Magnesium: its role in nutrition and carcinogenesis

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* Corresponding author:8UV]XOD%áDV]F]\N'HSDUWPHQWRI)HUPHQWDWLRQ7HFKQRORJ\DQG7HFKQLFDO0LFURELRORJ\ $JULFXOWXUDO8QLYHUVLW\LQ.UDNRZ%DOLFNDVWUHHW.UDNRZ3RODQGSKRQHID[ HPDLOXEODV]F]\N#XUNUDNRZSO &RS\ULJKWE\WKH1DWLRQDO,QVWLWXWHRI3XEOLF+HDOWK1DWLRQDO,QVWLWXWHRI+\JLHQH

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8UV]XOD%áDV]F]\N $OHNVDQGUD'XGD&KRGDN 'HSDUWPHQWRI)HUPHQWDWLRQ7HFKQRORJ\DQG7HFKQLFDO0LFURELRORJ\ $JULFXOWXUDO8QLYHUVLW\LQ.UDNRZ3RODQG $%675$&7 Magnesium (Mg_{SOD\VDNH\UROHLQPDQ\HVVHQWLDOFHOOXODUSURFHVVHVVXFKDVLQWHUPHGLDU\PHWDEROLVP'1$UHSOLFDWLRQ} DQGUHSDLUWUDQVSRUWLQJSRWDVVLXPDQGFDOFLXPLRQVFHOOSUROLIHUDWLRQWRJHWKHUZLWKVLJQDOOLQJWUDQVGXFWLRQ'LHWDU\VRXUFHV ULFKLQPDJQHVLXPDUHZKROHDQGXQUHILQHGJUDLQVVHHGVFRFRDQXWVDOPRQGVDQGJUHHQOHDI\YHJHWDEOHV+DUGZDWHULV also considered to be an important source of magnesium beneficial to human health. The daily dietary intake of magnesium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dietary intake of magnesium may also significantly affect the development and exacerbation of ADHD (Attention Deficit-Hyperactivity Disorder) symptoms in children. The known links between magnesium and carcinogenesis still remain unclear DQGFRPSOH[ZLWKFRQIOLFWLQJUHVXOWVEHLQJUHSRUWHGIURPPDQ\H[SHULPHQWDOHSLGHPLRORJLFDODQGFOLQLFDOVWXGLHVIXUWKHU knowledge is thus required. Mg_{ions are enzyme cofactors involved in DNA repair mechanisms that maintain genomic}

stability and fidelity. Any magnesium deficiencies could thereby cause a dysfunction of these systems to occur leading to DNA mutations. Magnesium deficiency may also be associated with inflammation and increased levels of free radicals where both inflammatory mediators and free radicals so arising could cause oxidative DNA damage and therefore tumour formation. The presented review article now provides a summary discussion of the various research performed concern-LQJWKHLPSDFWWKDWORZPDJQHVLXPLQWDNHKDVRQWXPRXULQFLGHQFHWKLVLQFOXGHVLPSDLUPHQWRIPDJQHVLXPKRPHRVWDVLV IUHTXHQWO\REVHUYHGLQWXPRXUFHOOVWKHLQIOXHQFHRIPDJQHVLXPGHSOHWLRQRQWKHSURJUHVVLRQRIH[LVWLQJWXPRXUVDQGWKH occurrence of hypo-magnesaemia when patients are treated with certain anticancer drugs.

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The Mg ion is vital to many cellular processes >@$IWHUSRWDVVLXP0J_{is the second most prevalent} cation in the intracellular fluid and the fourth most com-PRQLQWKHKXPDQERG\LHDIWHUFDOFLXPSRWDVVLXP and sodium). Its importance in regulating large number RIELRFKHPLFDOUHDFWLRQVKDVEHHQORQJHVWDEOLVKHG> @ 0DJQHVLXP DFWLYDWHV PDQ\ HQ]\PHV FUXFLDOO\ among which are those that perform hydrolysis and SKRVSKDWHJURXSWUDQVIHU>@$73K\GURO\VLVWR$'3LV the most significant catalytic role of magnesium in cell HQHUJ\PHWDEROLVP>@0J_{LVFRPSOH[HGZLWK$73} $'3DQG*73QHFHVVDU\IRUWKHDFWLYLW\RIHQ]\PHV involved in phosphate group transfer such as glucoki-QDVH SKRVSKRIUXFWRNLglucoki-QDVH SKRVSKRJO\FHUDWH NLQDVH DQGS\UXYDWHNLQDVH>@,QIDFWDOOUHDFWLRQVLQYROYLQJ ATP require the presence of MgLRQV>@7KLVLRQ also plays an important role in the synthesis of nucleic DFLGVDQGSURWHLQV>@DQGLVYLWDOIRUPDLQWDLQLQJ JHQRPLF VWDELOLW\ WKURXJK HQVXULQJ WKH ILGHOLW\ RI DNA replication and repair processes. More than half of the magnesium found in the cell nucleus is closely DVVRFLDWHGZLWKQXFOHLFDFLGVDQGIUHHQXFOHRWLGHV>@ and it is observed that DNA molecules adopt a more packed structure in the presence of Mg,QDGGLWLRQ magnesium has a critical role in modulating cell cycle SURJUHVVLRQFHOOSUROLIHUDWLRQGLIIHUHQWLDWLRQDQGDSRS-WRVLV>@)XUWKHUPRUH0J_{cations frequently} modu-ODWHLRQWUDQVSRUWE\SXPSVFDUULHUVDQGLRQFKDQQHOV In this manner Mg may thus be a modulator of signal transduction and cytosolic concentrations of electrolytes such as CaDQG.>@

