a new view of carcinogenesis and an alternative approach...

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CANCER AS A GENETIC DISEASEThe genetic basis of cancer was dis-

covered more than a century ago, whenDavid von Hansemann observed thatcells from various carcinoma sampleshad chromosomal alterations. At the be-ginning of the 20th century TheothorBovery suggested that cancer might re-sult as a consequence of these chromo-somal aberrations, laying the founda-tions for viewing cancer as a geneticdisease (1). But the idea of cancer as agenetic disease was not widely acceptedat that time. If cancer was caused by agenetic mutation, it was not clear whythere was a delay of many years be-tween the exposure to a mutagenicagent and the onset of cancer, or whythe incidence of cancer increased so dra-matically with age. Over time, the ob-servations that no single gene defectcauses cancer and that several muta-tions could be required for cancer to de-

velop explained the long latent periodof cancer and the age distribution of thisdisease (2–4). In the second half of the20th century, the idea that the develop-ment of cancer required the acquisitionof several mutations began to be widelyaccepted, and efforts were made toidentify which genes were involved incarcinogenesis (5,6). In the 1980s thefirst human oncogenes and tumor-sup-pressor genes were discovered, and theidea that cancer was caused by muta-tions in these two types of genes wasgaining firm ground (7–11). Mutationsin oncogenes would increase the synthe-sis of proteins that stimulate cell prolif-eration, and mutations in tumor-sup-pressor genes would result in the loss ofproteins that restrain cell proliferationand induce apoptosis. The accumulationof several mutations in these two typesof genes would allow cells to proliferatein an uncontrolled fashion and would

lead to cancer. It was believed at thattime that cancer would be explained bya relatively low number of mutations inthese genes, and that cancer wouldeventually be treatable by reversing orexploiting these genetic changes.

Molecular analyses of human tumorscarried out in the last decade have re-vealed that the genetic alterations ofcancer cells are much more numerousand unstable than previously thought(12). For instance, by sampling colorec-tal premalignant polyp and carcinomacell genomes, Stoler et al. (13) found thatthe mean number of genomic changesper carcinoma cell was approximately11,000. In addition, much evidence hasaccumulated stating that mutations(changes in the DNA sequence) are notthe only cause of the altered gene ex-pression of cancer cells. Epigenetic alter-ations (heritable and reversible changesother than the DNA sequence) and ane-uploidy (numerical and structural ab-normalities in chromosomes) are com-mon alterations in tumor cells, whichmodify gene expression and may alsoplay a crucial role in carcinogenesis(14–18). Such is the genetic complexityand variability of tumor cells, that the

A New View of Carcinogenesis and an Alternative Approachto Cancer Therapy

Miguel López-Lázaro

Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain

During the last few decades, cancer research has focused on the idea that cancer is caused by genetic alterations and thatthis disease can be treated by reversing or targeting these alterations. The small variations in cancer mortality observed duringthe previous 30 years indicate, however, that the clinical applications of this approach have been very limited so far. The devel-opment of future gene-based therapies that may have a major impact on cancer mortality may be compromised by the highnumber and variability of genetic alterations recently found in human tumors. This article reviews evidence that tumor cells, in ad-dition to acquiring a complex array of genetic changes, develop an alteration in the metabolism of oxygen. Although bothchanges play an essential role in carcinogenesis, the altered oxygen metabolism of cancer cells is not subject to the high geneticvariability of tumors and may therefore be a more reliable target for cancer therapy. The utility of this novel approach for the de-velopment of therapies that selectively target tumor cells is discussed.© 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.orgOnline address: http://www.molmed.orgdoi: 10.2119/molmed.2009.00162

Address correspondence and reprint requests to Miguel López-Lázaro, Department of

Pharmacology, Faculty of Pharmacy, Profesor Garcia Gonzalez 2, 41012 Sevilla, Spain.

Phone: + 34 954 55 63 48; Fax: + 34 954 55 60 74; E-mail: [email protected].

Submitted November 6, 2009; Accepted for publication December 26, 2009; Epub

(www.molmed.org) ahead of print December 28, 2009.

R E V I E W A R T I C L E

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idea of understanding cancer in terms ofchanges in specific genes is losingground in favor of proposals that seekto rationalize cancer in terms of a lim-ited number of acquired phenotypes(the so-called hallmarks of cancer) andaltered cellular pathways (19–21). Weare beginning to realize that the highgenetic variability of tumor cells is a se-rious obstacle for the design of gene-based therapies that may have a majorimpact on cancer mortality (12,21).

