In . J. Mol. Sci. 2013, 14, 13893-13908; doi:10.3390/ijms140713893
In e na ional Jou nal o
Molecula Sciences
ISSN 1422-0067
www.mdpi.com/jou nal/ijms
Re iew
Sa cosine as a Po en ial P os a e Cance Bioma ke —A Re iew
Na alia Ce nei 1,2, Zbynek Hege 2, Ja omi Gumulec 1,2,3, Ond ej Zi ka 1,2, Michal Masa ik 1,2,3,
Pe Babula 1,2, Tomas Eckschlage 4, Ma ie S ibo o a 5, Rene Kizek 1,2 and Voj ech Adam 1,2,*
1 Cen al Eu opean Ins i u e o Technology, B no Uni e si y o Technology, Technicka 3058/10,
CZ-61600 B no, Czech Republic; E-Mails: [email p o ec ed] (N.C.);
[email p o ec ed] (Z.H.); [email p o ec ed] (J.G.); zi [email protected] (O.Z.);
[email p o ec ed] (M.M.); pe [email protected] (P.B.); [email p o ec ed] (R.K.)
2 Depa men o Chemis y and Biochemis y, Facul y o Ag onomy, Mendel Uni e si y in B no,
Zemedelska 1, CZ-61300 B no, Czech Republic
3 Depa men o Pa hological Physiology, Facul y o Medicine, Masa yk Uni e si y, Kamenice 5,
CZ-61200 B no, Czech Republic
4 Depa men o Paedia ic Haema ology and Oncology, 2nd Facul y o Medicine,
Cha les Uni e si y, and Uni e si y Hospi al Mo ol, V U alu 84, CZ-15006 P ague 5,
Czech Republic; E-Mail: [email p o ec ed]
5 Depa men o Biochemis y, Facul y o Science, Cha les Uni e si y, Albe o 2030,
CZ-12840 P ague 2, Czech Republic; E-Mail: [email p o ec ed]
* Au ho o whom co espondence should be add essed; E-Mail: [email p o ec ed];
Tel.: +420-5-4513-3350; Fax: +420-5-4521-2044.
Recei ed: 22 May 2013; in e ised o m: 20 June 2013 / Accep ed: 22 June 2013 /
Published: 4 July 2013
Abs ac : P os a e cance (CaP) is he mos common ype o umou disease in men.
Ea ly diagnosis o cance o he p os a e is e y impo an , because he soone he cance is
de ec ed, he be e i is ea ed. Acco ding o ha ac , he e is g ea in e es in he
inding o new ma ke s including amino acids, p o eins o nucleic acids. P os a e speci ic
an igen (PSA) is commonly used and is he mos impo an bioma ke o CaP. This ma ke
can only be de ec ed in blood and i s sensi i i y is app oxima ely 80%. Mo eo e , ea ly
s ages canno be diagnosed using his p o ein. Cu en ly, he e does no exis a es o
diagnosis o ea ly s ages o p os a e cance . This ac mo i a es us o ind ma ke s sensi i e
o he ea ly s ages o CaP, which a e easily de ec ed in body luids including u ine. A
po en ial is he e o e a ibu ed o he non-p o ein amino acid sa cosine, which is gene a ed
by glycine-N-me hyl ans e ase in i s biochemical cycle. In his e iew, we summa ize
OPEN ACCESS
In . J. Mol. Sci. 2013, 14 13894
analy ical me hods o quan i ica ion o sa cosine as a CaP ma ke . Mo eo e , pa hways o
he connec ion o syn hesis o sa cosine and CaP de elopmen a e discussed.