The adult human body contains approximately ±JRIPDJQHVLXP>@RIZKLFKDURXQG± LVPLQHUDOLVHGLQERQHVZKHUHDV±LVIRXQGLQ PXVFOHVDQGVRIWWLVVXH>@2QO\RIPDJQHVLXPLV SUHVHQWLQEORRGSODVPDDQGHU\WKURF\WHV>@ZKHUHWKH latter contain three times more than the former. About RI PDJQHVLXP LV IUHH DQG WKH UHVW EHLQJ ERXQGPDLQO\WRQXFOHLFDFLGV$73QHJDWLYHO\FKDUJHG phospholipids and proteins. The highest magnesium concentrations were found in microsomes containing ULERVRPHVHQGRSODVPLFUHWLFXOXPPLWRFKRQGULDDQG QXFOHL>@

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,WZRXOGDSSHDUWKDWPLQHUDOPDOQXWULWLRQLQFOXGLQJ PDJQHVLXP GHILFLHQF\ LV QRZDGD\V TXLWH FRPPRQ the daily intake of magnesium in most industrialised countries is insufficient and does not meet the current recommended daily allowance (RDA). The effects of magnesium deficiency become especially acute when GHPDQGLQFUHDVHVIRUH[DPSOHGXULQJSUHJQDQF\ODFWD-WLRQH[SHQGHGHIIRUWRUDULVHRIERG\JURZWK,Q3RODQG the recommended RDA for dietary magnesium is at least PJIRUDGXOWQRQSUHJQDQWZRPHQDQGPJIRU DGXOWPHQWKHDYHUDJHDGXOW5'$LQZHVWHUQVRFLHWLHV EHLQJDERXWPJ>@7KHDFWXDOPDJQHVLXPUHTX-irement depends on levels of general activity (metabolic GHPDQGW\SHRIZRUNOLIHVW\OHDQGSRVVLEOHGLVHDVH 'LHWDU\ VRXUFHV ULFK LQ PDJQHVLXP DUH FRFRD QXWVDOPRQGVZKROHVHHGVXQJURXQGJUDLQVOHJXPHV DQG JUHHQ OHDI\ YHJHWDEOHV >@ 7KH JUHHQ SDUWV RI plants are particularly rich in magnesium because it constitutes the prosthetic ion in chlorophyll. Another VRXUFHLVFRQVLGHUHGWREHKDUGZDWHUZKLFKKDVEHHQ shown to benefit human health in some parts of the ZRUOG>@)RUH[DPSOHVRPHKDUGZDWHUFDQSURYLGH XSWRPJRIPDJQHVLXPGDLO\0RUHRYHULQDUHDV ZKHUHWKHUHLVKLJKFRQVXPSWLRQRIKDUGZDWHUWKHVH PLJKWDFWXDOO\VXSSO\WKH5'$RIPDJQHVLXP>@$ study by 0DGHMHWDO>@VKRZHGWKDWWKHFRQWULEXWLRQ RIGULQNLQJZDWHUWRPDJQHVLXPLQWDNHZDVORZ amongst the elderly from the Warsaw region. Another VWXG\GHPRQVWUDWHGWKDWWDSZDWHUXVHGE\ZRPHQIRU SUHSDULQJ EHYHUDJHV DQGRU PHDOV FRQWULEXWHG WRWKHWRWDOPDJQHVLXPGLHWDU\LQWDNH>@$VXUYH\RI \HDUVROGVWXGHQWVIURP:DUVDZXQLYHUVLWLHVGH-monstrated that magnesium intake from bottled waters ZDVDERXWRIWKH5'$>@

The bioavailability of magnesium depends largely RQWKHIRUPRIWKHIRRGVWXII,QIUHVKXQSURFHVVHGIUXLWV DQGYHJHWDEOHVRULQXQUHILQHGZKROHJUDLQVPDJQHVLXP is present at much higher concentrations compared WRSURFHVVHGIRRG,QWKHODWWHUPDJQHVLXPLVJUHDWO\ reduced through procedural losses during production and thus little becomes absorbed by the human body. Another reason for lower magnesium intake through foodstuffs could be that the essential nutrient content LQVRLOLVGHSOHWHG>@,QDGGLWLRQWKHPLQHUDOFRQWHQW (including magnesium) in the edible parts of plants are usually lower in the new high-yielding varieties of QRZRWZRURZ\FKZSá\ZXQLHGRERUXPDJQH]XQDSURJUHVMĊLVWQLHMąF\FKQRZRWZRUyZRUD]Z\VWĊSRZDQLDKLSRPDJQH]HPLL w trakcie leczenia pacjentów niektórymi lekami przeciwnowotworowymi.

