies have consistently showna beneficial effect of high selenium levels in theprevention of cancer.'' Of these studies, the ma-jority have shown a clear antitumorigenic/chemopreventive effect of selenium in mammarygland, liver, skin, pancreas, esophagus, and coloncancers.-' At least half of these studies have showna reduction of tumor yield by more than 50 per-cent with selenium supplementation of 1-2.5 mg/kg in addition to an already selenium-replete diet.*Reviews of these studies have concuired that h igh-level exposure to specific selenium compounds isantitumorigenic.^'' The studies show dose-depen-dent responses at levels ihat do not show toxicity(Table 2). This high level of supplementation.


Selenium and Cancer

however, has not been repli-cated iti human studies as itwould necessitate levels signili-cantly higher than those cur-rently used in human research.

Although the mecha-nisms have not yet been clearlyoutlined, it has been shown inanimal models that selenium in-hibits tumorigenesis duringboth the initiation and laterstages of carcinogenesis. andthat it inhibits both chemicallyand virally induced tumors. Theeffects of selenium appear to bereversible, in that theanticarcinogenic effect is re-versed when selenium is with-drawn." Selenium also alterscarcinogen metabolism, inhib-its tumor cell proliferation, en-hances apoptosis. and suppresses tumor angiogen-esis.-' Supranutritional levels of selenium supple-mentation, exceeding that necessary to make ad-equate levels of glutathione peroxidase. have alsobeen shown to increase the cytotoxic activities ofnatural killer cells and macrophages. and up-regu-late the expression of interleukin-2 receptors.^^This immune-enhancing effect has been demon-strated both in animaP'' and human studies,'̂ " whereeight-week doses of 200 meg yeast-based seleniumin humans significantly increased cytotoxic lym-phocyte and rnacrophage activity.^' Because theantitumorigenic effects of selenium In rodent stud-ies occurred at levels of 100 mcg/kg body weight(average human selenium intake is 1-4 mcg/kgbody weight worldwide), research has focused onthe metabolically active forms of selenium thatwould allow for nontoxic levels of seleniumsupplementation.''''

Antitumorigenic activity has been observedin metabolites ol naturally occurring forms of sele-nium: selenomethionine. selenocysteine.methylselen(x:ysteine. and inorganic selenium salts- selenite and selenate metabolized toselenodiglutathione.'''The selenized yeast used in theNPC Trial contained only 20-percent

Table 2. Antilumorigenic Effect of Different Selenium Compounds

Dose of Selenium for 50%Compound

Se-methylselenocysteine

Selenobetaine

Selenobetaine methyl ester

Selenite

Seienomethionine

Selenocystine

inhibition (ppm)

2

2

2-3

3

4-5

4-5

From: Whanger PD. Selenocompounds in plants and animals andtheir biological significance. J Am Coll Nutr 2002; 21: 223-232.

selenomethionine. The remaining selenocompoundswere selenocysteine. Se-methylselenocystcine.selenoethionine, selenogiutathione. seleno-diglutathione. and selenite.'"*" lp and colleagues'̂ 'compared sodium selenite to selenomethionine anddemonstrated that selenite was more effective in pre-venting chemically induced mammary tumors, eventhough tissue levels of selenium were significantlyhigher in those given selenomethionine. These data,showing the effects of selenium compounds werenot based on tissue levels but on the specific meta-bolic fates of different fomis of selenium, have initi-ated research on selenium metabolites aschemopreventive agents.

Earlier studies found low-molecular weightforms of selenium not used in synthesis ofseienoproteins are instrumental in the metabolismof selenium. These methylated selenium compoundsare found in plants and in the metabolic breakdownof sodium selenide in humans, and were ultimatelyfound to be responsible for the chemopreventiveeffect of selenium (Figure 5).̂ ^ In one study, themethylated selenium compound seleniummethyl selenocysteine was found to be more effectivein suppressing mammary tumors than either seleniteor selenomethionine in the dosage range of I -3


Selenium and Cancer

Figure 5. Methylated Selenium Compounds and their Entry into the Inorganic Selenium Pool

(Hydrogen selenide)

(Se-methylselenocysteine) (Methylselenide) (Selenobetaine)

(Dimetfiyiseienoxide) Dimethylselenide (Selenobetaine methyl ester)

(Trimethylselenonium ion)

From: Ganthar HE, Lawrence JR. Chemical transformations of selenium in living organisms.Improved forms of selenium for cancer prevention. Tetrahedon 1997;53:12299-12310.