Keywo ds: cance o p os a e; bioma ke s; ea ly diagnos ic; p os a ic speci ic an igen;
non-in asi e ma ke s; u ine; amino acids
1. In oduc ion
1.1. His o y
Sa cosine, also known as N-me hylglycine wi h he chemical o mula CH3NHCH2COOH, was
i s ly isola ed and named by Ge man chemis Jus us on Liebig in 1847. I is a non-p o einogenic
amino acid ha occu s as an in e media e p oduc in he syn hesis and deg ada ion o amino acid
glycine [1]. Acco ding o he Web o Knowledge da abase, he e is an inc easing incidence o keywo d
sa cosine as well as an inc easing numbe o ci a ions since 2009. This phenomenon con i ms g owing
in e es in sa cosine as a po en ial ma ke o a p os a e cance . The i s publica ion desc ibing he
ela ionship be ween changes in le el o sa cosine and p og ession o a p os a e cance was published
in Na u e by S eekuma e al. in 2009 [1]. Since hen sa cosine has been in es iga ed as a new ma ke
o p os a e cance by Issaq e al. [2] and has been iden i ied as a me aboli e g ea ly inc easing du ing
p og ession o a p os a e cance and me as a ic p ocess; which can be de ec ed in u ine [3].
1.2. Backg ound
Acco ding o da a desc ibing CaP mo ali y and incidence in US in yea 2013 p os a e cance
exhibi s he highes incidence (238,590 es ima ed new cases) and second highes mo ali y (29,720
es ima ed dea hs) o all cance ypes diagnosed in males [4]. Thanks o mo e de eloped me hods o
diagnosis is imp o ed also he p ognosis o pa ien s wi h CaP. The e o e he ac ha sa cosine does
no occu o occu s in negligible concen a ion in u ine o heal hy pe sons is c i ical o i s e alua ion
o po en ial disease ma ke [1]. This phenomenon educes he isk o alse posi i e and alse nega i e
esul s [5]. The possibili y o use sa cosine as a ma ke o ea ly s ages o de elopmen o p os a e
cance has been discussed in ew pape s [6–8]. Thanks o he applica ion o sa cosine as a umou
ma ke , low cos analy ical me hods o i s de e mina ion in he u ine, issue and blood plasma samples
a e being sea ched and de eloped. Biosyn hesis o sa cosine has been shown o be ce ainly a ec ed
by he cance ogenesis (Figu e 1). This phenomenon was desc ibed by Mukhe jee e al. whose esea ch
e ealed an impo an ole o glycine N-me hyl ans e ase (GNMT) in he me abolism o issues o
p os a e cance [9]. I has been ound ha GNMT is in ol ed in he me abolism o me hionine as well
as in he gluconeogenesis and ans o ma ion o sa cosine o glycine (Figu e 1). Howe e , he ole o
sa cosine in ca cinogenesis has no been ully unde s ood and emains unknown, as indica e he esul s
o he s udy published by Hakimi e al. [10]. Modula ing he unc ion o GNMT can be used o
de elop new s a egies o ea men o p os a e cance . In addi ion, GNMT could se e as a new
umou ma ke o diagnose malignan p og ession o p os a e cance [11]. The mos equen ly used CaP
sc eening ma ke —p os a e speci ic an igen (PSA) is o gan speci ic bu canno speci y he s age and
In . J. Mol. Sci. 2013, 14 13895
he ype o disease, so i s use o p os a e cance sc eening is insu icien [12]. The e o e, nowadays
p os a ic an igen 3 (PCA 3) [13–15] and annexin (A3) [5,16–18] a e he mos widely used and gene ally
accep ed ma ke s o non-in asi e CaP in u ine. The e a e also o he newly discussed po en ial ma ke s
o CaP ha may be use ul in he diagnosis o p og ession o p os a e cance , which can be de ec ed in
u ine, such as alpha-me hylacyl-CoA acemase (AMACR) [19–21], which le el is ele a ed in p os a ic
adenoca cinoma and high-g ade in aepi helial neoplasia. TMPRSS2-ETS usion gene con e sions ha
is e y common and speci ic in al e a ions in he p os a e cance cells. These gene ic al e a ions lead
he o e exp ession o ETS genes encoding he E26 amily o ansc ip ion ac o s in ol ed in cell
p oli e a ion [22]. Ano he used ma ke is he a io o ee o o al PSA— / PSA. I was con i med ha
his bioma ke can be e dis inguish be ween pa ien s wi h p os a e cance om pa ien s wi h a benign
hype plasia o he p os a e [23]. P oPSA— he mos s able sub o m o PSA associa ed wi h cance also
exhibi s po en ial, because se e al s udies sugges ed he clinical use ulness o p oPSA in he de ec ion
o p os a e cance using di e en non-comme cial assays [24,25]. Some high po en ial se um bioma ke s
a e: kallik ein 2, u okinase- ype plasminogen ac i a o /u okinase- ype plasminogen ac i a o ecep o ,
in e leukin-6/in e leukin-6 ecep o , pigmen epi helium-de i ed ac o (PEDF), ib onec in 1,
ch omog anin A ce uloplasmin and o he s [26,27], ne e heless hei clinical u iliza ion and hei ole
in he ac i e su eillance scena io needs o be s udied u he . The aim o his e iew is o desc ibe he
molecula ly-biological aspec s and biochemical pa hways o biosyn hesis o sa cosine and o summa ize
he basic da a abou sui abili y o chosen analy ical echniques o de e mina ion o sa cosine in
a ious ma ixes.
