144 | LÓPEZ-LÁZARO | MOL MED 16(3-4)144-153, MARCH-APRIL 2010
CANCER AS A GENETIC DISEASE
The gene ic basis o cance was dis-
co e ed mo e han a cen u y ago, when
Da id on Hansemann obse ed ha
cells om a ious ca cinoma samples
had ch omosomal al e a ions. A he be-
ginning o he 20 h cen u y Theo ho
Bo e y sugges ed ha cance migh e-
sul as a consequence o hese ch omo-
somal abe a ions, laying he ounda-
ions o iewing cance as a gene ic
disease (1). Bu he idea o cance as a
gene ic disease was no widely accep ed
a ha ime. I cance was caused by a
gene ic mu a ion, i was no clea why
he e was a delay o many yea s be-
ween he exposu e o a mu agenic
agen and he onse o cance , o why
he incidence o cance inc eased so d a-
ma ically wi h age. O e ime, he ob-
se a ions ha no single gene de ec
causes cance and ha se e al mu a-
ions could be equi ed o cance o de-
elop explained he long la en pe iod
o cance and he age dis ibu ion o his
disease (2–4). In he second hal o he
20 h cen u y, he idea ha he de elop-
men o cance equi ed he acquisi ion
o se e al mu a ions began o be widely
accep ed, and e o s we e made o
iden i y which genes we e in ol ed in
ca cinogenesis (5,6). In he 1980s he
i s human oncogenes and umo -sup-
p esso genes we e disco e ed, and he
idea ha cance was caused by mu a-
ions in hese wo ypes o genes was
gaining i m g ound (7–11). Mu a ions
in oncogenes would inc ease he syn he-
sis o p o eins ha s imula e cell p oli -
e a ion, and mu a ions in umo -sup-
p esso genes would esul in he loss o
p o eins ha es ain cell p oli e a ion
and induce apop osis. The accumula ion
o se e al mu a ions in hese wo ypes
o genes would allow cells o p oli e a e
in an uncon olled ashion and would
lead o cance . I was belie ed a ha
ime ha cance would be explained by
a ela i ely low numbe o mu a ions in
hese genes, and ha cance would
e en ually be ea able by e e sing o
exploi ing hese gene ic changes.
Molecula analyses o human umo s
ca ied ou in he las decade ha e e-
ealed ha he gene ic al e a ions o
cance cells a e much mo e nume ous
and uns able han p e iously hough
(12). Fo ins ance, by sampling colo ec-
al p emalignan polyp and ca cinoma
cell genomes, S ole e al. (13) ound ha
he mean numbe o genomic changes
pe ca cinoma cell was app oxima ely
11,000. In addi ion, much e idence has
accumula ed s a ing ha mu a ions
(changes in he DNA sequence) a e no
he only cause o he al e ed gene ex-
p ession o cance cells. Epigene ic al e -
a ions (he i able and e e sible changes
o he han he DNA sequence) and ane-
uploidy (nume ical and s uc u al ab-
no mali ies in ch omosomes) a e com-
mon al e a ions in umo cells, which
modi y gene exp ession and may also
play a c ucial ole in ca cinogenesis
(14–18). Such is he gene ic complexi y
and a iabili y o umo cells, ha he
A New View o Ca cinogenesis and an Al e na i e App oach
o Cance The apy
Miguel López-Láza o
Depa men o Pha macology, Facul y o Pha macy, Uni e si y o Se ille, Se ille, Spain
Du ing he las ew decades, cance esea ch has ocused on he idea ha cance is caused by gene ic al e a ions and ha
his disease can be ea ed by e e sing o a ge ing hese al e a ions. The small a ia ions in cance mo ali y obse ed du ing
he p e ious 30 yea s indica e, howe e , ha he clinical applica ions o his app oach ha e been e y limi ed so a . The de el-
opmen o u u e gene-based he apies ha may ha e a majo impac on cance mo ali y may be comp omised by he high
numbe and a iabili y o gene ic al e a ions ecen ly ound in human umo s. This a icle e iews e idence ha umo cells, in ad-
di ion o acqui ing a complex a ay o gene ic changes, de elop an al e a ion in he me abolism o oxygen. Al hough bo h
changes play an essen ial ole in ca cinogenesis, he al e ed oxygen me abolism o cance cells is no subjec o he high gene ic
a iabili y o umo s and may he e o e be a mo e eliable a ge o cance he apy. The u ili y o his no el app oach o he de-
elopmen o he apies ha selec i ely a ge umo cells is discussed.
© 2010 The Feins ein Ins i u e o Medical Resea ch, www. eins einins i u e.o g
Online add ess: h p://www.molmed.o g
doi: 10.2119/molmed.2009.00162
Add ess co espondence and ep in eques s o Miguel López-Láza o, Depa men o
Pha macology, Facul y o Pha macy, P o eso Ga cia Gonzalez 2, 41012 Se illa, Spain.
