Anti-Cancer Agents in Medicinal Chemistry, 2008, 8, 305-312

305

The Warburg Effect: Why and How do Cancer Cells Activate Glycolysis in the
Presence of Oxygen?
Miguel Lpez-Lzaro*
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Spain
Abstract: Cells can obtain energy through the oxygen-dependent pathway of oxidative phosphorylation (OXPHOS) and through the
oxygen-independent pathway of glycolysis. Since OXPHOS is more efficient in generating ATP than glycolysis, it is recognized that the
presence of oxygen results in the activation of OXPHOS and the inhibition of glycolysis (Pasteur effect). However, it has been known for
many years that cancer cells and non-malignant proliferating cells can activate glycolysis in the presence of adequate oxygen levels
(aerobic glycolysis or Warburg effect). Accumulating evidence suggests that the persistent activation of aerobic glycolysis in tumor cells
plays a crucial role in cancer development; the inhibition of the increased glycolytic capacity of malignant cells may therefore represent a
key anticancer strategy. Although some important knowledge has been gained in the last few years on this growing field of research, the
basis of the Warburg effect still remains poorly understood. This communication analyzes why cancer cells switch from OXPHOS to
glycolysis in the presence of adequate oxygen levels, and how these cells manage to avoid the inhibition of glycolysis induced by oxygen. Several strategies and drugs that may interfere with the glycolytic metabolism of cancer cells are also shown. This information may
help develop anticancer approaches that may have clinical relevance.

Key Words: Aerobic glycolysis, glycolysis inhibitors, metabolism, dysoxic metabolism, hypoxia-inducible factor 1, reactive oxygen species,
hydrogen peroxide, superoxide anion.
1. INTRODUCTION
Most of the energy that cells need to live is produced in the
mitochondria through an oxygen-dependent process called oxidative phosphorylation (OXPHOS). This process couples the oxidation of NADH and FADH2 with the phosphorylation of ADP to
form ATP, the chemical energy currency of cells. OXPHOS is oxygen-dependent because the electrons resulting from the oxidation of
NADH and FADH2 need to be ultimately accepted by oxygen (O2).
Cells can also produce ATP through glycolysis, which takes place
in the cytosol and does not require O2. In the process of glycolysis,
one molecule of glucose is broken down into two molecules of
pyruvate, resulting in the production of ATP. This process consumes NAD+, which can be regenerated by the conversion of pyruvate to lactate (Fig. 1). OXPHOS is more efficient in generating
ATP than glycolysis; the oxidation of one molecule of glucose
gives a net yield of 30 ATPs via OXPHOS and 2 ATPs via glycolysis. It is comprehensible, therefore, that cells generate ATP through
OXPHOS when they have enough O2 levels. This was first noted by
Pasteur in the late 19th century, who observed that, as the O2 levels
decreased, the generation of ATP shifted from OXPHOS to glycolysis (Pasteur effect) [1-4].
In the first half of the 20th century, Otto Warburg first observed
that cancer cells had increased rates of glycolysis despite the presence of adequate O2 levels [5]. This phenomenon, called aerobic
glycolysis or Warburg effect, has repeatedly been observed in cancer cells [6-8]. Indeed, the widespread clinical use of the imaging
technique positron-emission tomography using the glucose analogue tracer 18fluorodeoxyglucose (FdG PET) has demonstrated that
the glycolytic phenotype is observed in most human cancers [6]. It
has also been known for several decades that the metabolic switch
from OXPHOS to aerobic glycolysis is not a unique feature of tumor cells, as it is also found in non-transformed proliferating cells
[9-11]. These experimental observations raise two questions that
have long puzzled cancer biologists. First, if OXPHOS is more
efficient in generating ATP than glycolysis, why do cancer cells
and non-malignant proliferating cells activate glycolysis when the
O2 levels are adequate? Second, if O2 acts as a glycolysis inhibitor
*Address correspondence to this author at the Department of Pharmacology,
Faculty of Pharmacy, C/ Profesor Garca Gonzlez, 41012 Sevilla, Spain;
Fax: +34 954 23 37 65; E-mail: mlopezlazaro@us.es
1871-5206/08 $55.00+.00