Sources of Se-methy!selenocysteineSe-methylselenocysteine occurs naturally

in plants. It is found in high levels in Astragalusand in selenium-enriched garlic, broccoli, leeks,and onions.̂ ''*^̂ Astragalus species may accumu-late 1.000-10,000 meg se!enium/g. 80 percent asSe-methylselenocysteine/** These plants also ac-cumulate selenium as selenopeptides,selenocystathionine. and other selenium com-pounds. There are no or very little measurableamounts of selenium occurring as selenite in theseaccumulator plants.''' Selenium-enriched yeast hasbeen found to contain from six- to 20-percent Se-methylsclenocysteine and 8 5-percentselenomethionine (Table 3).'*''Accumulator plantsproduce methylated forms of selenium as a wayto detoxify inorganic selenate. Methylated formsof selenium, such as Se-methylselenocysteine.have a toxicity equal to selenomethionine. a mini-mally toxic form of selenium.'"'

Selenium and Breast CancerHuman Epidemiological Studies

In four studies, plasma, serum, or eryth-rocyte levels of selenium were found to be sig-nificantly lower in breast cancer cases compared

to healthy controls.'" '"A study of Japanese womenusing toenail selenium revealed a significant dif-ference between the levels in newly diagnosedbreast cancer patients and those of healthywomen.''•" The nail levels in the healthy womencorrelated with an apparent protective effect ofselenium at daily intakes of 200-300 meg. Sele-nium toenail levels in the breast cancer patients,conversely, correlated with a selenium intake ofroughly one-half of this amount, which is closerto the intakes observed in Western industrializedcountries. However, other epidemiological stud-ies show no relationship between toenail seleniumlevels.'""'''' serum selenium levels,''̂ ""* or dietaryselenium'''' and breast cancer risk or incidence.

The well-publici/ed trial of 62.641women in the Nurses' Health Study also showedno protective effect of selenium on breast cancer.''̂This study involved assessing selenium intake asreflected in toenail clippings and found a relativerisk for breast cancer of 1.1 tor those in the lowestquintile of selenium and no trends for increasingprotection across rising quintiles of toenail sele-nium levels. Unfortunately, toenail selenium mea-surements in this study were found to be a poormethod of measurin" selenium: the correlation


Selenium and Cancer

Table 3. Variations in Selenocompounds in Various Yeasts

Percentage of Distribution

Sources of Yeast SeCys SEM Other

SUNY-Albany 2.1 62.6 35.2Norwich England 6.6 23.3 70.0Nutrition 21 10.6 16.0 81.5

SeCys and SEM, respectively, indicate selenocysteine andselenomethionine but no SeMCYS was found in any ofthese yeasts.From: Whanger PD. Selenocompounds in plants andanimals and their biological significance. J Am Coll Nutr 2002;21:223-232.

coefficient for two measurements of toenail sele-nium was only 0.48, and the measurement of one.sample of toenail selenium would only accountfor 25 percent of the variability in toenail sele-nium levels."" As eriticized by Clark. lead inves-tigator of the Nutritional Prevention of CancerTrial, the Nurses" Health Study use of toenail se-lenium as a measurement, "suggests the potentialfor considerable miselassitlcation in the exposurevariable that could result in a sub.stantial attenua-tion of the observed relative risk."'"- In otherwords, tbe negative findings of the Nurses' HealthStudy could be a result of using a method of mea-suring selenium that does not correlate with sub-sequent measurements or selenium intake, andwould result in inadequate data on selenium andbreast cancer risk.

Breast Cancer Animal StudiesThe mammary gland has been the most

studied of all the organs in whieh tumorigenesisis affected by selenium/"' Selenium has beenshown to inhibit many different mammary tumormodels: mouse virus-induced mammary tumors,chemical carcinogen-induced mammary tumors,and spontaneous mammary tumors in the mouse.The research of Medina and colleajiues'"* found

that Se-methylseienocysteine,selenobetaine. and a garlic-basedform. Se-allylselenoeysteine. are themost efficacious forms of selenium inmammary tumor prevention in animalmodels. For an in-depth review of se-lenium and mechanisms of action inmammary tumor chemoprevention seeMedina et al.""