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cereals and some vegetables than their established co-XQWHUSDUWV0RGHUQFXOWLYDUVZLWKUDSLGUDWHVRIJURZWK DQGKLJK\LHOGRIWKHHGLEOHSDUWVDUHJHQHWLFDOO\XQDEOH WRDFKLHYHKLJKFRQFHQWUDWLRQVRIPLQHUDOVWKLVEHLQJ GHVFULEHGDVDJHQHWLFGLOXWLRQHIIHFW>@,WLVDOVR seen that agricultural and food production techniques often lead to reduced magnesium levels in vegetables and meat. The preference for high-calorie foods that DUH PLFURQXWULHQW SRRU IUHTXHQWO\ FRQWULEXWHV WR WKH QHJDWLYHEDODQFHRIPDJQHVLXP%HVLGHVPDJQHVLXP deficiency may be the result of several adverse nutri-WLRQDOKDELWVWKHPRVWLPSRUWDQWEHLQJ

'ULQNLQJFRIIHHDQGVWURQJWHDHVSHFLDOO\LQODUJH DPRXQWVOHDGLQJWRLQFUHDVHGPDJQHVLXPH[FUHWLRQ • An excessive fat intake from foodstuffs with a high

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• A rapid or/and prolonged period of losing weight i.e. adopting a low-protein and high fibre diet can decrease intestinal magnesium absorption for those WU\LQJWRORVHZHLJKW

• Excessive drinking of alcoholic beverages that both interfere with absorption and increase the excretion/ UHPRYDORIPDJQHVLXP

• Consuming too much food containing phosphates ZKLFKDUHDEOHWRELQGPDJQHVLXP

• Eating a high-calcium diet or taking calcium sup- SOHPHQWVRYHUORQJSHULRGVFDOFLXPUHGXFLQJPD-gnesium absorption. MaSOHPHQWVRYHUORQJSHULRGVFDOFLXPUHGXFLQJPD-gnesium is however well absorbed if the amount of calcium in foods is twice WKHOHYHORIPDJQHVLXP>@

A negative magnesium balance also occurs in indi-YLGXDOVH[SRVHGWRFKURQLFVWUHVVSHRSOHZLWKLQFUHDVHG urinary losses (through magnesium wasting genetic disorders) and patients treated with certain medicines VXFKDVGLXUHWLFVDPLQRJO\FRVLGHDQWLELRWLFVRUVHGD-WLYHVDQGF\WRVWDWLFGUXJV>@

The Mg_{ion is quite difficult to assimilate. On} DYHUDJHRQO\RIWKHVXSSOLHGHOHPHQWLVDEVRUEHG RIZKLFKRFFXUVE\SDVVLYHGLIIXVLRQ,QFDVHVRIVL-JQLILFDQWPDJQHVLXPGHILFLHQF\RIPDJQHVLXP available from foodstuffs can be absorbed. Magnesium absorption is improved when this element is supplied in the form of small doses i.e. spread over several meals. In KXPDQVPDJQHVLXPDEVRUSWLRQUDQJHVIURPDERXW for diets containing a small amounts of magnesium to IRUWKRVHZLWKKLJKPDJQHVLXP>@0DJQHVLXP is better absorbed as a food component than in the form of oral magnesium supplements. The assimilation of PDJQHVLXP LV IDFLOLWDWHG E\ DQ DFLGLF HQYLURQPHQW GLHWVULFKLQDQLPDOSURWHLQVXQVDWXUDWHGIDWVYLWDPLQ %YLWDPLQ'VRGLXPODFWRVHDQGVHFUHWLRQRILQVXOLQ DQGSDUDWK\URLGKRUPRQH>@&RQYHUVHO\WKHELRDYD-ilability of magnesium from foodstuffs is reduced by the

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Mg are absorbed mainly in the ileum and jejunum >@7KLVSURFHVVRIDEVRUSWLRQLVWKHVXPRIWZRPH-chanisms: one of them being passive diffusion and the other is facilitated diffusion. The latter process depends on the metabolic energy supply and the concentration of Mg ions. Magnesium absorption occurs in parallel with water absorption and is dependent on the extent of Mg_{LRQGLVVRFLDWLRQ>@}

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High amounts of magnesium are especially required for cells from metabolically intensive working organs VXFKDVEUDLQKHDUWDQGPXVFOH7KHQRUPDOIXQFWLRQRI these organs are thus particularly sensitive to any ma-JQHVLXPGHILFLHQF\DVWURQJOLNHOLKRRGRIWKLVDULVLQJ is indicated by observing the following symptoms: per-PDQHQWZHDNQHVVIDWLJDELOLW\LPSDLUHGFRQFHQWUDWLRQ DQGDWWHQWLRQLQFUHDVHGVWUHVVVXVFHSWLELOLW\WUHPEOLQJ DQGWLQJOLQJRIWKHKDQGVFDOIPXVFOHFUDPSVWUHPEOLQJ H\HOLGVPHQWDODQGSK\VLFDOK\SHUDFWLYLW\UHVWOHVVQHVV DQ[LHW\DQGLUULWDELOLW\LUUHJXODUKHDUWEHDWKHDUWSDOSL-WDWLRQVKHDGDFKHV>@