(Pasteur effect), how do these cells manage to activate glycolysis in

the presence of O2 ?
An understanding of the Warburg effect might be exploited
therapeutically, as the sustained activation of glycolysis in tumor
cells seems to play a crucial role in cancer development. For instance, recent data suggest that cancer cells may depend on glycolysis for ATP generation and that cancer cells dependence on glycolytic energy progressively increases as malignant transformation
occurs [7, 12-14]. Furthermore, it has been demonstrated that the
accumulation of glucose metabolites caused by the constitutive
activation of glycolysis results in the activation of hypoxiainducible factor 1 (HIF-1) [15, 16]. The activation of HIF-1 increases the transcription of many genes that code for proteins that
favor cancer development, including proteins involved in glucose
metabolism, apoptosis resistance, invasion, metastasis and angiogenesis [17-19]. Evidence suggests that the persistent activation of
glycolysis can also favor tumor growth [20, 21], as well as tumor
invasion and metastasis via acidification of the tumor microenvironment [22, 23]; indeed, it has been proposed recently that the
glycolytic phenotype is necessary for evolution of invasive human
cancers [6, 22]. The present communication analyzes why cancer
cells switch from OXPHOS to aerobic glycolysis and how they
avoid O2-induced glycolysis inhibition. In addition, possible strategies aimed at inhibiting glycolysis in cancer cells are discussed, and
several drugs that may interfere with the glycolytic metabolism of
cancer cells are examined. This knowledge may help develop effective antitumor strategies.
2. WHY DO CANCER CELLS ACTIVATE GLYCOLYSIS IN
THE PRESENCE OF O2 ?
The first explanation for the phenomenon of aerobic glycolysis
was given by Otto Warburg several decades ago. He proposed that
cancer cells have increased glycolytic rates despite the presence of
O2 because these cells have irreversible damages to OXPHOS [5].
Despite being rejected in the beginning, recent observations seem to
support this hypothesis. For instance, it has been reported that cells
from the most common cancer types have decreased expression of
ATP synthase [24, 25], a protein complex required for OXPHOS.
Mitochondrial mutations, which may lead to malfunction in OXPHOS, have also been observed in tumor cells [7]. It has also been
shown that inactivation of p53one of the most commonly mutated genes in cancermay trigger the Warburg effect; p53 is in 2008 Bentham Science Publishers Ltd.

306 Anti-Cancer Agents in Medicinal Chemistry, 2008, Vol. 8, No. 3

Miguel Lpez-Lzaro

Fig. (1). Simplified diagram of the processes of glycolysis and oxidative phosphorylation (OXPHOS). Cells can produce ATP in the cytosol through glycolysis
by converting glucose into pyruvate. This process consumes NAD+, which can be regenerated by reducing pyruvate to lactate in a reaction catalyzed by the
enzyme lactate dehydrogenase (LDH). Pyruvate can also be used to produce ATP in the mitochondria through OXPHOS. Pyruvate passes the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). Pyruvate transport into the mitochondrial matrix across the inner mitochondrial
membrane (IMM) is driven by an electrochemical H+ gradient across this membrane. Once in the matrix, pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate to acetyl-CoA; this enzyme is inhibited by pyruvate dehydrogenase kinase (PDK). Acetyl-CoA is oxidized in the tricarboxylic acid cycle
(TCA) to CO2, producing NADH and FADH2. The electrons of NADH and FADH2 are transported along the electron transport chain (ETC) to O2. This electron transport drives the pumping of H+ from the mitochondrial matrix to the intermembrane space. This generates an electrochemical H+ gradient across the
inner mitochondrial membrane, which is used by ATP synthase to phosphorylate ADP to form ATP.