Methylselenocysteine. a me-tabolite of selenomethionine, is twiceas active as selenomethionine at sup-pressing mammary tumors in rodentsat 2 meg Se/g diet."" Adding sele-nium-enriched garlic at the dosage of3 mcg/g diet reduced mammary tumorincidence in rodents from 83 percentto 33 percent, while plain garlic alonereduced the incidence to 60 percent.Se-allylselenocysteine was also effec-

tive at reducing tumor yield, indicating the natu-rally occurring form of selenium found in garlicmay also be part of a chemoprevention strategy.*'Both Se-methyl selenocysteine and Se-allylselenocysteine have no toxicity. low bodyaccumulation, and greater in vivo efficacy, as op-posed to selenite or selenate.-''"'

One animal study, however, did show se-lenium supplementation (4 mcg/mL drinking wa-ter) actually increased tlbroadenoma incidence byadenovirus type 9 in rats."" The same studyshowed that the same amount of selenium alsoinhibited the incidence of carcinogen-inducedlarge bowel cancers, while facilitating the inci-dence of carcinogen-induced small bowel cancers.No explanation was given for the differing effectsof selenium in these carcinogenic states.

Selenium and Colon CancerEpidemiologieal Studies of Seleniumin Colorectal Cancer

It is expected that 50 percent of thepopulation in Western countries will develop atleast one colorectal tumor by age 7{).'"' Epidemio-logieal studies have found an inverse associationbetween dietary intake of selenium and colon can-cer risk.''̂ Coioiectal cancer patients were found


Selenium and Cancer

to have significantly lower serutn seleniutn (41.8mcg/mL) and significantly higher set um manga-nese and iron levels compared lo controls.'"*'•'"''Studies of selenium status in patients with stom-ach and colorectal cancer found that both plasmalevels of seieniutn. erythrocyte selenium, andplasma glutathione-peroxidase levels were signifi-cantly lower than healthy subjects.'"** On follow-up in 2002. the Nutiitional Prevention of CancerTrial™ showed a marginally significant preventiveeffect of selenized yeast supplementation on theincidence of colorectal cancer (pÔ.O.'i?). This trialalso included an active colorectal screenitig pro-gratn. Of 1.312 randomized subjects in the trial,599 underwent endoscopic screening for colorectalcaticer duiing the time ot the blinded trial. Thoseon selenium experienced a borderline significantdecrease in risk of incident colorectal polyps.-'

Animal Studies of Selenium inColorectal Cancer

Although there is an epidemiological as-sociation in humans between increased dietaryselenium and decreased incidence of colon can-cer, dietary selenomethionine does not appear tohave a chemopreventive effect in animal studiesof colorectal cancer.'"''

Selenium-ent iched broccoli has been usedas a food source of Se-methylselenocysteine. Astudy using this source of selenium in rodents w ithpreneoplastic colon tumors found it was statisti-cally more effective at teducing premalignantchanges and colon tumor incidence than equiva-lent concentrations of low-selenium broccoli, se-lenite. selenate. or selenomethionine."" Rats fedthe high-selenium broccoli received I mcg/g dietand demonstrated a significant 50-percent reduc-tion in the incidence of two types of preneoplasticlesions (p=O.OI; p=().O2). The selenomethionitie-fed animals had nti reduction in the incidence oftumors and. although the standardselenomethionine. selenate and selenite dietsshowed higher levels of glutathione peroxidase inthe liver, they were not effective at reducing theincidence of colon tumors.

Tbe multiple-intestinal neoplasia mouse,a genetic model lor human intestinal cancer and

familial adenomatous polyposis. has responded intrials to dietary additions of selenium-enrichedbroccoli with significant decreases in both smalland large intestinal tumors.'" The mice were fedhigh-selenium btoccoli, the equivalent of 2.1 megselenium/g food for 10 weeks. The tutnors thatdid occur were significantly smaller, and eventhough there was only a minitnal increase in liverand plasma selenium levels, the increase corre-lates negatively with tumor number.