A magnesium deficit is more pronounced in older LQGLYLGXDOVZKHQJDVWURLQWHVWLQDODQGUHQDOPHFKDQL-sms for magnesium conservation invariably become LQHIILFLHQW,WLVDOVRIRXQGWKDWFKLOGUHQDWKOHWHVSHRSOH who physically work hard or people living in very hot climates (i.e. loss of magnesium through sweat) are particularly vulnerable to magnesium deficiencies.

It is believed that magnesium depletion plays an LPSRUWDQW UROH LQ WKH DHWLRORJ\ RI PDQ\ GLVRUGHUV VXFKDVFDUGLRYDVFXODUGLVHDVHWKURPERVLVDWKHURVF-OHURVLVLVFKHPLFKHDUWGLVHDVHP\RFDUGLDOLQIDUFWLRQ K\SHUWHQVLRQDUUK\WKPLDVDQGFRQJHVWLYHKHDUWIDLOXUH LQKXPDQGLDEHWHVPHOOLWXVGLVHDVHVRIWKHJDVWURLQ-WHVWLQDO WUDFW OLYHU FLUUKRVLV WK\URLG DQG SDUDWK\URLG GLVHDVH>@7KHUHLVDOVRDFRUUHODWLRQEHWZHHQDFKURQLF deficiency of certain minerals and the occurrence of ADHD. Insufficient dietary intake of magnesium may significantly affect the development of and in enlarging WKHV\PSWRPVRI$'+'LQFKLOGUHQ>@

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The role of magnesium in cancer formation is complex. Numerous studies have focused on the effect RIPDJQHVLXPGHILFLHQF\RQWXPRXULQFLGHQFHZKHUH an unbalanced magnesium homeostasis is frequently observed in tumour cells and that either magnesium

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deficiency or supplementation can affect the progression of existing tumours.

It has been found that magnesium could impact car-FLQRJHQHVLVE\WZRPHFKDQLVPV>@([SHULPHQWDODQG clinical data have suggested that magnesium deficiency might be associated with inflammation and/or increased levels of free radicals. Magnesium-deficient animals show an increased susceptibility to LQ YLYR oxidative stress and their tissues are more susceptible to LQYLWUR SHUR[LGDWLRQ >@ %RWK LQIODPPDWRU\ PHGLDWRUV DQG free radicals might lead to oxidative DNA damage and WKHUHE\FDQFHUIRUPDWLRQ>@

Magnesium is also known to stabilise the structure of nucleic acids and is a vital co-factor of enzymes LQYROYHGLQ'1$UHSOLFDWLRQUHSDLUDQGJHQHH[SUHV-VLRQ>@'1$UHSDLUPHFKDQLVPVDUHUHVSRQVLEOHIRU PDLQWHQDQFHRIJHQRPLFVWDELOLW\DQGILGHOLW\WKXVDQ\ magnesium deficiency may contribute to defects in these systems and the appearance of DNA mutations. Accumulation of genomic alterations may thereby lead WRWXPRXUJHQHVLV>@

Some studies have demonstrated that magnesium homeostasis is impaired in neoplastic cells in which the cation is accumulated in tumours which behave as magnesium traps. Neoplastic cells show extremely high affinities for magnesium even when cultured at ORZ PDJQHVLXP FRQFHQWUDWLRQ >@ 7KH WHQGHQF\ RI neoplastic cells to accumulate magnesium could be related to abnormal sodium-dependent magnesium extrusion. Another reason may be the over-expression RIWUDQVLHQWUHFHSWRUSRWHQWLDOPHODVWDWLQ7530>@ 7KLV7530LVDQXELTXLWRXVO\H[SUHVVHGLRQFKDQQHO that plays a central role in magnesium homeostasis as ZHOODVLQPDJQHVLXPXSWDNHPHFKDQLVPV>@

)XUWKHUPRUH VHUXP PDJQHVLXP FRQFHQWUDWLRQV were frequently found to be decreased in patients with VROLGQHRSODVLDVLQGHSHQGHQWRIWKHUDS\ZLWKWKHGH-crease being correlated with the stage of malignancy >@7KHVHUHVXOWVVXJJHVWWKDWLQQHRSODVWLFGLVHDVH WKHPDJQHVLXPUHTXLUHPHQWLVLQFUHDVHGQRWRQO\LQ WXPRXU WLVVXH EXW DOVR LQ HU\WKURF\WHV7KH LQFUHDVH in erythrocyte magnesium content may be related to YDULRXVFKDQJHVLQWKHHU\WKURF\WHPHPEUDQHIDFLOL-tating intracellular magnesium transport to the tumour. The concomitant decrease in serum magnesium may therefore be due to enhanced uptake of magnesium by erythrocytes from the extracellular pool. Such altera-WLRQVLQPDJQHVLXPGLVWULEXWLRQPD\E\WKHVHPHDQV play an important role in neoplastic development and JHQHWLFLQVWDELOLW\>@