Despite the complexity and variabilityof the cancer genome, much research isdevoted to characterizing the geneticprofile of tumors to rationalize and per-sonalize cancer therapy (22–24). The re-cent approval of several cancer-targetedtherapies (therapies that are intended totarget the molecular defects of cancercells specifically) indicate that the alteredgenome of cancer cells can be exploitedtherapeutically (25). The landmark eventin this new field was the development ofimatinib mesylate (Gleevec) for the treat-ment of chronic myeloid leukemia(CML). This drug was developed as a se-lective inhibitor of the kinase BCR-ABL,the fusion protein product of a chromo-somal translocation that is involved inthe pathogenesis of CML. Clinical trialsrevealed that imatinib mesylate inducedcomplete hematological remission in avery high percentage of patients withchronic-phase CML (26). Although thisdrug has become the standard of care forCML, it is important to note that ima-tinib mesilate does not cure the disease(it just keeps it under control for manypatients for as long as they take thedrug) and that some patients treatedwith this drug develop resistance totreatment (27,28). Other targeted thera-pies have been approved for cancer treat-ment in recent years; however, none ofthese therapies have led to major im-provements in the survival of patientswith the most common types of cancer. Itis important to be reminded that cancermortality has not changed much duringthe last three decades (29), and that thesmall declines observed in recent yearsin some types of cancer (that is, lung, co-

lorectal, breast and prostate cancer) arenot attributable only to better therapiesbut also to the implementation of pre-vention and early detection campaigns(30,31).

Although the genetic alterations oftumor cells are extremely numerous andunstable (12,13,21), we are moving to-ward an era of personalized treatmentsbased on the genetic profile of eachtumor (22–24). It is expected that muchtime and effort and many resources willbe necessary to develop therapies thatwill be useful in a small percentage ofpatients with cancer. In addition tobuilding up a complex array of geneticchanges, tumor cells acquire an alterationin the metabolism of oxygen, a processthat plays an important role in carcino-genesis and could be exploited to de-velop therapies for a broad range of pa-tients with cancer.

KEY ROLE OF ALTERED OXYGENMETABOLISM IN CANCER

Nonmalignant cells use oxygen (O2) togenerate energy in the form of ATPthrough the process of oxidative phos-phorylation (oxphos). Accumulating evi-dence indicates that, instead of fully cou-pling the metabolism of O2 with thegeneration of energy, cancer cells activateglycolysis to meet their energy demandsand use O2 to generate excessive levels ofthe reactive oxygen species (ROS) super-oxide anion (O2

•–) and hydrogen perox-ide (H2O2). This alteration in the metabo-lism of O2 (dysoxic metabolism) is acommon feature of cancer cells and playsan important role in carcinogenesis(32–38).

It is well known that uncontrolled cellproliferation is the most relevant featureof cancer. It is also recognized that thegenetic defects of cancer cells result in analtered gene expression and in the pro-duction of signals that make these cellsproliferate in an uncontrolled fashion.Equally important for cell proliferation isthat the dividing cell duplicates all itscellular components to create twodaughter cells (Figure 1A). To do this,proliferating cells must take nutrients

from the blood and use them to synthe-size all the macromolecules and cellularcomponents required for the formationof a new cell. The cellular uptake of glu-cose from the blood and the activation ofglycolysis are essential processes for cellproliferation, because the activation ofglycolysis provides most of the buildingblocks required for the synthesis of thesemacromolecules and cellular components(37). Several glycolytic enzymes are over-expressed in cancer cells and have beenshown to play an important role in can-cer (39–41). The increased cellular uptakeof glucose and the upregulation of gly-colysis of cancer cells can indeed be ob-served with clinical tumor imaging (fluo-rodeoxyglucose positron-emissiontomography) and is currently used forearly diagnosis and better managementof oncology patients (42).

The fact that the blood vessels deliverboth glucose and O2 is a problem for theactivation of glycolysis, because thepresence of O2 is known to cause glycol-ysis inhibition (Pasteur effect). This situ-ation suggests that to proliferate cancercells must develop the capacity to acti-vate glycolysis in the presence of O2

(Figure 1A), a characteristic that wasfirst observed several decades ago bythe Nobel laureate Otto Warburg. War-burg also proposed that the high gly-colytic rates he observed in cancer cellsdespite the presence of O2 were causedby a defect in respiration (oxidativephosphorylation) and that this defectwas the origin of cancer (43).