Phone: + 34 954 55 63 48; Fax: + 34 954 55 60 74; E-mail: [email p o ec ed].
Submi ed No embe 6, 2009; Accep ed o publica ion Decembe 26, 2009; Epub
(www.molmed.o g) ahead o p in Decembe 28, 2009.
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MOL MED 16(3-4)144-153, MARCH-APRIL 2010 | LÓPEZ-LÁZARO | 145
idea o unde s anding cance in e ms o
changes in speci ic genes is losing
g ound in a o o p oposals ha seek
o a ionalize cance in e ms o a lim-
i ed numbe o acqui ed pheno ypes
( he so-called hallma ks o cance ) and
al e ed cellula pa hways (19–21). We
a e beginning o ealize ha he high
gene ic a iabili y o umo cells is a se-
ious obs acle o he design o gene-
based he apies ha may ha e a majo
impac on cance mo ali y (12,21).
Despi e he complexi y and a iabili y
o he cance genome, much esea ch is
de o ed o cha ac e izing he gene ic
p o ile o umo s o a ionalize and pe -
sonalize cance he apy (22–24). The e-
cen app o al o se e al cance - a ge ed
he apies ( he apies ha a e in ended o
a ge he molecula de ec s o cance
cells speci ically) indica e ha he al e ed
genome o cance cells can be exploi ed
he apeu ically (25). The landma k e en
in his new ield was he de elopmen o
ima inib mesyla e (Glee ec) o he ea -
men o ch onic myeloid leukemia
(CML). This d ug was de eloped as a se-
lec i e inhibi o o he kinase BCR-ABL,
he usion p o ein p oduc o a ch omo-
somal ansloca ion ha is in ol ed in
he pa hogenesis o CML. Clinical ials
e ealed ha ima inib mesyla e induced
comple e hema ological emission in a
e y high pe cen age o pa ien s wi h
ch onic-phase CML (26). Al hough his
d ug has become he s anda d o ca e o
CML, i is impo an o no e ha ima-
inib mesila e does no cu e he disease
(i jus keeps i unde con ol o many
pa ien s o as long as hey ake he
d ug) and ha some pa ien s ea ed
wi h his d ug de elop esis ance o
ea men (27,28). O he a ge ed he a-
pies ha e been app o ed o cance ea -
men in ecen yea s; howe e , none o
hese he apies ha e led o majo im-
p o emen s in he su i al o pa ien s
wi h he mos common ypes o cance . I
is impo an o be eminded ha cance
mo ali y has no changed much du ing
he las h ee decades (29), and ha he
small declines obse ed in ecen yea s
in some ypes o cance ( ha is, lung, co-
lo ec al, b eas and p os a e cance ) a e
no a ibu able only o be e he apies
bu also o he implemen a ion o p e-
en ion and ea ly de ec ion campaigns
(30,31).
Al hough he gene ic al e a ions o
umo cells a e ex emely nume ous and
uns able (12,13,21), we a e mo ing o-
wa d an e a o pe sonalized ea men s
based on he gene ic p o ile o each
umo (22–24). I is expec ed ha much
ime and e o and many esou ces will
be necessa y o de elop he apies ha
will be use ul in a small pe cen age o
pa ien s wi h cance . In addi ion o
building up a complex a ay o gene ic
changes, umo cells acqui e an al e a ion
in he me abolism o oxygen, a p ocess
ha plays an impo an ole in ca cino-
genesis and could be exploi ed o de-
elop he apies o a b oad ange o pa-
ien s wi h cance .
KEY ROLE OF ALTERED OXYGEN
METABOLISM IN CANCER
Nonmalignan cells use oxygen (O2) o
gene a e ene gy in he o m o ATP
h ough he p ocess o oxida i e phos-
pho yla ion (oxphos). Accumula ing e i-
dence indica es ha , ins ead o ully cou-
pling he me abolism o O2wi h he
gene a ion o ene gy, cance cells ac i a e
glycolysis o mee hei ene gy demands
and use O2 o gene a e excessi e le els o
he eac i e oxygen species (ROS) supe -
oxide anion (O2
•–) and hyd ogen pe ox-
ide (H2O2). This al e a ion in he me abo-
lism o O2(dysoxic me abolism) is a
common ea u e o cance cells and plays
an impo an ole in ca cinogenesis
(32–38).
I is well known ha uncon olled cell
p oli e a ion is he mos ele an ea u e
o cance . I is also ecognized ha he
gene ic de ec s o cance cells esul in an
al e ed gene exp ession and in he p o-
duc ion o signals ha make hese cells
p oli e a e in an uncon olled ashion.