volved in the activity of cytochrome c oxidase, a protein complex

involved in OXPHOS [26]. However, recent data have shown that
glycolysis inhibition in cancer cells can enhance OXPHOS activity;
this seems to indicate that the Warburg effect is not caused by irreversible damages to OXPHOS [21, 27]. This last observation is
supported by the fact that the Warburg effect has also been observed in non-transformed proliferating cells, which are not supposed to have irreversible damages to OXPHOS.
Based on mathematical models and empirical observations, it
has been proposed recently that cancer cells activate aerobic glycolysis because the persistent activation of glycolysis leads to environmental acidosis, which is toxic to normal cells but harmless to
cancer cells. The sustained activation of glycolysis would therefore
provide cancer cells with a powerful growth advantage that would
prevail over an efficient ATP generation through OXPHOS [6].
However, it is known that normal cells (e.g. lymphocytes) activate
aerobic glycolysis when they are proliferating but come back to
OXPHOS when they are in a resting state [11]. If cells activate
aerobic glycolysis in order to get a powerful growth advantage, it is
not clear why cancer cells keep this advantage while normal cells
come back to OXPHOS and give up this benefit. Although we cannot rule out that cancer cells and non-malignant proliferating cells
activate aerobic glycolysis for different reasons, it seems sensible to
believe that there may be common reasons that explain the Warburg
effect in both cell types.
Established biochemical evidence indicates that, in addition to
generating ATP, the activation of glycolysis serves the key purpose
of providing carbon skeletons for biosyntheses. This implies that
the activation of glycolysis is essential for cell proliferation, as cell

proliferation requires the synthesis of new molecules (e.g. nucleic

acids, lipids, proteins) and as glycolysis provides most of the building blocks required for the synthesis of these molecules [2-4]. For
instance, as represented in Fig. (2), cells need to synthesize nucleic
acids in order to proliferate (S-phase of the cell cycle). The starting
point for nucleotide biosynthesis is the sugar ribose-5-phosphate,
which is derived from the glycolytic metabolite glucose-6-phosphate. Likewise, the glycolytic metabolites glucose 6-phosphate, 3phosphoglycerate, phosphoenolpyruvate and pyruvate are key precursors in the biosynthesis of several amino acids (i.e. His, Ser,
Cys, Gly, Tyr, Phe, Trp, Ala, Val, Leu) [4] required for the synthesis of proteins. In addition, the glycolytic metabolite dihydroxyacetone phosphate is the key precursor of glycerol, a necessary metabolite for the synthesis of lipids. Lipid formation also requires
fatty acids, and experimental data support that glucose-induced
cytosolic synthesis of acetyl CoA is required for the synthesis of
fatty acids [27-29].
The essential role of glycolysis in cell proliferation is supported
by experimental observations that have revealed that cell proliferation is inhibited in normal and cancer cells placed in glucose deficient media containing high levels of alternative energy sources, or
in cells treated with the non-metabolizable glucose analogue 2deoxyglucose (3) [11, 30-32]. These observations support that cancer cells and non-malignant proliferating cells may activate glycolysis in the presence of O2 in order to proliferate (Fig. 2). In other
words, if glycolysis was always inhibited in the presence of O2,
cells could not keep sustained proliferative rates under aerobic conditions. It is important to note that, despite being a powerful reason,
there is evidence that suggests that non-malignant proliferating cells

The Warburg Effect

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307

Fig. (2). Key role of glycolysis in cell proliferation. Cell proliferation requires the presence of mitogenic signals and the synthesis of new macromolecules (e.g.
nucleic acids, lipids, proteins). Glycolysis provides building blocks (e.g. glucose 6-phosphate, dihydroxyacetone phosphate, 3-phosphoglycerate, phosphoenolpyruvate, pyruvate) that participate in the synthesis of these macromolecules. If glycolysis was always inhibited in the presence of O2 (Pasteur effect), cell
proliferation would be restricted under aerobic conditions. This may contribute to explain why normal proliferating cells and cancer cells activate glycolysis in
the presence of O2.