Figu e 1. Scheme o biological unc ions o sa cosine a bo h physiological and non-
physiological condi ions. CaP—p os a e ca cinoma; GNMT—glycine N-me hyl ans e ase;
SARDH—sa cosine dehyd ogenase.
In . J. Mol. Sci. 2013, 14 13896
2. Me hods
A li e a u e sea ch co e ing he opic o he e iew was pe o med in ollowing da abases: Web o
Science (Thomson Reu e s, New Yo k, NY, USA), PubMed (Uni ed S a es Na ional Lib a y o
Medicine, Be hesda, MD, USA) Coch ane Lib a y (Coch ane Collabo a ion, Bal imo e, MD, USA),
and Scopus (Else ie , Ams e dam, Ne he land) as i is shown in Figu e 2. The p esen ed igu e shows
a cou se o he p ocess o he pape s publica ions de o ed o sa cosine. We looked o s udies ela ed o
sa cosine and i s me abolic p ope ies, i s molecula ly-biological p ope ies and possibili ies o i s analysis.
Figu e 2. O e iew o he da abases used o he e alua ion o he pape s ela ed o he
opic o he e iew.
The used keywo ds a e shown in Figu e 2. Keywo d sa cosine in umou issue ga e 77 esul s in
all used da abases. Keywo d sa cosine in u ine e ealed 417 esul s in all da abases and keywo d
In . J. Mol. Sci. 2013, 14 13897
sa cosine in se um p o ided 438 esul s wi hin all he da abases. Duplica ing a icles we e sub ac ed
o each e m om hese coun s. Se en a icles we e sub ac ed o he keywo d sa cosine in umou
issue, 14 a icles o sa cosine in se um and 7 a icles o sa cosine in u ine. The esul ing numbe o
a icles was subjec ed o eadou o a icles ha we e no di ec ly ela ed o he e iew opic.
We wi hd ew 65 a icles ha we e no ela ed o he keywo d sa cosine in umou issue, 393 a icles
o he keywo d sa cosine in se um and 332 a icles o sa cosine in u ine. The esul ing numbe n is
he sum o non- ecu ing a icles in all he da abases ela ed o he sea ched keywo ds. The inal
numbe s we e as ollows: 5 o sa cosine in umou issue, 31 o sa cosine in se um and 78 o
sa cosine in u ine. These numbe s gi e clea e idence o he impo ance o sa cosine as a po en ial
bioma ke , whose possibili y o be de e mined in u ine ep esen s he g ea es po en ial. This ac is
impo an , because u ine is one o he mos accessible and s able body luids o analysis [28].