Low magnesium levels limit endothelial cells proli-IHUDWLRQPLJUDWLRQDQGGLIIHUHQWLDWLRQLQYLWUR>@7KLV ILQGLQJLVVXSSRUWHGE\RWKHUVWXGLHVZKHUHIRULQVWDQFH LQFDVHVRIPDJQHVLXPGHSOHWLRQPLFHZLWK/HZLV lung

FDUFLQRPDGHYHORSOHVVYDVFXODULVHGWXPRXUV>@$QR-ther study on mice with xenografted solid tumours (/H

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or C38 colon adenocarcinoma) showed that mice with nutritionally-induced magnesium deficiency exhibit significant growth reduction of primary solid tumours compared to magnesium-sufficient controls. According WRWKHDXWKRUVDORZPDJQHVLXPFRQWHQWUHGXFHVWKH number of cells engaged in the S phase of the cell cycle >@,WLVVXJJHVWHGWKDWPDJQHVLXPGHILFLHQF\LQKLELWV WXPRXUFHOOSUROLIHUDWLRQDQGQHRDQJLRJHQHVLV>@

There is also convincing evidence from other animal studies that magnesium could exert a protective effect LQWKHHDUO\VWDJHVRIFDUFLQRJHQHVLV>@0DJQHVLXP LQKLELWVOHDGDQGQLFNHOLQGXFHGOXQJWXPRXUVLQPLFH nickel-induced carcinogenesis in the rat kidney and 3-methylcholantrene-induced fibro-sarcomas in rats >@,WKDVDOVREHHQUHSRUWHGWKDWPDJQHVLXP supplementation reduces the incidence of experimental-ly induced colon cancer in animals which might be rela-ted to a decrease of colonic epithelial cell proliferation >@2WKHUVWXGLHVGHPRQVWUDWHWKDWDGLHWSRRULQ magnesium increases the incidences of thymic tumours DQG OHXNDHPLDV > @$QLPDOV ZLWK QXWULWLRQDOO\--induced magnesium deficiency showed an increased vulnerability LQYLYR to oxidative stress and their tissues were more susceptible to LQYLWUR peroxidation. Increased UDGLFDOUHODWHGGDPDJHRIQXFOHLFDFLGVSURWHLQVDQG lipids may thus lead to many cellular perturbations and GHYHORSPHQWRIFDQFHU>@

Magnesium appears to be protective at the early stages RIFDUFLQRJHQHVLVKRZHYHULWSURPRWHVWKHJURZWKRI H[LVWLQJWXPRXUVDWODWHUVWDJHV>@0DJQHVLXPGHILFLHQF\ VHHPVWRIDYRXULQYDVLRQDQGPHWDVWDWLFFRORQLVDWLRQ>@

The availability of magnesium may affect metasta-tisation in two ways. It seems that a low magnesium content stimulates the first stage of angiogenesis by synthesis of vascular endothelial growth factor (VEGF) and formation of a pro-inflammatory environment. In FRQWUDVW GHFUHDVHG PDJQHVLXP DYDLODELOLW\ LQKLELWV WKHVHFRQGVWHSRIDQJLRJHQHVLVERWKHQGRWKHOLDOFHOO SUROLIHUDWLRQDQGPLJUDWLRQ>@

Magnesium deficiency has thus been proposed as a risk factor for some type of human cancer. Several epidemiological studies have demonstrated that a ma-gnesium-rich diet may reduce the occurrence of colon FDQFHU>@$QRWKHUVWXG\UHYHDOHGQRFRUUH-ODWLRQEHWZHHQGLHWDU\LQWDNHRIPDJQHVLXPSRWDVVLXP VRGLXP FDOFLXP SKRVSKRUXV LURQ RU ZDWHUVROXEOH YLWDPLQVZLWKEODGGHUFDQFHUULVN>@7KHUHVXOWVRID case-control study demonstrated a correlation between low dietary magnesium and increased risk of lung FDQFHU>@7KHREVHUYHGHIIHFWZDVPRUHSURQRXQFHG DPRQJVWWKHHOGHUO\FXUUHQWVPRNHUVGULQNHUVDQGWKRVH ZLWKDODWHVWDJHGLVHDVH,QFRQWUDVWDSURVSHFWLYHVWXG\ KDVQRWVXSSRUWHGWKHVHHDUOLHUILQGLQJV>@DQGLQIDFW