Selenium and Prostate CancerAn epidetniological, case-control study of

33,737 men followed for six years cotnpared toe-nail selenium levels and incidence of advancedprostate cancer."- When those with the highestlevel of seleniutn were cornpared to those withthe lowest, the former had a 65-percent reducedrisk of getting advanced prostate cancer. The rangeof toenail seleniutn levels was reflective of a largerange of dietary seleniutn intakes and reflected theditferences that would be found in the diets of resi-dents of Boston. Massachusetts (0.74 mcg/g), anarea of low-seleniutn soil content, and South Da-kota (1.17 mcg/g). an area of relatively high-sele-nium soil content."'

A similar study followed 10.456 men forsix years and evaluated those diagno.sed with pros-tate cancer during that period."^ The men who hadplasma selenium levels and plasma alpha- andgamtna-tocopherol levels above the median had a5()-petcent teduced risk of prostate cancer. Thesedata correspond to other work showing a protec-tive effect of selenium and vitamin E against pros-tate cancer."^

The NPC Trial reported a 63-percentlower incidence of prostate cancer in individualstaking selenium and. as a result, there has beenheightened interest in research exploring mecha-nistns for selenium in prostate chemoprevention.''"A foilow-upof the trial, including three additionalyears of treatment (1993-1996), saw the incidenceremain significantly less at 52 percent (p-{).005).^"There ate currently four trials in progress exam-ining the effect of selenomethionine or high-sele-nium baker's yeast on specific populations of pros-tate cancer patietits.""


Selenium and Cancer

The first, the Negative Biopsy Trial, willevaluale 700 men with persistently elevated pros-tatic specific antigen (PSA) and recent negativebiopsy. The hypothesis is that selenium may pre-vent the progression of cancer in the 2,i percent ofmen in this population who have early cancermissed by biopsy. They will be randomized to 200or 400 meg selenium from high-selenium yeast orplacebo for 57 months.

The HGPIN Trial (High-Grade ProstaticIntraepithelial Neoplasia) will evaluate 470 menwith high-grade prostatic intraepithelial neopia-sia who are at risk for subsequent prostate cancer,but have not been treated with snrgery or irradia-tion. If these men are biopsy-negative for cancer,they will be given either placebo or 200 meg sele-nium as selenomethionine and will be followedfor three years. This study will evaluate the abil-ity of selenium to prevent the transformation ofneoplasia to invasive cancer.

The Preprostatectomy Trial will evaluate110 men with prediagnosed. localized pro.statecancer who choose treatment with prostatectomy.Further treatment will consist of either 200 or 400meg selenium from high-selenium yeast or pla-cebo for 6-8 weeks prior to surgery. This trial willevaluate biomarkers of inflammation and tissueselenium levels.

The Watchful Waiting Trial will evaluate264 men with localized cancer and low-grade tu-mors and a life expectancy of less than 10 yearswho have elected not to participate in standardtreatment. Watchful waiting with no treatment isconsidered an acceptable alternative in this popu-lation. They will be given 200 or 800 meg high-selenium yeast or placebo. More information aboutthese and other selenium trials is available at http://clinicaltrials.gov/

In a preliminary irial with a design simi-lar to the Watchful Waiting Trial. 24 men with bi-opsy-proven prostate cancer were given either1.600 or 3.200 meg seieni/.ed yeast for an aver-age of 12 months."^ Although subjects on 3,200meg daily reported side effects, they did not cor-respond to plasma selenium levels and all subjectsin the study had normal blood chemistries for theduration of the study.

Mechanisms of selenium in prostate can-cer have not been fully explained, but there is evi-dence that selenium induces apoptosis in prostatecancer ceils, while having no detrimental effecton normal prostate epithelium. This apoptotic ac-tion may be prevented by arachidonic acid andthe 5-lipoxygena.se products formed from arachi-donic acid metabt)lisni. '"̂ This knowledge maylead to recommendations that high fat diets con-taining arachidonic acid should be avoided in thoseon .selenium-containing protocols for the treatmentof prostate cancer.