3. Molecula Biology o Sa cosine
Glycine N-me hyl ans e ase (GNMT) ac s as an essen ial componen ha in luences syn hesis o
sa cosine [29–32]. Syn hesis o GNMT is con olled by he same gene named GNMT. I has ecen ly been
epo ed ha he GNMT gene is loca ed on he sho (p) a m o ch omosome 6 a posi ion 12 (Figu e 3)
and ac s as a umou -suscep ible gene [33]. Acco ding o he s udy by Ianni e al., T allele o he
s9462856 SNP in he p omo e egion o he GNMT gene is o e exp essed in pa ien s su e ing om
CaP and i s o e exp ession signi ican ly inc eases he isk o he disease [34]. Pheno ypic analysis o
h ee GNMT haplo ypes (A, B, and C) indica ed ha haplo ype C had he highes p omo e ac i i y and
haplo ype B had signi ican ly highe ac i i y compa ed o he haplo ype A. The di e ence be ween he
haplo ypes B and C is due o he T allele o SNP1 ha exe s a s ong disequilib ium [35]. The GNMT
gene con ains in TATA-less co e p omo e egion he Sp1 si e and a CCAAT-box [36] ha is one o
he mos ubiqui ous elemen s being p esen in 30% o all euka yo ic p omo e s [37–39]. This egion
ep esen s a binding si e o he ansc ip ional ac o , NF-Y, a ime wi h his one-like subuni s
NF-YB/NF-YC and he sequence-speci ic NF-YA [40,41]. NF-Y is a sequence-speci ic ansc ip ion
ac o wi h nucleosome-like p ope ies in nonspeci ic DNA binding ha helps o es ablish pe missi e
ch oma in modi ica ions a CCAAT p omo e s [38].
The exp ession o he GNMT induced in his manne leads o syn hesis o GNMT ha con ibu es o
he egula ion o he le el o S-adenosylme hionine (SAM) and in luences gene exp ession by
a ec ing he DNA me hyla ion [34]. DNA me hyla ion is an essen ial p ocess in he body. Me hyl
g oups ans e ed by SAM a e used o syn hesize many essen ial compounds including c ea ine and/o
phospha idylcholine. In addi ion, DNA me hyla ion is essen ial o egula ion o gene exp ession [42].
De iciency o dono s o me hyl g oup (e.g., choline and me hionine) o coenzymes o me abolism o
me hyl g oup (e.g., ola e and i amin B12) dis u bs he in acellula le els o S-adenosylme hionine,
igge s he DNA hypome hyla ion, and p omo es cance s o he li e , p os a e, and o he o gans [35,43].
Pa ien s su e ing om CaP ha e been e ealed o show a dec eased me hyla ion o DNA, whe eas
pa ien s posi i e o he GNMT T allele had a lowe le el o me hyla ed DNA han con ols wi h he
same allele [34]. GNMT also binds a numbe o polycyclic a oma ic hyd oca bons and inhibi s he
o ma ion o DNA adduc s [30].

In . J. Mol. Sci. 2013, 14 13898
Figu e 3. S uc u e o human cine-N-me hyl ans e ase (GNMT) gene in connec ion wi h
scheme o sa cosine genesis in biochemical pa hway.
Due o p ope ies o GNMT, i s excessi e p oduc ion causes a clea age o glycine o sa cosine and
ele a ed he p esence o sa cosine in u ine (Figu es 1 and 3). S able e al. epo ed ha inc eased lux
h ough o GNMT esul s in he inc eased o ma ion o homocys eine and sa cosine h ough inc eased
u iliza ion o SAM [44]. This makes sa cosine in e es ing in he ield o non-in asi e cance bioma ke s.
Ele a ed le els o sa cosine co ela ed wi h p og ession o p os a e cance and me as a ic p ocess.
Supplemen a ion o sa cosine o p os a e cance cell lines induced a selec ion o in asi e pheno ype in
cul u e [19]. Dahl e al. epo ed o he i s ime on a signi ican up egula ion o a po en oncop o ein
human epide mal g ow h ac o ecep o 2 (HER2/neu) in and ogen-dependen p os a e cance cells upon
exposu e o exogenous sa cosine. Tha indica es ha sa cosine may be in ol ed in egula ion o HER2/neu.