Equally impo an o cell p oli e a ion is
ha he di iding cell duplica es all i s
cellula componen s o c ea e wo
daugh e cells (Figu e 1A). To do his,
p oli e a ing cells mus ake nu ien s
om he blood and use hem o syn he-
size all he mac omolecules and cellula
componen s equi ed o he o ma ion
o a new cell. The cellula up ake o glu-
cose om he blood and he ac i a ion o
glycolysis a e essen ial p ocesses o cell
p oli e a ion, because he ac i a ion o
glycolysis p o ides mos o he building
blocks equi ed o he syn hesis o hese
mac omolecules and cellula componen s
(37). Se e al glycoly ic enzymes a e o e -
exp essed in cance cells and ha e been
shown o play an impo an ole in can-
ce (39–41). The inc eased cellula up ake
o glucose and he up egula ion o gly-
colysis o cance cells can indeed be ob-
se ed wi h clinical umo imaging ( luo-
odeoxyglucose posi on-emission
omog aphy) and is cu en ly used o
ea ly diagnosis and be e managemen
o oncology pa ien s (42).
The ac ha he blood essels deli e
bo h glucose and O2is a p oblem o he
ac i a ion o glycolysis, because he
p esence o O2is known o cause glycol-
ysis inhibi ion (Pas eu e ec ). This si u-
a ion sugges s ha o p oli e a e cance
cells mus de elop he capaci y o ac i-
a e glycolysis in he p esence o O2
(Figu e 1A), a cha ac e is ic ha was
i s obse ed se e al decades ago by
he Nobel lau ea e O o Wa bu g. Wa -
bu g also p oposed ha he high gly-
coly ic a es he obse ed in cance cells
despi e he p esence o O2we e caused
by a de ec in espi a ion (oxida i e
phospho yla ion) and ha his de ec
was he o igin o cance (43).
Al hough he ac i a ion o glycolysis
in he p esence o O2(ae obic glycolysis
o he Wa bu g e ec ) has epea edly
been obse ed in cance cells (37,42,44),
i is no clea why and how his phenom-
enon occu s. I i s p oposed ha o p o-
li e a e cance cells (and no mal p oli e -
a ing cells) mus ac i a e glycolysis
despi e he p esence o O2(33,37). As
shown in Figu e 1A, cell p oli e a ion
would be comp omised i glycolysis
we e always inhibi ed in he p esence o
O2(33,37). The same p oposal was la e
made by o he s (45). As o how his phe-
nomenon occu s, e idence sugges s ha
146 | LÓPEZ-LÁZARO | MOL MED 16(3-4)144-153, MARCH-APRIL 2010
NEW VIEW OF CARCINOGENESIS AND ALTERNATIVE APPROACH TO THERAPY
Figu e 1. Cance de elopmen equi es bo h he acquisi ion o DNA al e a ions and a change in he me abolism o oxygen (dysoxic me-
abolism). (A) The uncon olled cell p oli e a ion ha cha ac e izes cance equi es signals o cell p oli e a ion and he syn hesis o new
mac omolecules ( o example, nucleic acids, lipids, p o eins). Glycolysis p o ides building blocks ( o example, glucose 6-phospha e, dihy-
d oxyace one phospha e, 3-phosphoglyce a e, phosphoenolpy u a e, py u a e) ha pa icipa e in he syn hesis o hese mac omole-
cules. The p esence o O2can inhibi glycolysis (Pas eu e ec ) and, he e o e, he biosyn hesis o new mac omolecules equi ed o he
uncon olled cell p oli e a ion ha cha ac e izes cance . (B) A change in he me abolism o O2(dysoxic me abolism) would allow he ac-
i a ion o glycolysis in he p esence o O2and, he e o e, cell p oli e a ion and cance de elopmen .
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he change in he me abolism o O2
(dysoxic me abolism) (Figu e 1B) is c u-
cial o he ac i a ion o glycolysis in he
p esence o O2(37). B ie ly, high ATP le -
els ep ess glycolysis ia allos e ic inhibi-
ion o phospho uc okinase, a key en-
zyme in he egula ion o glycolysis. The
possible basis o he Pas eu e ec is ha
he p esence o O2allows ATP syn hesis
h ough oxphos, which causes an al-
los e ic inhibi ion o phospho uc oki-
nase esul ing in he inhibi ion o glycol-
ysis. This p oposed mechanism sugges s
ha glycolysis is no di ec ly inhibi ed by
O2, bu by ATP, and ha he p esence o
O2will no cause he inhibi ion o glycol-
ysis when O2is no used o gene a e
enough ATP (37). The me abolic swi ch
om oxphos o glycolysis commonly ob-
se ed in cance cells (43,46–48), along
wi h he inc eased p oduc ion o O2
•–
and H2O2 ound in hese cells (49–53),
suppo s he idea ha cance cells ha e
his al e a ion in he me abolism o O2.