Studies of SeleniumSupplementation withChemotherapy

The use of selenium repletion in cancerpatients to normalize selenoprotein levels and actas an immune-augmentive strategy has been stud-ied in several cancer types. One study, using bothzinc and .selenium, was conducted with patientsbeginning chemotherapy for the treatment ofcolorectal carcinoma, gastric adenocarcinoma. oresophageal carcinoma."" All patients had received60 days of chemotherapy and had significantly lowserum selenium and zinc levels at initiation oftreatment. Thirty were given nutritional supple-mentation of 200 meg/day selenium in additionto 21 mg/day zinc during the course of chemo-therapy; 30 controls were given no selenium orzinc. At the end of the chemotherapy course. 70percent of those given the nutritional supplementsshowed no sign of further decline in nutritionalstatus and actually had an improvement in appe-tite and energy level. Their serum selenium andzinc levels rose significantly, although not to thelevel of cancer-free controls (Table 4). Eighty per-cent of those on chemotherapy without the supple-ments, however, had a significant worsening innutritional status (prealbumin. albumin/globulinratio, transferrin. cholesterol, total protein) andsymptoms related to malnutrition.

Selenium supplementation was evaluatedin 62 women diagnosed with ovarian cancer cur-rently undergoing chemotherapy.'-" The patientshad previously undergone surgery and one eycie


Selenium and Cancer

of inlravenoLis therapy withcisplatin and cyclophospha-iiiide. Half were given an an-lioxidant formula daily: 60mg beta-carotene. 8{)() mg vi-lamin C. 144 mg vitamin E.! 8 mg ribotlavin, 180 mg nia-cin. and 200 meg seleniumfrom yeast in divided doses.The remaining 31 patients re-ceived only chemotherapy.While the control group hada consistent decline in sele-nium hair and serum levels

during chemotherapy, thesupplemented group had anincrease in both parameters in addition to an in-crease in erythrocyte glutathione peroxidase lev-els and a significant stabilization of neutrophilcount compared to controls. After two and threemonths, the supplemented group had a significantdecrease of hair loss, flatulence, abdominal pain.weakness, malaise, and anorexia.

Advanced squamous cell carcinoma of thehead and neck is associated with significantiinmunosuppression and has a poor prognosis withsurgery or chemotherapy. Patients with this typeof cancer who had previously received nochemotherapy were given 200 meg sodiumselenite starting on the first day of surgery orradiation treatment and followed for 60 days.'-'Compared to a placebo group with the samestaging who also received radiation or surgicalinterventions, the selenium-supplemented groupdemonstrated a significant increase in immuneactivity: tumor cylolysis by cytotoxiclymphocytes, lymphocyte proliferation, andresponse to phytohemagglutinin. a mitogen thatstimulates T lymphocyte responses. Those whoreceived selenium or placebo, but no treatment,showed no improvement in immune parameters.

Table 4. Serum Zinc and Selenium Levels in ChemotherapyPatients and Controls

0 days 60 days Control

Selenium (ng/dL) 55.7 ± 7.3' 62.4 ± 9.3" 65.0 ± 12.0Zinc (ng/dL) 78.9 ± 7.8* 84.2 ± 5.4"" 87.5 ± 9.70Copper (lag/dL) 110.9 ±16* 101.1 ±12.8" 95.5 ±13.2

• P < 0.01 A vs C; '• P < 0.05 B vs A ; ' " P < 0.02 B vs AFrom: Federico A, lodice P, Federico P, el af. Effects of selenium and zinc supplements onnutritional status in patients with cancerof the digestive tract. EurJC/;n A/ufr2001 ;55:293-297.

ConclusionAdequate selenium is necessary for nor-

mal functioning of the immune system and thy-roid glatid. Selenium deficiency has been associ-ated with thyroid disease and a variety of cancers.In numerous animal studies, selenium has dem-onstrated cytotoxic activity against tumor cells andsignificant immune-enhancing properties. Sele-nium is the basis of several key selenoprotein en-zymes that have antioxidant effects. The doses ofselenium used in animal and humanchemoprevention studies have been greater thandoses necessary for the maximal production ofthese enzymes, and it has been hypothesized theactivity of selenium at these levels is due to otherselenium compounds such as Se-methylselenocysteine. selenobetaine. and Se-allylselenocysteine.Thebenefit of using seleniumin conjunction with chemotherapy or radiationtherapy in specific cancers appears worthy of fur-ther investigation.

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