Howe e , in o ma ion abou hese cellula mechanisms will be needed o de ailed cla i ica ion [45].
4. Me abolism o Sa cosine
Me aboli es play essen ial ole in an unde s anding he biological eac ions and he eby he changes
in hei le els con ibu e o he de elopmen o new diagnos ic and he apeu ic me hods o diagnose
speci ic diseases [46,47]. Biochemical pa hways o o ma ion and oxida ion o sa cosine occu in
mi ochond ia and a e p o ided by wo basic pa hways (Figu e 3). Phos a idyle hylamine is me hyla ed
epea edly by S-adenosylme hionine (SAM) du ing ansul u a ion o phospha idylcholine in he i s
In . J. Mol. Sci. 2013, 14 13899
pa hway wi h he esul ing in e media e p oduc be aine. This eac ion o ms dime hylglycine and
egene a es me hionine om homocys eine [44]. Dime hylglycine is subsequen ly con e ed o
sa cosine ia dime hylglycine dehyd ogenase (DMGDH) [46,48]. The second me abolic pa hway
c ea es sa cosine du ing he ans o ma ion o he me hyl g oup o S-adenosylme hionine ca alysed by
he enzyme glycine-N-me hyl ans e ase (GNMT), ha is a e ame o iden ical 32 kDa subuni s [49,50].
These wo eac ions ul ima ely p oduce 5, 10-me hylene e ahyd o ola e and a e dependen on oxidized
la op o eins [e.g., la in adenine dinucleo ide (FAD+)] [46]. This pa hway also includes an oxida i e
phase, which emo es he me hyl g oup om sa cosine o c ea e glycine and an ac i e one-ca bon uni by
sa cosine dehyd ogenase (SARDH), a mi ochond ial fla op o ein [51] which, in a s udy by Mon ose e al.,
was obse ed wi hin he umou issue wi h GNMT and o he enzymes and can explain he inc eases in
sa cosine le els [48]. The absence o he ac i i y o SARDH in ol es also con e sion o choline o
glycine in humans; his is ansmi ed gene ically and ep esen s a diso de in me abolism o amino
acid ha is mani es ed as sa cosinemia, a su plus o sa cosine accompanied by high concen a ions o
sa cosine in blood and u ine [52].
5. Me abolomic o P os a e Cance
In he las decade, ad ances in nuclea magne ic esonance spec oscopy (NMR) and mass
spec ome y (MS) ha e been applied o iden i y me abolomics o p os a e cance ha may show a
clinically use ul bioma ke s [53]. NMR exploi s he beha iou o molecules when placed in a magne ic
ield, allowing he iden i ica ion o di e en nuclei based on hei esonan equency.
MS de e mines he composi ion o molecules based on he mass- o-cha ge a io in cha ged pa icles.
The esul an me aboli e de ec ion and quan i ica ion is acqui ed as a da a se called a spec um [54].
Tumou me abolomic p o ile is highly dependen on i s o gan o o igin, and exhibi s unique pa e ns
dependen on cance ype as well as di e en ia ion s a us [55]. P os a e cance has a dis inc me abolic
p o ile cha ac e ized by high le els o o al choline ( Cho) and phosphocholine, oge he wi h
inc easing amoun s o he glycoly ic p oduc s lac a e and alanine [56]. In he s udyo Swanson e al.,
heal hy glandula issues demons a ed signi ican ly highe concen a ions o ci a e and polyamines
han heal hy s omal and p os a e cance issues, while heal hy glandula and s omal issues
demons a ed lowe concen a ions o choline, phosphocholine plus glyce ophosphocholine and o al
cholin ( Cho) han p os a e cance issues [57]. The esul s in cance me abolomic achie ed h ough in
i o MRSI and ex i o NMR in es iga ions du ing he i s 11 yea s o he 21s cen u y a e illus a ing
he a eas whe e hese echnologies can be bes ansla ed in o clinical p ac ice [58].