Although the activation of glycolysisin the presence of O2 (aerobic glycolysisor the Warburg effect) has repeatedlybeen observed in cancer cells (37,42,44),it is not clear why and how this phenom-enon occurs. I first proposed that to pro-liferate cancer cells (and normal prolifer-ating cells) must activate glycolysisdespite the presence of O2 (33,37). Asshown in Figure 1A, cell proliferationwould be compromised if glycolysiswere always inhibited in the presence ofO2 (33,37). The same proposal was latermade by others (45). As to how this phe-nomenon occurs, evidence suggests that


N E W V I E W O F C A R C I N O G E N E S I S A N D A L T E R N A T I V E A P P R O A C H T O T H E R A P Y

Figure 1. Cancer development requires both the acquisition of DNA alterations and a change in the metabolism of oxygen (dysoxic me-tabolism). (A) The uncontrolled cell proliferation that characterizes cancer requires signals for cell proliferation and the synthesis of newmacromolecules (for example, nucleic acids, lipids, proteins). Glycolysis provides building blocks (for example, glucose 6-phosphate, dihy-droxyacetone phosphate, 3-phosphoglycerate, phosphoenolpyruvate, pyruvate) that participate in the synthesis of these macromole-cules. The presence of O2 can inhibit glycolysis (Pasteur effect) and, therefore, the biosynthesis of new macromolecules required for theuncontrolled cell proliferation that characterizes cancer. (B) A change in the metabolism of O2 (dysoxic metabolism) would allow the ac-tivation of glycolysis in the presence of O2 and, therefore, cell proliferation and cancer development.



the change in the metabolism of O2

(dysoxic metabolism) (Figure 1B) is cru-cial for the activation of glycolysis in thepresence of O2 (37). Briefly, high ATP lev-els repress glycolysis via allosteric inhibi-tion of phosphofructokinase, a key en-zyme in the regulation of glycolysis. Thepossible basis of the Pasteur effect is thatthe presence of O2 allows ATP synthesisthrough oxphos, which causes an al-losteric inhibition of phosphofructoki-nase resulting in the inhibition of glycol-ysis. This proposed mechanism suggeststhat glycolysis is not directly inhibited byO2, but by ATP, and that the presence ofO2 will not cause the inhibition of glycol-ysis when O2 is not used to generateenough ATP (37). The metabolic switchfrom oxphos to glycolysis commonly ob-served in cancer cells (43,46–48), alongwith the increased production of O2

•–

and H2O2 found in these cells (49–53),supports the idea that cancer cells havethis alteration in the metabolism of O2.This alteration may play a crucial role incarcinogenesis by allowing the activationof glycolysis in the presence of O2 and,therefore, the uncontrolled cell prolifera-tion that characterizes cancer (Figure 1B).

A deviation of the metabolism of O2

from the pathway that generates ATP tothe pathway that generates ROS may benecessary for cell proliferation and tumorgrowth (Figure 1B) (33,37). Evidence sug-gests that this metabolic switch may alsoplay an important role in tumor metasta-sis (34). Hypoxia-inducible factor 1(HIF-1) is a key regulator of O2 homeo-stasis, and the activation of HIF-1 isknown to play a vital role in the mostrelevant aspects of carcinogenesis, in-cluding cell survival, angiogenesis, inva-sion, metastasis, cellular immortalizationand metabolic reprogramming (54–56).Because an increased production of H2O2

(57) and the accumulation of glycolyticmetabolites (58) are known to activateHIF-1, it has been proposed that thedysoxic metabolism represented in Fig-ure 1B may play an important role in theactivation of HIF-1 (32). This dysoxic me-tabolism results in increased productionof O2

•– and H2O2, and evidence suggests

that the accumulation of these ROScauses oxidative stress and plays an im-portant role in carcinogenesis (35,36, 59,60). The key role of ROS in carcinogene-sis is supported by experimental datashowing that cancer cells commonlyhave increased levels of ROS (49–53),that ROS can induce cell malignanttransformation (61,62) and that the ma-lignant phenotype of cancer cells can bereversed by reducing the cellular levelsof ROS (63–68). Overall, evidence sug-gests that the alteration in the metabo-lism of O2 represented in Figure 1B is acommon feature of cancer cells and mayplay a key role in carcinogenesis (32–38).