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VKRZHGQRVLJQLILFDQWDVVRFLDWLRQVEHWZHHQWRWDO&D 0J)H&X6HDQG=QLQWDNHVDQGOXQJFDQFHUULVN Minerals supplementation also did not affect lung cancer ULVN 3DUDGR[LFDOO\ LW ZDV REVHUYHG WKDW PDJQHVLXP intake may increase lung cancer risk. This discrepancy may be due to difficulties in correctly evaluating dietary composition and the fact that smoking is a very strong ULVNIDFWRUIRUOXQJFDQFHU>@

Several studies have investigated the possible re-lationship between magnesium availability in drinking water and a risk of some type of cancers. An epide-miological study demonstrated that drinking water rich LQ PDJQHVLXP UHGXFHG WKH ULVN RI OLYHU FDQFHU >@ nevertheless the regional vs. global nature of this link was not determined nor were its possible biochemical mechanisms explored. As a probable explanation of WKHVHUHVXOWVWKHHIIHFWRIDOFRKROZDVFRQVLGHUHGDV alcohol consumption both harms the liver and reduces PDJQHVLXPFRQFHQWUDWLRQVLQWKHERG\>@$QRWKHU study suggested a significant protective effect of magne-sium intake from drinking water on the risk of ovarian FDQFHUPRUWDOLW\>@VLPLODUILQGLQJVEHLQJREVHUYHGIRU SURVWDWHFDQFHU>@$GHFUHDVHGULVNRIRHVRSKDJHDO cancer was demonstrated in a case-control study when PDJQHVLXPOHYHOVLQGULQNLQJZDWHUZHUHHOHYDWHG>@ 0RUHRYHU D VLJQLILFDQW LQYHUVH UHODWLRQVKLS EHWZHHQ calcium and magnesium concentrations in water with WKHRFFXUUHQFHRIEUHDVWFDQFHUKDVEHHQUHSRUWHG>@ &RQYHUVHO\ D VXEVHTXHQW VWXG\ VKRZHG QR FRUUHOD-tion between magnesium levels in water and colonic FDQFHU>@ZKLFKLQWXUQFRQWUDGLFWWKHUHVXOWVIURP prospective studies that show a diet rich in magnesium UHGXFLQJWKHRFFXUUHQFHRIFRORQLFFDQFHU>@ One study has found that there is a strong inverse rela-tionship between water hardness and pancreatic cancer ULVN>@KRZHYHUDQRWKHUVWXG\GLGQRWGHPRQVWUDWH any significant relationships between dietary intake of magnesium or iron with the risk of contracting pancre-DWLFFDQFHULQPHQ>@2QO\DPRGHUDWHO\ORZULVN associated with total magnesium intake was observed amongst overweight individuals. These observations ZHUHVLPLODUWRDIXUWKHUVWXG\ZKLFKUHSRUWHGDVWURQJ association between dietary magnesium intake and colo-UHFWDOFDQFHUDPRQJVWWKRVHZKRZHUHRYHUZHLJKW>@

A matched case-control study investigated the re-lationship between nitrate exposure in drinking water DQGWKHULVNRIGHDWKIURPUHFWDOFDQFHU>@ZKHUHOH-vels of magnesium or calcium in drinking water were tested to see if they could change the effect of nitrates RQ UHFWDO FDQFHU ULVN UHVXOWV KRZHYHU LQGLFDWHG WKDW magnesium had no effect on the correlation between nitrate exposure and higher risk of rectal cancer. In con-WUDVWDQRWKHUVWXG\GHPRQVWUDWHGDVLJQLILFDQWWUHQGLQ an increased risk of colon cancer mortality with raised QLWUDWHOHYHOVLQGULQNLQJZDWHUZKHUHPDJQHVLXPZDV

VHHQWRLQIOXHQFHWKLVUHODWLRQVKLS>@1LWUDWHH[SRVXUH in drinking water was found not to be associated with a higher mortality risk from brain cancer and magnesium intake via drinking water did not modify this particular UHODWLRQVKLS>@

The link between trihalomethanes (TTHM) levels in public water supplies and the risk of pancreatic FDQFHU KDV EHHQ DOVR LQYHVWLJDWHG >@ +HUH LW ZDV shown that magnesium in drinking water influenced the correlation between TTHM exposure and pancreatic FDQFHUULVN,QDQRWKHUVWXG\PDJQHVLXPPRGLILHGWKH effects of TTHM exposure on the risk of developing UHFWDOFDQFHU>@

It has been suggested that a high serum Ca : Mg ratio might be a risk factor for postmenopausal breast cancer >@7KHPHWDEROLVPRIPDJQHVLXPLVFORVHO\OLQNHG with that of calcium and the biochemical antagonism EHWZHHQERWKLRQVPDNHVLWLPSRUWDQWWRWUHDWWRJHWKHU WKHSULQFLSDODVSHFWVRIWKLVFRPSHWLWLYHEHKDYLRXU>@ Magnesium and calcium ions control an important and diverse range of cellular processes. Magnesium levels directly affect transient receptor potential melastatin 7 (TRPM7) related to Ca influx besides calcium–adeno-sine triphosphatase (Ca–ATP) levels. An imbalance of &D0JLQWDNHPD\LPSDLU'1$UHSDLUFHOOSUROLIHUDWLRQ and differentiation. These disturbances could so lead to FDQFHUIRUPDWLRQ>@