6. Analy ical Techniques o De ec ion o Sa cosine
Cu en ly, new me hods o eliable de ec ion o sa cosine ha e been de eloped o con i m o
con adic sa cosine as a possible ma ke o p os a e cance [2,7,59].
6.1. Mic oa ay-Based Analysis
Mic oa ay echnology is based on he assump ion ha he amoun o mRNA o each gene
co ela es wi h p o eins amoun . Howe e , i is well know ha a co ela ion be ween RNA exp ession
and p o ein exp ession a ely holds because o pos ansla ional modi ica ion, p o ein deg ada ion and
In . J. Mol. Sci. 2013, 14 13900
eedback o p o ein on RNA exp ession [9]. S udying o gene exp ession p o ides use ul in o ma ion
o bo h clinical and basic esea ches [60]. Mic oa ay-based mul iplex bioma ke analysis o usion
genes in u ine samples has been desc ibed [5]. Some p omising non-in asi e bioma ke s wi h po en ial
o de ec ion in he u ine we e de e mined as PCA3, usion genes, e.g., TMPRSS2:ETS, TERT,
AMACR, GSTP1, MMP9, VEGF, ANXA3 and sa cosine [5]. The new u ine es s should be use ul in
ea ly diagnosis o p os a e cance and de ec ion o agg essi e umou s wi h he goal o adically
imp o ing ea men o CaP.
6.2. Ch oma og aphy
De ec ion o bioma ke s using liquid ch oma og aphy (LC) is cu en ly one o he mos widely used
analy ical echniques. Ad an age o LC applica ion consis s in epea able and high h oughpu
de ec ion o low molecula mass compounds. I is he e o e possible o de ec and quan i y e y low
concen a ions o analy es in he p esence o a ious in e e ing componen s. Ve y good esul s ha e
been ob ained by using ch oma og aphy in andem wi h mass spec ome y used o de e mina ion o
sa cosine in u ine samples. This me hod is highly sensi i e and allows de e mining sa cosine in e y
low concen a ions. Howe e , he e is one g ea ad an age, his me hod is able o sepa a e sa cosine
om i s isome s and alanine, which may be esponsible o a alse-posi i e and alse-nega i e esul s.
Jen zmik e al. used gas ch oma og aphy wi h andem mass spec ome y o de e mine sa cosine [7].
I was de ec ed in he samples o bo h malignan and non-malignan issues a e adical p os a ec omy
om 92 pa ien s su e ing om p os a e cance . Signi ican di e ences in concen a ions o sa cosine
in malignan and non-malignan issues we e ound. Concen a ion o sa cosine was mo e han 7%
highe in malignan issues compa ed o non-malignan . Based on hese esul s i was concluded ha
sa cosine could no be conside ed as a sui able p edic o o CaP [7]. In ano he published s udy gas
ch oma og aphy (GC) and mass spec ome y (MS) we e used. The esul s showed ha he
sa cosine/alanine a ios in pa ien s wi h ea ly and ad anced p os a e cance we e ai ly cons an
showing no s a is ically signi ican di e ences be ween T-s ages [61]. I was he e o e concluded ha
sa cosine is no a sui able ma ke o p os a e cance . By compa ing PSA wi h T-s ages in he same
g oup o pa ien s i was ound ha PSA in he T1–T2 g oup o pa ien s was signi ican ly lowe han in
he T3–T4 g oup o pa ien s con i ming he well know me i s and limi a ions o his ma ke [61].
Re e se phase high pe o mance liquid ch oma og aphy (HPLC) is he mos u ilized echnique o
sepa a ion o amino acids [62,63] o pep ides [64]. HPLC wi h andem mass spec ome y, which is
p esen ly one o he mos widely used analy ical me hods, was used o de e mine sa cosine and six
o he me aboli es in u ine [65]. This me hod is able o de e mine sa cosine in much lowe le els han
gas ch oma og aphy. The echnique de eloped in his s udy is e y simple, as , sensi i e, obus and
epea able. Ce nei e al. showed ha elec ochemical de ec ion is also a sui able me hod o de ec sa cosine
in e y low concen a ion. Howe e , his me hod can be used o analyse eal samples only a e applica ion
o sui able p e- ea men [21,66]. Applica ion o ion-exchange liquid ch oma og aphy is also sui able
o sepa a e amino acids [21]. I can be used o analyse all o ganic compounds ha con ain amino acids [67].