A NEW MODEL OF CARCINOGENESISThe most accepted model of carcino-

genesis postulates that tumorigenesis iscaused by DNA alterations and that can-cer can be treated by reversing or ex-ploiting these alterations (Figure 2A). Anew model of carcinogenesis is proposedin Figure 2B. According to this newmodel, the development of any cancerrequires that the future tumor cell bothacquires a complex set of DNA alter-ations and develops an alteration in themetabolism of O2. It is widely acknowl-edged that the altered genome of tumorcells plays a key role in carcinogenesis.Evidence suggests that an alteration in

the metabolism of O2 from the pathwaythat generates energy to the pathwaythat produces ROS may also play an im-portant role in the development of cancer(discussed in this review). This newmodel considers that both alterationsmust cooperate for the formation of acancer; the acquisition of DNA alter-ations leads to an alteration in the metab-olism of O2 and vice versa. Indeed, thereis evidence that the transition from a nor-mal to a malignant phenotype broughtabout by cancer-causing genes is associ-ated with a progressive energy switchfrom oxphos to glycolysis (69). Alter-ations in p53, one of the most frequentlymutated tumor-suppressor genes in can-cer, have also been proposed to partici-pate in the metabolic switch from oxphosto glycolysis (48). Mitochondrial muta-tions may reduce the activity of oxphosand have been associated with an in-crease in the cellular production of ROS(70). The activation of several oncogenesis also known to increase the cellularproduction of O2

•– and H2O2 (71–74).Conversely, an alteration in the metabo-lism of O2 (from the pathway that gener-ates ATP to the pathway that generatesO2

•– and H2O2) can lead to the acquisi-tion of DNA alterations. H2O2 is indeedwell known to induce DNA alterations,

Figure 2. Models of carcinogenesis. In addition to the acquisition a complex array of DNAalterations proposed in the accepted model of carcinogenesis (A), the model discussedin this review (B) proposes that cancer develops an alteration in the metabolism of oxy-gen. Although both changes must interact for the development of cancer, the alteredoxygen metabolism of tumor cells is not subject to the high genetic complexity and vari-ability of tumors and may therefore be a more reliable target for cancer therapy.



including DNA damage, mutations andgenetic instability (75–78).

Most carcinogenic agents have beenshown to induce DNA alterations. Mostcarcinogenic agents also induce oxidativestress (38,79), and a deviation in the me-tabolism of O2 toward the pathway thatgenerates ROS is a key feature of oxida-tive stress (38,60,79). An example of howa carcinogenic agent can induce bothDNA alterations and an alteration in themetabolism of O2 is shown in Figure 3.Most chemical carcinogens need to beenzymatically activated to become geno-toxic, and the cytochrome P450 (P450)enzymes are the most prominent en-zymes involved in such activation (80).The activity of P450 enzymes is associ-ated with the generation of O2

•– andH2O2 (81), and H2O2 is well known to in-duce DNA alterations (75–78). An in-crease in the generation of H2O2 is associ-ated with the activation of HIF-1 (32,57),which can lead to the repression of ox-phos and the activation of glycolysis(82,83). The accumulation of glycolyticintermediates caused by the activation ofglycolysis can also increase the activityof HIF-1 (58) (Figure 3). Carcinogenicagents can induce DNA alterations andan altered O2 metabolism independentlyof P450. For instance, the increase in theintracellular pH induced by some car-cinogenic agents seems to be crucial forthe development of cancer (84,85). A risein the intracellular pH can increase the

production of O2•– (86) and lead to DNA

alterations and a dysoxic metabolismthrough the pathways represented inFigure 3. Because exposure to manyother carcinogenic factors has been asso-ciated with an increased production ofROS (38,59,79), these carcinogenic factorsmay also lead to DNA alterations and adysoxic metabolism through the path-ways represented in Figure 3.

According to the most accepted modelof carcinogenesis, the DNA alterations of

tumor cells are a target for cancer ther-apy (Figure 2A). However, as discussedin above, the high number and variabil-ity of these DNA alterations is an obsta-cle for the design of gene-based therapiesthat may have a major impact on cancermortality (12,21). The importance of thenew model of carcinogenesis representedin Figure 2B is that it offers an alternativetarget for the treatment of cancer, whichis not subject to the high genetic variabil-ity of tumor cells and may therefore bemore easily targeted. How the altered O2

metabolism of cancer could be used ther-apeutically to kill tumor cells selectivelyis discussed in the following section.