+\SRPDJQHVDHPLDLVREVHUYHGLQFKHPRWKHUDS\ especially in the treatment of tumours with cisplatin or when used in combination with 5-fluorouracil as well LQUDGLRWKHUDS\>@&LVSODWLQLVNQRZQWRFDXVH renal tubular damage thus impairing magnesium conse-rvation which lead to the clinical syndromes of magne-VLXPGHILFLHQF\>@6RPHVWXGLHVKRZHYHULQGLFDWH that magnesium supplementation during chemotherapy with cisplatin/paclitaxel in patients with ovarian cancer provides renal protection with no apparent reduction of DQWLWXPRXU HIIHFWV >@ +\SRPDJQHVDHPLD ZDV DOVR observed during treatments with the anti-epidermal growth factor receptor (EGFR) antibody (cetuximab) >@&HWX[LPDEFDXVHVDUHYHUVLEOHLQKLELWLRQRI magnesium reabsorption in the renal distal convoluted WXEXOH>@'HVSLWHWKLVLWLVQRWFOHDUZKHWKHURU not supplementation should be used on patients with hypo-magnesaemia. Some authors have also suggested that hypo-magnesaemia may be beneficial in cancer therapy by sensitising neoplastic cells to chemotherapy RUUDGLRWKHUDS\WUHDWPHQWV>@

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Dietary factors are considered to account for appro-[LPDWHO\RIFDQFHUPRUWDOLW\LQWKH:HVWHUQ:RUOG >@$IWHUWREDFFRGLHWLVWKHVHFRQGSUHYHQWDEOHFDXVH

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RI FDQFHU 0DJQHVLXP LV DQ HVVHQWLDO PLFURQXWULHQW which vitally impacts on numerous enzymatic processes in the cell and more attention should be paid for having an adequate content of this element in diet.

Magnesium deficiencies tend to increase tumour incidence in animals and humans where this element af-IHFWVWXPRXUJURZWKDQJLRJHQHVLVDQGPHWDVWDWLVDWLRQ +RZHYHUGHVSLWHGHFDGHVRIFOLQLFDODQGHSLGHPLRORJL-FDOLQYHVWLJDWLRQPRUHSUHFLVHNQRZOHGJHRQLWVUROHLQ carcinogenesis is still lacking or is inconsistent. More studies should be undertaken to elucidate the contribu-tion that magnesium makes on the different stages of tumour formation and development.

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1. $QDVWDVVRSRXORX-7KHRSKDQLGHV T.: Magnesium–DNA interactions and the possible relation of magnesium to carcinogenesis. Irradiation and free radicals. Crit Rev 2QFRO+HPDWRO

 $QJKLOHUL/0DJQHVLXPFDOFLXPDQGFDQFHU0DJQHV 5HV±55.

3. %HUQDUGLQL ' 1DVXOHZLF] $ 0D]XU $ 0DLHU -$.: Magnesium and microvascular endothelial cells: a role in inflammation and angiogenesis. )URQW %LRVFL ±

 %RGQDU/:FLVOR**DVRZVND%RGQDU$6\QRZLHF $6]DUOHM:FLVáR.6]F]\OLN&.: Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: A randomised phase II study. (XU-&DQFHU-

5. %RLV36DQGERUQ(%0HVVLHU3(.: A study of thymic lymphosarcoma developing in magnesium-deficient rats. &DQFHU5HV

 &DVWLJOLRQL60DLHU-$0.: Magnesium and cancer: a GDQJHURXVOLDVRQ0DJQHV5HV66 7. &KDNUDERUWL 6 &KDNUDERUWL 7 0DQGDO 0 0DQGDO

$'DV6*KRVK6.: Protective role of magnesium in FDUGLRYDVFXODU GLVHDVH$ UHYLHZ 0RO &HOO %LRFKHP 2002;

8. &KDQJ&&&KHQ&&:X'&<DQJ&<: Nitrate in drinking water and the risk of death from rectal cancer: 'RHVKDUGQHVVLQGULQNLQJZDWHUPDWWHU"-7R[LFRO(Q-YLURQ+HDOWK$

9 &KLX+)&KDQJ&&<DQJ&< Magnesium and cal-cium in drinking water and risk of death from ovarian cancer. Magnes Res 2004;-

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11 &KLX+)7VDL66:X71<DQJ&< Effect modifi-cation of the association between trihalomethanes and pancreatic cancer by drinking water hardness: Evidence IURPDQHFRORJLFDOVWXG\(QYLURQ5HV  &RKHQ/.LW]HV5 Early radiation induced proctosig-moiditis responds to magnesium therapy. Magnesium

13 'DYLV' Declining fruit and vegetable nutrient composi-tion: what is the evidence? +RUW6FLHQFH-19.  'HOYD3: Magnesium and coronary heart disease. Mol

Aspects Med 2003;-78.