This al e a ion may play a c ucial ole in
ca cinogenesis by allowing he ac i a ion
o glycolysis in he p esence o O2and,
he e o e, he uncon olled cell p oli e a-
ion ha cha ac e izes cance (Figu e 1B).
A de ia ion o he me abolism o O2
om he pa hway ha gene a es ATP o
he pa hway ha gene a es ROS may be
necessa y o cell p oli e a ion and umo
g ow h (Figu e 1B) (33,37). E idence sug-
ges s ha his me abolic swi ch may also
play an impo an ole in umo me as a-
sis (34). Hypoxia-inducible ac o 1
(HIF-1) is a key egula o o O2homeo-
s asis, and he ac i a ion o HIF-1 is
known o play a i al ole in he mos
ele an aspec s o ca cinogenesis, in-
cluding cell su i al, angiogenesis, in a-
sion, me as asis, cellula immo aliza ion
and me abolic ep og amming (54–56).
Because an inc eased p oduc ion o H2O2
(57) and he accumula ion o glycoly ic
me aboli es (58) a e known o ac i a e
HIF-1, i has been p oposed ha he
dysoxic me abolism ep esen ed in Fig-
u e 1B may play an impo an ole in he
ac i a ion o HIF-1 (32). This dysoxic me-
abolism esul s in inc eased p oduc ion
o O2
•– and H2O2, and e idence sugges s
ha he accumula ion o hese ROS
causes oxida i e s ess and plays an im-
po an ole in ca cinogenesis (35,36, 59,
60). The key ole o ROS in ca cinogene-
sis is suppo ed by expe imen al da a
showing ha cance cells commonly
ha e inc eased le els o ROS (49–53),
ha ROS can induce cell malignan
ans o ma ion (61,62) and ha he ma-
lignan pheno ype o cance cells can be
e e sed by educing he cellula le els
o ROS (63–68). O e all, e idence sug-
ges s ha he al e a ion in he me abo-
lism o O2 ep esen ed in Figu e 1B is a
common ea u e o cance cells and may
play a key ole in ca cinogenesis (32–38).
A NEW MODEL OF CARCINOGENESIS
The mos accep ed model o ca cino-
genesis pos ula es ha umo igenesis is
caused by DNA al e a ions and ha can-
ce can be ea ed by e e sing o ex-
ploi ing hese al e a ions (Figu e 2A). A
new model o ca cinogenesis is p oposed
in Figu e 2B. Acco ding o his new
model, he de elopmen o any cance
equi es ha he u u e umo cell bo h
acqui es a complex se o DNA al e -
a ions and de elops an al e a ion in he
me abolism o O2. I is widely acknowl-
edged ha he al e ed genome o umo
cells plays a key ole in ca cinogenesis.
E idence sugges s ha an al e a ion in
he me abolism o O2 om he pa hway
ha gene a es ene gy o he pa hway
ha p oduces ROS may also play an im-
po an ole in he de elopmen o cance
(discussed in his e iew). This new
model conside s ha bo h al e a ions
mus coope a e o he o ma ion o a
cance ; he acquisi ion o DNA al e -
a ions leads o an al e a ion in he me ab-
olism o O2and ice e sa. Indeed, he e
is e idence ha he ansi ion om a no -
mal o a malignan pheno ype b ough
abou by cance -causing genes is associ-
a ed wi h a p og essi e ene gy swi ch
om oxphos o glycolysis (69). Al e -
a ions in p53, one o he mos equen ly
mu a ed umo -supp esso genes in can-
ce , ha e also been p oposed o pa ici-
pa e in he me abolic swi ch om oxphos
o glycolysis (48). Mi ochond ial mu a-
ions may educe he ac i i y o oxphos
and ha e been associa ed wi h an in-
c ease in he cellula p oduc ion o ROS
(70). The ac i a ion o se e al oncogenes
is also known o inc ease he cellula
p oduc ion o O2
•– and H2O2(71–74).
Con e sely, an al e a ion in he me abo-
lism o O2( om he pa hway ha gene -
a es ATP o he pa hway ha gene a es
O2
•– and H2O2) can lead o he acquisi-
ion o DNA al e a ions. H2O2is indeed
well known o induce DNA al e a ions,
Figu e 2. Models o ca cinogenesis. In addi ion o he acquisi ion a complex a ay o DNA
al e a ions p oposed in he accep ed model o ca cinogenesis (A), he model discussed
in his e iew (B) p oposes ha cance de elops an al e a ion in he me abolism o oxy-
gen. Al hough bo h changes mus in e ac o he de elopmen o cance , he al e ed
oxygen me abolism o umo cells is no subjec o he high gene ic complexi y and a i-
abili y o umo s and may he e o e be a mo e eliable a ge o cance he apy.