TARGETING THE ALTERED OXYGENMETABOLISM OF TUMOR CELLS FOR THETREATMENT OF CANCER

Tumor cells and normal cells metabo-lize O2 differently; this difference couldbe exploited to target tumor cells selec-tively (Figure 4). Normal cells have fulloxphos capacity, low production of H2O2

and glycolysis inhibition in the presenceof O2. Normal cells do not need to main-tain high glycolytic activity to ensuretheir survival. Cancer cells have an alter-

Figure 3. Carcinogenic agents can induce DNA alterations and an alteration in the me-tabolism of oxygen. This figure represents an example of how a carcinogenic agent caninduce both DNA alterations and a dysoxic metabolism via P450. See text for referencesand further details.

Figure 4. Utility of the altered oxygen metabolism of cancer cells to selectively kill them.Cancer cells and normal cells metabolize oxygen differently. Because the basal levels ofH2O2 are higher in cancer cells than in normal cells, a specific increase in the concentra-tions of H2O2 may lead to cytotoxic concentrations in cancer cells but not in normal cells.In addition, because the activation of glycolysis in cancer cells is essential to prevent celldeath induced by ATP depletion and H2O2 accumulation, the attenuation of glycolysis incancer cells can induce their death. Normal cells would be less affected by this strategy,because they do not need to have increased glycolytic rates to ensure their survival. Seetext for further details. Dotted lines indicate that the pathway or process is repressed.Bolded lines indicate that the process is activated or that the levels of the molecule areincreased.



ation in the metabolism of O2 (dysoxicmetabolism), which is associated withoxphos repression, increased productionof H2O2 and increased glycolytic activity.The high glycolytic activity of cancercells is essential for their survival, be-cause it prevents cell death induced byATP depletion and H2O2 accumulation.The dysoxic metabolism of cancer cellscan be exploited to kill cancer cells selec-tively by increasing the cellular levels ofH2O2 and/or by attenuating glycolysis.These effects could be achieved by theuse of prooxidant agents and glycolysisinhibitors, alone or in combination.

Selective Killing of Cancer Cells byH2O2 and Prooxidant Agents

Recent data suggest that oxidativestress may play a role in the anticanceractivity of many chemotherapeuticagents commonly used in cancer treat-ment, including paclitaxel, cisplatin, dox-orubicin, arsenic trioxide, bortezomib,procarbazine and etoposide (87–101). Forinstance, although it has been known formany years that the microtubule proteintubulin is the therapeutic target for pacli-taxel (taxol), recent experiments haveshown that H2O2 plays an important rolein paclitaxel-induced cancer cell death(87,89). The role of ROS in the activity ofmany anticancer agents is increasinglybeing acknowledged, and the inductionof oxidative stress by prooxidant agentsis emerging as an attractive anticancerstrategy (36,94,99,102–106).

H2O2 seems to be a key player in ox-idative stress–induced cancer cell death.Many anticancer agents, such as pacli-taxel, doxorubicin and arsenic trioxide,produce H2O2 (87,90,92), and H2O2 isknown to be an efficient inducer of celldeath in cancer cells (36,93,107). Interest-ingly, cancer cells seem more susceptibleto H2O2-induced cell death than nonma-lignant cells (108–110). Investigating sev-eral cancer and normal cell lines, Chen etal. (108) observed that high concentra-tions of ascorbic acid selectively killedcancer cells and that this effect was medi-ated by H2O2. They showed, for instance,that a concentration of 50 μmol/L H2O2

induced a higher percentage of celldeath in Burkitt lymphoma cells than250 μmol/L in normal lymphocytes andnormal monocytes (108). In vitro and invivo data indicate that tumor cells pro-duce higher concentrations of H2O2 thantheir normal counterparts (49–53). Thesedata, and the fact that there is a thresholdof H2O2 above which cells cannot sur-vive, may explain why specific concentra-tions of H2O2 induce selective killing ofcancer cells (36). Overall, evidence sug-gests that increasing the levels of H2O2 incancer cells by using prooxidant agentsmay be an important therapeutic strategy.The concentration of a prooxidant agentrequired to generate levels of H2O2 thatkill cancer cells but not normal cellscould be determined in cell culture exper-iments. Then, by using an appropriateroute of administration, such concentra-tions should be achieved in vivo to ob-serve a selective antitumor effect.