and cancer cells do not activate aerobic glycolysis with the sole
purpose of proliferating [33]. For instance, the activation of aerobic
glycolysis seems to play an important role in the protection against
cell death induced by reactive oxygen species (ROS) such as hydrogen peroxide [10, 34-37]. Likewise, it has been proposed that,
although OXPHOS produces more energy per molecule of glucose
than glycolysis, glycolysis is capable of producing ATP considerably faster than OXPHOS as long as glucose supplies are unlimited.
Growing cells have an enormous demand for ATP to fuel their
growth, and glycolysis seems much better suited to meeting this
demand [27, 38].
3. HOW DO CANCER CELLS ACTIVATE GLYCOLYSIS IN
THE PRESENCE OF O2 ?
Recent reports have shown evidence that suggests that cancer
cells have an alteration in O2 metabolism (dysoxia or dysoxic metabolism), which may drive tumor growth, invasion and metastasis
[20, 23, 39]. This section discusses that this alteration in O2 metabolism may also play a key role in the Warburg effect. In the process
of OXPHOS, ATP generation is coupled with a reaction in which
O2 is reduced to H2O. But under certain conditions, O2 can also be
reduced to H2O via the ROS superoxide anion (O2) and hydrogen
peroxide (H2O2). Fig. (3) represents that a deviation of O2 metabolism from the route that generates ATP to the route that produces
O2 and H2O2 can activate aerobic glycolysis.
A decrease in O2 metabolism via OXPHOS can activate aerobic
glycolysis. It is recognized that high ATP levels can repress glycolysis via allosteric inhibition of phosphofructokinase (PFK), a key
enzyme in the regulation of glycolysis [2]. The possible basis of the
Pasteur effect is that O2 allows ATP synthesis through OXPHOS;

this produces an allosteric inhibition of PFK resulting in glycolysis

inhibition [2, 39]. This implies that glycolysis is not directly inhibited by O2, but by ATP. It makes sense to think, therefore, that the
presence of O2 will not cause the inhibition of glycolysis when O 2
is not used to generate ATP. Accordingly, Fig. (3) proposes that
cells manage to activate glycolysis in the presence of O2 by reducing O2 metabolism through OXPHOS. A decrease in O2 metabolism
through OXPHOS would reduce ATP generation; this would release PFK inhibition by ATP and would activate glycolysis. The
activation of glycolysis would compensate the decreased ATP generation through OXPHOS.
An increase in O2 metabolism through the ROS O2 and H2O2
may also produce aerobic glycolysis. It is known that O2! can produce intracellular alkalinization (!pHi) [40, 41] and that intracellular alkalinization can activate glycolysis by increasing the activity
of PFK; the activity of this enzyme is extremely sensitive to small
changes in pH in the physiological range, a high pH increasing the
activity of this enzyme) [39, 42, 43]. Although the activation of the
enzyme PFK is fundamental in the activation of glycolysis, cells
need to increase the expression of glucose transporters (e.g.
GLUTs) and glycolytic enzymes (e.g. hexokinase, PFK, pyruvate
kinase) to keep sustained glycolytic rates. It is now well accepted
that an increase in the cellular levels of H2O2 activates HIF-1 [39,
44-46]. HIF-1 activation plays a key role in the transcription of
genes that code for glucose transporters and glycolytic enzymes
[17, 47-49]; indeed, it has been observed that cells lacking HIF-1
exhibit decreased glycolytic capacity [48]. H2O2 can also activate
Akt [50-52] and the oncogenes ras, src, and myc [53, 54], which are
involved in the synthesis of glucose transporters and glycolytic
enzymes [55, 56]. Although Akt, ras and src are known to activate