148 | LÓPEZ-LÁZARO | MOL MED 16(3-4)144-153, MARCH-APRIL 2010
NEW VIEW OF CARCINOGENESIS AND ALTERNATIVE APPROACH TO THERAPY
including DNA damage, mu a ions and
gene ic ins abili y (75–78).
Mos ca cinogenic agen s ha e been
shown o induce DNA al e a ions. Mos
ca cinogenic agen s also induce oxida i e
s ess (38,79), and a de ia ion in he me-
abolism o O2 owa d he pa hway ha
gene a es ROS is a key ea u e o oxida-
i e s ess (38,60,79). An example o how
a ca cinogenic agen can induce bo h
DNA al e a ions and an al e a ion in he
me abolism o O2 is shown in Figu e 3.
Mos chemical ca cinogens need o be
enzyma ically ac i a ed o become geno-
oxic, and he cy och ome P450 (P450)
enzymes a e he mos p ominen en-
zymes in ol ed in such ac i a ion (80).
The ac i i y o P450 enzymes is associ-
a ed wi h he gene a ion o O2
•– and
H2O2(81), and H2O2is well known o in-
duce DNA al e a ions (75–78). An in-
c ease in he gene a ion o H2O2is associ-
a ed wi h he ac i a ion o HIF-1 (32,57),
which can lead o he ep ession o ox-
phos and he ac i a ion o glycolysis
(82,83). The accumula ion o glycoly ic
in e media es caused by he ac i a ion o
glycolysis can also inc ease he ac i i y
o HIF-1 (58) (Figu e 3). Ca cinogenic
agen s can induce DNA al e a ions and
an al e ed O2me abolism independen ly
o P450. Fo ins ance, he inc ease in he
in acellula pH induced by some ca -
cinogenic agen s seems o be c ucial o
he de elopmen o cance (84,85). A ise
in he in acellula pH can inc ease he
p oduc ion o O2
•– (86) and lead o DNA
al e a ions and a dysoxic me abolism
h ough he pa hways ep esen ed in
Figu e 3. Because exposu e o many
o he ca cinogenic ac o s has been asso-
cia ed wi h an inc eased p oduc ion o
ROS (38,59,79), hese ca cinogenic ac o s
may also lead o DNA al e a ions and a
dysoxic me abolism h ough he pa h-
ways ep esen ed in Figu e 3.
Acco ding o he mos accep ed model
o ca cinogenesis, he DNA al e a ions o
umo cells a e a a ge o cance he -
apy (Figu e 2A). Howe e , as discussed
in abo e, he high numbe and a iabil-
i y o hese DNA al e a ions is an obs a-
cle o he design o gene-based he apies
ha may ha e a majo impac on cance
mo ali y (12,21). The impo ance o he
new model o ca cinogenesis ep esen ed
in Figu e 2B is ha i o e s an al e na i e
a ge o he ea men o cance , which
is no subjec o he high gene ic a iabil-
i y o umo cells and may he e o e be
mo e easily a ge ed. How he al e ed O2
me abolism o cance could be used he -
apeu ically o kill umo cells selec i ely
is discussed in he ollowing sec ion.
TARGETING THE ALTERED OXYGEN
METABOLISM OF TUMOR CELLS FOR THE
TREATMENT OF CANCER
Tumo cells and no mal cells me abo-
lize O2di e en ly; his di e ence could
be exploi ed o a ge umo cells selec-
i ely (Figu e 4). No mal cells ha e ull
oxphos capaci y, low p oduc ion o H2O2
and glycolysis inhibi ion in he p esence
o O2. No mal cells do no need o main-
ain high glycoly ic ac i i y o ensu e
hei su i al. Cance cells ha e an al e -
Figu e 3. Ca cinogenic agen s can induce DNA al e a ions and an al e a ion in he me-
abolism o oxygen. This igu e ep esen s an example o how a ca cinogenic agen can
induce bo h DNA al e a ions and a dysoxic me abolism ia P450. See ex o e e ences
and u he de ails.
Figu e 4. U ili y o he al e ed oxygen me abolism o cance cells o selec i ely kill hem.
Cance cells and no mal cells me abolize oxygen di e en ly. Because he basal le els o
H2O2a e highe in cance cells han in no mal cells, a speci ic inc ease in he concen a-
ions o H2O2may lead o cy o oxic concen a ions in cance cells bu no in no mal cells.
In addi ion, because he ac i a ion o glycolysis in cance cells is essen ial o p e en cell
dea h induced by ATP deple ion and H2O2accumula ion, he a enua ion o glycolysis in
cance cells can induce hei dea h. No mal cells would be less a ec ed by his s a egy,
because hey do no need o ha e inc eased glycoly ic a es o ensu e hei su i al. See
ex o u he de ails. Do ed lines indica e ha he pa hway o p ocess is ep essed.