Selective Killing of Cancer Cells byGlycolysis Inhibition

The increased glycolytic activity ofcancer cells seems to be important forkeeping adequate energy levels in thesecells. Xu et al. (111) observed that the in-hibition of glycolysis severely depletedATP in cancer cells and induced celldeath, especially in cancer cells with mi-tochondrial respiration defects. The de-pendence of cancer cells on glycolytic en-ergy seems to increase as malignanttransformation occurs (69). It has beenproposed that this increased dependenceon glycolysis for energy generation is animportant metabolic difference betweennormal and malignant cells that mayserve for developing therapeutic strate-gies to preferentially kill cancer cells(44,112,113). Several glycolysis inhibitorshave shown anticancer effects (for exam-ple, 2-deoxy-D-glucose, lonidamine,3-bromopyruvate and dichloroacetate)and some of them have entered the clini-cal trial stage of investigation (37,44,112,114). For example, it has been shown thatdichloroacetate, a known glycolysis in-hibitor that has been used in humans fordecades in the treatment of lactic acidosis

and inherited mitochondrial diseases, in-duced marked anticancer effects in mice(115). The authors found that dichloroac-etate in the drinking water at clinicallyrelevant doses for up to 3 months pre-vented and reversed tumor growth invivo, without apparent toxicity and with-out affecting hemoglobin, transaminaseor creatinine levels. They concluded thatthe ease of delivery, selectivity and effec-tiveness of dichloroacetate make thisagent an attractive candidate for cancertherapy, one that can be rapidly trans-lated into phase II–III clinical trials (115).Other strategies could be used to inhibitor exploit the increased glycolytic activ-ity of cancer cells. Because an increase inthe activity of the Na+/K+-ATPase pumpis associated with the activation of gly-colysis (116,117), the inhibition of thispump (for example, by cardiac glyco-sides) may result in the inhibition of gly-colysis and the selective killing of cancercells (113,118). The activation of glycoly-sis is known to increase the concentra-tion of protons in the cytosol. These pro-tons must be extruded to preventacid-induced cell death. The inhibition ofthe cellular systems involved in the ex-trusion of protons in cancer cells mayalso lead to the selective killing of cancercells (119).

Combination of Prooxidant Agentswith Glycolysis Inhibitors forAnticancer Therapy

Although ROS can induce cancer celldeath, tumor cells are known to developmechanisms that prevent ROS fromreaching cytotoxic levels. The glu-tathione and thioredoxin antioxidantsystems are crucial for detoxifying ROS.These antioxidant systems are activatedin cancer cells and play an importantrole in the development of resistance tomany anticancer agents (120–126). Like-wise, although the inhibition of glycoly-sis is an attractive anticancer strategy, invivo experiments suggest that the inhibi-tion of glycolysis may not be sufficientto induce potent anticancer effects. Ac-cordingly, although the glycolysis in-hibitor 2-deoxy-D-glucose is an efficient



inducer of cell death in vitro (127), its an-ticancer in vivo activity is not very highwhen it is used as a single agent. The an-ticancer activity of 2-deoxy-D-glucosehas been explored in combination withchemotherapeutic drugs and radiation,and some of these combinations haveentered clinical trials (44,112,128–132).

Prooxidant agents could be combinedwith glycolysis inhibitors to maximizetheir anticancer activity. Evidence indi-cates that prooxidant agents can increasethe cellular levels of H2O2 and that gly-colysis inhibitors can reduce the capacityof cells to detoxify H2O2. Experimentaldata have shown that malignant cells aremore susceptible to glucose deprivationthan nontransformed cells, and that anincrease in the levels of H2O2 may medi-ate the cytotoxic effect induced by glu-cose deprivation (53,133–135). Two possi-ble mechanisms may explain why theactivation of glycolysis performs an im-portant function in protecting tumor cellsfrom H2O2-induced cell death. First, theactivation of glycolysis increases the for-mation of pyruvate, which is an efficientscavenger of H2O2 (136–139). Second,glucose metabolism through the pentosephosphate pathway regenerates NADPHfrom NADP+ in a reaction in which glucose-6-phosphate is converted into6-phosphogluconolactone by the enzymeglucose-6-phosphate dehydrogenase. Theregeneration of NADPH is required forH2O2 detoxification through the glu-tathione peroxidase/glutathione reduc-tase system and through the thioredoxinperoxidase/thioredoxin reductase sys-tem (134,140,141) (Figure 5).