308 Anti-Cancer Agents in Medicinal Chemistry, 2008, Vol. 8, No. 3

HIF-1 [17, 55], the possibility that H2O2-induced transcription of

glucose transporters and glycolytic enzymes may occur independently of HIF-1 cannot be excluded [57].
Experimental observations support that many situations that
have been linked to the Warburg effect may be integrated in the
model represented in Fig. (3). As mentioned before, the first explanation to the Warburg effect was given by Otto Warburg, who proposed that this phenomenon was caused by irreversible damages to
OXPHOS [5]. While some observations support that cancer cells
have alterations in proteins involved in OXPHOS [7, 24-26], others
suggest that the Warburg effect is not caused by irreversible damages to OXPHOS [21, 27]. All these observations can be integrated
in the model shown in Fig. (3), which proposes any situation that
produces a decrease in OXPHOS activity in the presence of O2 can
produce the Warburg effect.
It has been discussed recently that cancer cells have increased
rates of aerobic glycolysis because of an adaptation to intermittent
hypoxia [6]. It is known that intermittent hypoxia increases O2!
generation [58, 59] and, according to the model represented in Fig.
(3), an increased O2! generation would lead to the activation of
aerobic glycolysis. The present model also agrees with the proposal
that intracellular alkalinization is involved in the Warburg effect
[60-62], as intracellular alkalinization may cause OXPHOS repression [39] and glycolysis activation [42, 60, 61]. Accordingly, experimental data suggest that intracellular alkalinization may inactivate p53 [63], and p53 inactivation may cause the Warburg effect
[26]. Although it has been shown that IL-3 can increase glycolysis
through activation of the Akt/Pim kinases [33, 64], IL-3-induced
activation of glycolysis might also be integrated in Fig. (3), as IL-3
can increase O2! generation [65] and the intracellular pH [66].

Fig. (3). A deviation of O2 metabolism from the route that generates ATP
(OXPHOS) to the route that produces O2 and H2O2 may cause the activation of glycolysis in the presence of O2 (aerobic glycolysis or Warburg
effect). This deviation of O2 metabolism would avoid the inhibition of glycolysis induced by the presence of O2 (Pasteur effect).

The increased generation of H2O2 caused by the alteration in O2

metabolism shown in Fig. (3) might explain the activation of aerobic glycolysis induced by several apparently unrelated factors. Because the activation of HIF-1, akt, ras, src and myc is involved in
the synthesis of glucose transporters and glycolytic enzymes, these