Bolded lines indica e ha he p ocess is ac i a ed o ha he le els o he molecule a e
inc eased.

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MOL MED 16(3-4)144-153, MARCH-APRIL 2010 | LÓPEZ-LÁZARO | 149
a ion in he me abolism o O2(dysoxic
me abolism), which is associa ed wi h
oxphos ep ession, inc eased p oduc ion
o H2O2and inc eased glycoly ic ac i i y.
The high glycoly ic ac i i y o cance
cells is essen ial o hei su i al, be-
cause i p e en s cell dea h induced by
ATP deple ion and H2O2accumula ion.
The dysoxic me abolism o cance cells
can be exploi ed o kill cance cells selec-
i ely by inc easing he cellula le els o
H2O2and/o by a enua ing glycolysis.
These e ec s could be achie ed by he
use o p ooxidan agen s and glycolysis
inhibi o s, alone o in combina ion.
Selec i e Killing o Cance Cells by
H2O2and P ooxidan Agen s
Recen da a sugges ha oxida i e
s ess may play a ole in he an icance
ac i i y o many chemo he apeu ic
agen s commonly used in cance ea -
men , including pacli axel, cispla in, dox-
o ubicin, a senic ioxide, bo ezomib,
p oca bazine and e oposide (87–101). Fo
ins ance, al hough i has been known o
many yea s ha he mic o ubule p o ein
ubulin is he he apeu ic a ge o pacli-
axel ( axol), ecen expe imen s ha e
shown ha H2O2plays an impo an ole
in pacli axel-induced cance cell dea h
(87,89). The ole o ROS in he ac i i y o
many an icance agen s is inc easingly
being acknowledged, and he induc ion
o oxida i e s ess by p ooxidan agen s
is eme ging as an a ac i e an icance
s a egy (36,94,99,102–106).
H2O2seems o be a key playe in ox-
ida i e s ess–induced cance cell dea h.
Many an icance agen s, such as pacli-
axel, doxo ubicin and a senic ioxide,
p oduce H2O2(87,90,92), and H2O2is
known o be an e icien induce o cell
dea h in cance cells (36,93,107). In e es -
ingly, cance cells seem mo e suscep ible
o H2O2-induced cell dea h han nonma-
lignan cells (108–110). In es iga ing se -
e al cance and no mal cell lines, Chen e
al. (108) obse ed ha high concen a-
ions o asco bic acid selec i ely killed
cance cells and ha his e ec was medi-
a ed by H2O2. They showed, o ins ance,
ha a concen a ion o 50 μmol/L H2O2
induced a highe pe cen age o cell
dea h in Bu ki lymphoma cells han
250 μmol/L in no mal lymphocy es and
no mal monocy es (108). In i o and in
i o da a indica e ha umo cells p o-
duce highe concen a ions o H2O2 han
hei no mal coun e pa s (49–53). These
da a, and he ac ha he e is a h eshold
o H2O2abo e which cells canno su -
i e, may explain why speci ic concen a-
ions o H2O2induce selec i e killing o
cance cells (36). O e all, e idence sug-
ges s ha inc easing he le els o H2O2in
cance cells by using p ooxidan agen s
may be an impo an he apeu ic s a egy.
The concen a ion o a p ooxidan agen
equi ed o gene a e le els o H2O2 ha
kill cance cells bu no no mal cells
could be de e mined in cell cul u e expe -
imen s. Then, by using an app op ia e
ou e o adminis a ion, such concen a-
ions should be achie ed in i o o ob-
se e a selec i e an i umo e ec .
Selec i e Killing o Cance Cells by
Glycolysis Inhibi ion
The inc eased glycoly ic ac i i y o
cance cells seems o be impo an o
keeping adequa e ene gy le els in hese
cells. Xu e al. (111) obse ed ha he in-
hibi ion o glycolysis se e ely deple ed
ATP in cance cells and induced cell
dea h, especially in cance cells wi h mi-
ochond ial espi a ion de ec s. The de-
pendence o cance cells on glycoly ic en-
e gy seems o inc ease as malignan
ans o ma ion occu s (69). I has been
p oposed ha his inc eased dependence
on glycolysis o ene gy gene a ion is an
impo an me abolic di e ence be ween
no mal and malignan cells ha may
se e o de eloping he apeu ic s a e-
gies o p e e en ially kill cance cells
(44,112,113). Se e al glycolysis inhibi o s
ha e shown an icance e ec s ( o exam-
ple, 2-deoxy-D-glucose, lonidamine,
3-b omopy u a e and dichlo oace a e)
and some o hem ha e en e ed he clini-
cal ial s age o in es iga ion (37,44,112,
114). Fo example, i has been shown ha
dichlo oace a e, a known glycolysis in-
hibi o ha has been used in humans o
decades in he ea men o lac ic acidosis
and inhe i ed mi ochond ial diseases, in-
duced ma ked an icance e ec s in mice
(115). The au ho s ound ha dichlo oac-
e a e in he d inking wa e a clinically
ele an doses o up o 3 mon hs p e-
en ed and e e sed umo g ow h in
i o, wi hou appa en oxici y and wi h-
ou a ec ing hemoglobin, ansaminase
o c ea inine le els. They concluded ha
he ease o deli e y, selec i i y and e ec-
i eness o dichlo oace a e make his
agen an a ac i e candida e o cance
he apy, one ha can be apidly ans-
la ed in o phase II–III clinical ials (115).