Ion-exchange ch oma og aphy me hod de eloped by Ce nei e al. e ealed ha le el o sa cosine in
u ine o pa ien s su e ing om CaP is se e al imes highe han ha o cu ed pa ien (Figu e 4).
In . J. Mol. Sci. 2013, 14 13901
The le el o sa cosine in heal hy pa ien s is only negligible [21]. Table 1 summa izes he me hod used
o sa cosine de ec ion.
Figu e 4. O e iew o concen a ion o sa cosine in u ine o pa ien s su e ing om
p os a e cance (CaP), ea ed pa ien s and con ols (heal hy people).
Table 1. Compa ison o me hods used o de e mina ion o sa cosine in di e en ma ixes.
In addi ion, he necessi y o p e- ea samples is also indica ed.
Me hod
Ma ix
Sample p e- ea men
Re .
Mic oa ay-based analysis
DNA
Medium
[5]
GC/MS
U ine, issue, se um
High
[61]
LC/MS
U ine, issue, se um
High
[65]
LC/ED
U ine, issue, se um
High
[21]
IEC
U ine, issue, se um
High
[21]
GC/MS: gas ch oma og aphy wi h mass spec ome y; LC/MS: liquid ch oma og aphy wi h mass
spec ome y; LC/ED: gas ch oma og aphy wi h elec ochemical de ec ion; IEC: ion exchange ch oma og aphy.
7. Summa y o Resul s Ob ained by Analysis o Samples om CaP Pa ien s
Table 2 shows di e en ypes o p os a e cance diagnosed and published in he s udies. Sa cosine
has been de e mined in majo i y o p esen ed wo ks. Despi e he ac ha some publica ions do no
claim sa cosine o be a po en ial ma ke o CaP, sa cosine was de ec ed and quan i ied in almos all
s udies in amoun s di e en om he con ols. This s a emen co esponds wi h esul s by Khan e al.
They alida ed sa cosine as an impo an oncome aboli e using bo h in i o and in i o p eclinical
models. Mo eo e hey con i med ha o e exp ession o GNMT in cells ele a ed also he sa cosine
le els bu had no e ec s on cell p oli e a ion [68].
Table 2 e eals he connec ion be ween sa cosine and p os a e cance . Sa cosine has been shown o
be apidly eleased in o he u ine supe na an [69]. Compa ed o s udy o S eekuma e al. [1],
Jen zmik e al. [69] suppose ha he da a by S eekuma e al. [1] a e mo e likely a esul o coho
In . J. Mol. Sci. 2013, 14 13908
72. Bianchi, F.; Dughe i, S.; Musci, M.; Bonacchi, A.; Sal ado i, E.; A cangeli, G.; Cupelli, V.;
Lancio i, M.; Masie i, L.; Se ni, S.; e al. Fully au oma ed solid-phase mic oex ac ion- as gas
ch oma og aphy-mass spec ome y me hod using a new ionic liquid column o high- h oughpu
analysis o sa cosine and N-e hylglycine in human u ine and u ina y sedimen s. Anal. Chim. Ac a
2011, 707, 197–203.
73. Cao, D.L.; Ye, D.W.; Zhu, Y.; Zhang, H.L.; Wang, Y.X.; Yao, X.D. E o s o esol e he
con adic ions in ea ly diagnosis o p os a e cance : A compa ison o di e en algo i hms o
sa cosine in u ine. P os a e Cance P os a ic Dis. 2011, 14, 166–172.
© 2013 by he au ho s; licensee MDPI, Basel, Swi ze land. This a icle is an open access a icle
dis ibu ed unde he e ms and condi ions o he C ea i e Commons A ibu ion license
(h p://c ea i ecommons.o g/licenses/by/3.0/).