Miguel Lpez-Lzaro

factors have been linked to the activation of aerobic glycolysis [15,

17, 55, 56]. Interestingly, it has been shown that H2O2 can activate
HIF-1 [44-46], akt [50-52], ras, src, and myc [53, 54]. The activity
of the Na+/K+-ATPase pump has also been associated with the activation of aerobic glycolysis [67, 68], and it has been observed that
H2O2 can activate Na+/K +-ATPase [69] and that catalase prevents
the activation of this pump [70]. In brief, it seems that many of the
situations that have been linked to the activation of aerobic glycolysis may be integrated in the model represented in Fig. (3).
HIF-1 is a heterodimeric transcription factor that consists of a
constitutively expressed HIF-1" subunit and a HIF-1# subunit, the
expression of which is highly regulated. HIF-1 overexpression has
been observed in the most common cancer types, and is therefore
considered a potential target for cancer therapy [17, 71]. The activation of HIF-1 seems to play an important role in the metabolic
switch from OXPHOS to aerobic glycolysis (Warburg effect), as
this transcription factor not only can activate aerobic glycolysis but
also repress OXPHOS [72, 73]. Indeed, experimental data have
shown that the activation of HIF-1 mediates the expression of pyruvate dehydrogenase kinase (PDK); this results in pyruvate dehydrogenase (PDH) inhibition, decreased conversion of pyruvate to acetyl-CoA, reduced activity of the tricarboxylic acid cycle and subsequent oxphos repression [72, 73] (Fig. 1). A recent article has reviewed that, in clear cell renal carcinoma (an perhaps in other human cancers), HIF-1 mediates increased glucose uptake, increased
lactate production, and decreased OXPHOS, thus delineating for
the first time the molecular mechanisms underlying the switch from
oxidative to glycolytic metabolism in human cancer [49]. Recent
evidence also suggests that an alteration in O2 metabolism (dysoxia)
may be the main mechanism responsible for HIF-1 activation under
hypoxic and aerobic conditions [39]; this supports the idea that an
alteration in O2 metabolism may cause the Warburg effect.
According to the model shown in Fig. (3), cancer cells would
activate glycolysis in the presence of O2 because of a deviation of
O2 metabolism from the route that generates ATP to the route that
produces O2 and H2O2. This alteration in O2 metabolism would
activate aerobic glycolysis by producing OXPHOS repression, increased generation of O2 and H2O2, intracellular alkalinization,
and HIF-1 activation (see Fig. 3). This model is supported by experimental data that have revealed that most cancers have HIF-1
overexpression [17, 18], alkaline intracellular pH values (7.127.65
compared with 6.997.20 in normal tissues) [60, 62, 74], excessive
generation of O2! and H2O2 [75-78] and structural alterations in
OXPHOS that may cause OXPHOS repression [7, 24-26].
4. GLYCOLYSIS INHIBITION: STRATEGIES AND DRUGS
The attenuation or inhibition of glycolysis in tumor cells may
be exploited for the development of cancer chemopreventive and
chemotherapeutic strategies. On the one hand, as illustrated in Fig.
(2) and discussed elsewhere [20, 22, 23], evidence suggests that
glycolysis is essential for cell proliferation, tumor invasion and
metastasis. The reduction of the glycolytic capacity of tumor cells
would restrict their ability to proliferate, invade adjacent tissues and
migrate to distant organs. This suggests that the attenuation of glycolysis in tumor cells may represent a useful strategy for preventing
or stopping the development of cancer (i.e. cancer chemoprevention). On the other hand, evidence supports that the activation of
glycolysis protects cells from H2O2-induced cell death [10, 34-37],
and that cancer cells are more susceptible to H2O2-induced cell
death than normal cells [78, 79]. In addition, cancer cells are more
dependent on glycolytic ATP than normal cells [7, 8, 12-14]. This
suggests that the inhibition of glycolysis may produce selective
killing of cancer cells and be a practical strategy for cancer chemotherapy (see ref. [105]).
Several strategies and drugs can be used to inhibit the glycolytic
metabolism of cancer cells. The fist and perhaps most straightforward way of inhibiting glycolysis is reducing the blood and intersti-