O he s a egies could be used o inhibi
o exploi he inc eased glycoly ic ac i -
i y o cance cells. Because an inc ease in
he ac i i y o he Na+/K+-ATPase pump
is associa ed wi h he ac i a ion o gly-
colysis (116,117), he inhibi ion o his
pump ( o example, by ca diac glyco-
sides) may esul in he inhibi ion o gly-
colysis and he selec i e killing o cance
cells (113,118). The ac i a ion o glycoly-
sis is known o inc ease he concen a-
ion o p o ons in he cy osol. These p o-
ons mus be ex uded o p e en
acid-induced cell dea h. The inhibi ion o
he cellula sys ems in ol ed in he ex-
usion o p o ons in cance cells may
also lead o he selec i e killing o cance
cells (119).
Combina ion o P ooxidan Agen s
wi h Glycolysis Inhibi o s o
An icance The apy
Al hough ROS can induce cance cell
dea h, umo cells a e known o de elop
mechanisms ha p e en ROS om
eaching cy o oxic le els. The glu-
a hione and hio edoxin an ioxidan
sys ems a e c ucial o de oxi ying ROS.
These an ioxidan sys ems a e ac i a ed
in cance cells and play an impo an
ole in he de elopmen o esis ance o
many an icance agen s (120–126). Like-
wise, al hough he inhibi ion o glycoly-
sis is an a ac i e an icance s a egy, in
i o expe imen s sugges ha he inhibi-
ion o glycolysis may no be su icien
o induce po en an icance e ec s. Ac-
co dingly, al hough he glycolysis in-
hibi o 2-deoxy-D-glucose is an e icien
150 | LÓPEZ-LÁZARO | MOL MED 16(3-4)144-153, MARCH-APRIL 2010
NEW VIEW OF CARCINOGENESIS AND ALTERNATIVE APPROACH TO THERAPY
induce o cell dea h in i o (127), i s an-
icance in i o ac i i y is no e y high
when i is used as a single agen . The an-
icance ac i i y o 2-deoxy-D-glucose
has been explo ed in combina ion wi h
chemo he apeu ic d ugs and adia ion,
and some o hese combina ions ha e
en e ed clinical ials (44,112,128–132).
P ooxidan agen s could be combined
wi h glycolysis inhibi o s o maximize
hei an icance ac i i y. E idence indi-
ca es ha p ooxidan agen s can inc ease
he cellula le els o H2O2and ha gly-
colysis inhibi o s can educe he capaci y
o cells o de oxi y H2O2. Expe imen al
da a ha e shown ha malignan cells a e
mo e suscep ible o glucose dep i a ion
han non ans o med cells, and ha an
inc ease in he le els o H2O2may medi-
a e he cy o oxic e ec induced by glu-
cose dep i a ion (53,133–135). Two possi-
ble mechanisms may explain why he
ac i a ion o glycolysis pe o ms an im-
po an unc ion in p o ec ing umo cells
om H2O2-induced cell dea h. Fi s , he
ac i a ion o glycolysis inc eases he o -
ma ion o py u a e, which is an e icien
sca enge o H2O2(136–139). Second,
glucose me abolism h ough he pen ose
phospha e pa hway egene a es NADPH
om NADP+in a eac ion in which
glucose-6-phospha e is con e ed in o
6-phosphogluconolac one by he enzyme
glucose-6-phospha e dehyd ogenase. The
egene a ion o NADPH is equi ed o
H2O2de oxi ica ion h ough he glu-
a hione pe oxidase/glu a hione educ-
ase sys em and h ough he hio edoxin
pe oxidase/ hio edoxin educ ase sys-
em (134,140,141) (Figu e 5).