CONCLUSIONSCancer kills more than six million peo-

ple worldwide every year (142). Themortality rate of this disease has notchanged much in the past few decadeseven in developed countries such as theUnited States (29). The small decreasesobserved in recent years in some types ofcancer (29) are not attributable only tobetter therapies, but also to the imple-mentation of prevention and early detec-tion campaigns. The goal of these cam-

paigns is to make people aware thatmany cancers can be prevented by fol-lowing several guidelines, and that can-cer therapy is effective when this diseaseis detected early (30,31). Despite thesecampaigns, many cancers are still diag-nosed when cells from a primary tumorhave already metastasized to other partsof the body. At this stage of disease,tumor cells are no longer localized andcan no longer be eliminated by surgeryor radiotherapy. The main form of treat-ment at this point is chemotherapy,which consists of delivering drugs sys-temically so that they can reach and killthe tumor cells. But most of these drugsare toxic to both tumor and normal cells,cause severe side effects in patients and,therefore, need to be used at suboptimallevels. The low efficacy of chemotherapyin patients with advanced cancers is re-flected in the low 5-year survival ratesobserved in these patients (29). For in-

stance, cancer statistics show that themost commonly diagnosed cancer in theworld is lung cancer (142), that approxi-mately 50% of patients diagnosed withlung cancer have distant metastasis (29)and that only 3% of these patients man-age to survive more than 5 years (29).The low efficacy of cancer therapy forthe treatment of patients with metastasismakes the development of novel thera-peutic approaches necessary.

A novel therapeutic approach hasemerged strongly in recent years. Thisapproach seeks to attack the tumor cellsselectively and is based on understand-ing of the differences between tumorcells and nonmalignant cells. It has beenknown for many years that tumor cellshave genetic alterations and much re-search has been done to identify these al-terations. Recent analyses of human can-cers have revealed, however, that thegenetic defects of tumor cells are much

Figure 5. Key role of glycolysis in the detoxification of H2O2. Increased glucose metabolismhelps detoxify H2O2 by increasing the levels of the H2O2 scavenger pyruvate and by re-generating NADPH. Glutathione reductase (GR) and thioredoxin reductase (TrxR) needNADPH to regenerate glutathione (GSH) and thioredoxin [Trx(SH)2], which are used by glu-tathione peroxidase (GPx) and thioredoxin peroxidase (TPx) to detoxify H2O2. Thiol (SH)- reactive agents can react with the SH groups of GSH and Trx(SH)2 and induce a prooxi-dant effect by disrupting the GR/GPx and TrxR/TPx antioxidant systems.



more numerous and unstable than ex-pected (12,13). In addition, the genetic al-terations of tumor cells are not the samein different types of cancer or even indifferent people with the same type ofcancer. Given these circumstances it willprobably be very difficult to develop fu-ture gene-based therapies that may beuseful in a wide range of patients withcancer (12,20,21). Despite the complexityof the cancer genome, much research isdevoted to characterizing the geneticprofile of tumors to rationalize and per-sonalize cancer therapy (22–24).

An alternative approach has been dis-cussed in this review. In addition to build-ing up a complex set of DNA changes, ev-idence suggests that the development ofany cancer requires that tumor cells ac-quire an alteration in the metabolism ofoxygen. Interestingly, this alteration in themetabolism of oxygen can make cancercells vulnerable to therapeutic interven-tion. Their increased basal levels of H2O2

and their higher dependence on glycoly-sis for their survival make cancer cellsmore susceptible than normal cells totreatment with prooxidant agents andglycolysis inhibitors. Because this alter-ation in the metabolism of oxygen seemsto be a common feature of tumor cells,this therapeutic approach could be usedfor the treatment of a wide range of pa-tients with cancer. Future research will re-veal whether this alternative approachwill be sufficient to increase the survivalof patients with advanced cancers, orwhether it will be necessary to use it incombination with traditional chemother-apy and/or novel targeted therapies.

DISCLOSUREThe authors declare that they have no

competing interests as defined by Molecu-lar Medicine, or other interests that mightbe perceived to influence the results anddiscussion reported in this paper.

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