15. 'ROO 5 3HWR 5 The causes of cancer: quantitative HVWLPDWHVRIDYRLGDEOHULVNVRIFDQFHULQWKH86WRGD\- 1DWO&DQFHU,QVW-

16 'U\ZLHĔ 0 ( 1DGROQD $ Assessment of mineral bottled water as a sources of selected minerals among students. 5RF]3DQVWZ=DNO+LJLQ Polish).

17 (YDQV75+DUSHU&/%HYHULGJH,*:DVWQDJH5 0DQVL-/ A randomised study to determine whether routine intravenous magnesium supplements are nec-essary in patients receiving cisplatin chemotherapy ZLWK FRQWLQXRXV LQIXVLRQ IOXRURXUDFLO (XU - &DQFHU $

18 )ROVRP$5+RQJ&3 Magnesium intake and reduced risk of colon cancer in a prospective study of women. $P-(SLGHPLRO

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 .DVSU]DN.6'LZDQ%$5LFH-0 Iron accelerates while magnesium inhibits nickel-induced carcinogenesis in the rat kidney. 7R[LFRORJ\

 .HVDYDQ<*LRYDQQXFFL()XFKV&60LFKDXG'6 A prospective study of magnesium and iron intake and pan-FUHDWLFFDQFHULQPHQ$P-(SLGHPLRO  .RQLNRZVND.5HJXOVND,ORZ%5yĪDĔVND'The

in-fluence of components of diet on the symptoms of ADHD in children. 5RF]3DQVWZ=DNO+LJ  .XR+:&KHQ36+R6&:DQJ/<<DQJ&<

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drinking water and status biomarkers of these minerals among elder people from Warsaw region. Rocz Panstw =DNO+LJLQ3ROLVK

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33. 0DKDELU6:HL4%DUUHUD6/'RQJ<4(W]HO&- 6SLW]05)RUPDQ05 Dietary magnesium and DNA repair capacity as risk factors for lung cancer. Carcino-JHQHVLV

 0DLHU-$01DVXOHZLF]*ROGHPDQ$6LPRQDFFL0 %RQLQVHJQD $ 0D]XU $ :ROI ), Insights into the mechanisms involved in magnesium-dependent inhibi-WLRQRISULPDU\WXPRUJURZWK1XWU&DQFHU 198.

35 0LFKDXG '6 6SLHJHOPDQ ' &OLQWRQ 6. 5LPP (% :LOOHWW :& *LRYDQQXFFL ( Prospective study RIGLHWDU\VXSSOHPHQWVPDFURQXWULHQWVPLFURQXWULHQWV DQGULVNRIEODGGHUFDQFHULQ86PHQ$P-(SLGHPLRO 36 0XDOOHP60RH2::KHQ(*)LVRIIVLGHPDJQHVLXP LVZDVWHG-&OLQ,QYHVW 37 1DVXOHZLF]$:LHWU]\N-:ROI),']LPLUD60DGHM -0DLHU-$05D\VVLJXLHU<0D]XU$2SROVNL$.: Magnesium deficiency inhibits primary tumor growth EXW IDYRUV PHWDVWDVLV LQ PLFH %LRFKLP %LRSK\V$FWD

38 3DVWHUQDN . .RFRW - +RUHFND $ %LRFKHPLVWU\ of PDJQHVLXP-(OHPHQWRO2010;

39 3DWLUR÷OX7ùDKLQ*.RQWDú2h]P.6DUD\PHQ5 Protective effect of magnesium supplementation on ex-perimental 3-methyl cholantrene-induced fibrosarcoma and changes in tissue magnesium distribution during FDUFLQRJHQHVLVLQUDWV%LRO7UDFH(OHP5HV 185.

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53 :DQJ$<RVKLPL17DQDND70RUL+ Inhibitory effects of magnesium hydroxide on c-myc expression and cell proliferation induced by methylazoxymethanol acetate LQUDWFRORQ&DQFHU/HWW

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57 <DQJ&<&KLX+)&KHQJ0)+VX7<&KHQJ0) :X71 Calcium and magnesium in drinking water and WKHULVNRIGHDWKIURPEUHDVWFDQFHU-7R[LFRO(QYLURQ +HDOWK$

58 <DQJ&<&KLX+)&KHQJ0)7VDL66+XQJ&) 7VHQJ<7 Pancreatic cancer mortality and total hard-QHVVOHYHOVLQ7DLZDQ¶VGULQNLQJZDWHU-7R[LFRO(QYLURQ +HDOWK$

59 <DQJ &< &KLX +) &KLX -) 7VDL 66 &KHQJ 0) Calcium and magnesium in drinking water and risk of death IURPFRORQFDQFHU-SQ-&DQFHU5HV1997;  <DQJ&<&KLX+)7VDL66&KHQJ0)/LQ0&

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61 <DQJ&<&KLX+)7VDL66:X71&KDQJ&& Mag-nesium and calcium in drinking water and the risk of death from esophageal cancer. Magnes Res 2002;  <DR;3DQLFKSLVDO..XUW]PDQ11XJHQW. Cisplatin

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