CONCLUSIONS
Cance kills mo e han six million peo-
ple wo ldwide e e y yea (142). The
mo ali y a e o his disease has no
changed much in he pas ew decades
e en in de eloped coun ies such as he
Uni ed S a es (29). The small dec eases
obse ed in ecen yea s in some ypes o
cance (29) a e no a ibu able only o
be e he apies, bu also o he imple-
men a ion o p e en ion and ea ly de ec-
ion campaigns. The goal o hese cam-
paigns is o make people awa e ha
many cance s can be p e en ed by ol-
lowing se e al guidelines, and ha can-
ce he apy is e ec i e when his disease
is de ec ed ea ly (30,31). Despi e hese
campaigns, many cance s a e s ill diag-
nosed when cells om a p ima y umo
ha e al eady me as asized o o he pa s
o he body. A his s age o disease,
umo cells a e no longe localized and
can no longe be elimina ed by su ge y
o adio he apy. The main o m o ea -
men a his poin is chemo he apy,
which consis s o deli e ing d ugs sys-
emically so ha hey can each and kill
he umo cells. Bu mos o hese d ugs
a e oxic o bo h umo and no mal cells,
cause se e e side e ec s in pa ien s and,
he e o e, need o be used a subop imal
le els. The low e icacy o chemo he apy
in pa ien s wi h ad anced cance s is e-
lec ed in he low 5-yea su i al a es
obse ed in hese pa ien s (29). Fo in-
s ance, cance s a is ics show ha he
mos commonly diagnosed cance in he
wo ld is lung cance (142), ha app oxi-
ma ely 50% o pa ien s diagnosed wi h
lung cance ha e dis an me as asis (29)
and ha only 3% o hese pa ien s man-
age o su i e mo e han 5 yea s (29).
The low e icacy o cance he apy o
he ea men o pa ien s wi h me as asis
makes he de elopmen o no el he a-
peu ic app oaches necessa y.
A no el he apeu ic app oach has
eme ged s ongly in ecen yea s. This
app oach seeks o a ack he umo cells
selec i ely and is based on unde s and-
ing o he di e ences be ween umo
cells and nonmalignan cells. I has been
known o many yea s ha umo cells
ha e gene ic al e a ions and much e-
sea ch has been done o iden i y hese al-
e a ions. Recen analyses o human can-
ce s ha e e ealed, howe e , ha he
gene ic de ec s o umo cells a e much
Figu e 5. Key ole o glycolysis in he de oxi ica ion o H2O2. Inc eased glucose me abolism
helps de oxi y H2O2by inc easing he le els o he H2O2sca enge py u a e and by e-
gene a ing NADPH. Glu a hione educ ase (GR) and hio edoxin educ ase (T xR) need
NADPH o egene a e glu a hione (GSH) and hio edoxin [T x(SH)2], which a e used by glu-
a hione pe oxidase (GPx) and hio edoxin pe oxidase (TPx) o de oxi y H2O2. Thiol (SH)-
eac i e agen s can eac wi h he SH g oups o GSH and T x(SH)2and induce a p ooxi-
dan e ec by dis up ing he GR/GPx and T xR/TPx an ioxidan sys ems.
REVIEW ARTICLE
MOL MED 16(3-4)144-153, MARCH-APRIL 2010 | LÓPEZ-LÁZARO | 151
mo e nume ous and uns able han ex-
pec ed (12,13). In addi ion, he gene ic al-
e a ions o umo cells a e no he same
in di e en ypes o cance o e en in
di e en people wi h he same ype o
cance . Gi en hese ci cums ances i will
p obably be e y di icul o de elop u-
u e gene-based he apies ha may be
use ul in a wide ange o pa ien s wi h
cance (12,20,21). Despi e he complexi y
o he cance genome, much esea ch is
de o ed o cha ac e izing he gene ic
p o ile o umo s o a ionalize and pe -
sonalize cance he apy (22–24).
An al e na i e app oach has been dis-
cussed in his e iew. In addi ion o build-
ing up a complex se o DNA changes, e -
idence sugges s ha he de elopmen o
any cance equi es ha umo cells ac-
qui e an al e a ion in he me abolism o
oxygen. In e es ingly, his al e a ion in he
me abolism o oxygen can make cance
cells ulne able o he apeu ic in e en-
ion. Thei inc eased basal le els o H2O2
and hei highe dependence on glycoly-
sis o hei su i al make cance cells
mo e suscep ible han no mal cells o
ea men wi h p ooxidan agen s and
glycolysis inhibi o s. Because his al e -
a ion in he me abolism o oxygen seems
o be a common ea u e o umo cells,
his he apeu ic app oach could be used
o he ea men o a wide ange o pa-
ien s wi h cance . Fu u e esea ch will e-
eal whe he his al e na i e app oach
will be su icien o inc ease he su i al
o pa ien s wi h ad anced cance s, o
whe he i will be necessa y o use i in
combina ion wi h adi ional chemo he -
apy and/o no el a ge ed he apies.
DISCLOSURE
The au ho s decla e ha hey ha e no
compe ing in e es s as de ined by Molecu-
la Medicine, o o he in e es s ha migh
be pe cei ed o in luence he esul s and
discussion epo ed in his pape .
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