The Warburg Effect

tial glucose levels by using insulin therapy. Mice can survive doses
of human insulin that results in a decrease of blood glucose by one
order of magnitude (approximately, from 240 mg/dL to 24 mg/dL).
The effect of insulin on xenograft tumors is currently under investigation [80].
Inhibition of glycolytic enzymes is another strategy that may
result in glycolysis inhibition in tumor cells. As illustrated in Fig.
(2), hexokinase (HK), phosphofructokinase (PFK) and pyruvate
kinase (PK) catalyze the three irreversible reactions of glycolysis;
these enzymes are important control sites of glycolysis [2]. HK is
the fist and rate-limiting reaction in glycolysis and catalyses the
phosphorylation of glucose to glucose-6-phosphate (G6P). This step
converts a non-ionic molecule (glucose) to an anion (G6P) that is
trapped in the cells. Lonidamine (1), a derivative of indazole-3carboxilic acid that is currently undergoing clinical trials for the
treatment of benign prostatic hyperplasia, can inhibit the phosphorylation of glucose by HK. This drug is currently undergoing
clinical trials in combination with other anticancer agents for the
treatment of different types of cancer [7, 80]. The pyruvate analog
3-bromopyruvate (3-BrPA) (2) is a HK inhibitor that has shown
potent anticancer activity in preclinical studies [12, 81]. The glucose
analog 2-deoxyglucose (2-DG) (3) is a competitive inhibitor of
glucose metabolism that competes with glucose for HK. Once 2DG (3) is phosphorylated by HK, it cannot be metabolized further;
this leads to accumulation of 2-DG (3) within the cell and results in
glycolysis inhibition [7]. This agent, however, seems to produce
toxic effects when used as a primary therapy and it is currently
being explored in combination with other anticancer agents [82].
Evidence suggests that HK and glucose-6-phosphate 1-dehydrogenase (G6PDH) are primary targets of imatinib (Gleevec) (4), an
anticancer drug already approved for clinical use [83]. As mentioned before, the activity of PFK is extremely sensitive to small
changes of pH in the physiological range, a high pH increasing the
activity of this enzyme [39, 42, 43]. Evidence suggests that cancer
cells have high intracellular pH values, which may activate PFK
and contribute to explain the high glycolytic rates of these cells [6062]. Activation of H+ extruders such as the Na+/H+-exchanger NHE1 has been shown to play a key role in the elevation of the intracellular pH in cancer cells. Inhibitors of NHE-1, such as amiloride or
5,5-dimethylamiloride (DMA) (5), may therefore reduce the intracellular pH, PFK activity and glycolysis, and produce anticancer
effects. Indeed, these two drugs have shown anticancer effects in
vivo [60, 84, 85]. In addition, it is well known that PFK is inhibited
by citrate [3]. The enzyme ATP citrate lyase (ACL) catalyzes the
conversion of citrate to cytosolic acetyl-CoA. Inhibitors of ATP
citrate lyase (ACL), such as SB-204990 (6), may cause citrate to
build up and inhibit glycolysis [14, 29, 86]. It has been shown that
SB-204990 (6) limits in vitro proliferation and survival of tumor
cells displaying aerobic glycolysis and reduces in vivo tumor
growth [29]. Inhibition of the enzyme pyruvate kinase (PK), which
catalyzes the third irreversible reaction of glycolysis (Fig. 2), represents another strategy for inhibiting glycolysis; this enzyme seems
to play an important role in tumor growth and invasion, and its
inhibition may produce anticancer effects [87].
Fig. (1) shows that the enzymes lactate dehydrogenase (LDH),
pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase
(PDK) play important roles in glycolysis and OXPHOS. The enzyme LDH catalyzes a reaction by which pyruvate is reduced to
lactate; this reaction permits the regeneration of NAD+, needed for
glycolysis to continue (Fig. 1). Recent observations showed that
attenuation of LDH reduced the glycolytic metabolism of cancer
cells and produced antitumor effects in animals [21, 27]. The
authors discussed that, because individuals with complete deficiency of LDH do not show any symptoms under ordinary circumstances, the inhibition of LDH activity may represent a relatively
nontoxic approach to interfere with tumor growth [21]. Deck et al.
synthesized several dihydroxynaphthoic acids that were potent in-

Anti-Cancer Agents in Medicinal Chemistry, 2008, Vol. 8, No. 3

309

hibitors of LDH [88]; these drugs might inhibit glycolysis and display anticancer effects. On the other hand, recent evidence suggests
that HIF-1 activation mediates the expression of PDK [72, 73]; this
enzyme repress OXPHOS by inhibiting PDH (Fig. 1) and may
therefore play a role in the activation of aerobic glycolysis. Inhibition of PDK may therefore attenuate glycolysis and produce anticancer effects. Several reports have shown that different groups of
compounds are inhibitors of PDK [89-95]; these drugs may inhibit
glycolysis and produce anticancer effects. Accordingly, a recent
study have shown that the PDK inhibitor dichloroacetate (DCA) (7)
produced marked anticancer effects [95]; DCA (7) is a known glycolysis inhibitor that has been used in humans for decades in the
treatment of lactic acidosis and inherited mitochondrial diseases.
The authors observed that DCA (7) in the drinking water at clinically relevant doses for up to 3 months prevented and reversed tumor growth in vivo, without apparent toxicity and without affecting
hemoglobin, transaminases, or creatinine levels. They concluded
that the ease of delivery, selectivity, and effectiveness make DCA
(7) an attractive candidate for cancer therapy which can be rapidly
translated into phase IIIII clinical trials.
Another strategy for reducing the increased glycolytic rates of
tumor cells is the inhibition of the synthesis of glucose transporters
and glycolytic enzymes. As discussed before, the activation of HIF1 plays a key role in the expression glucose transporters and glycolytic enzymes. Inhibition of HIF-1 may therefore reduce the persistent activation of aerobic glycolysis in tumor cells and produce
anticancer effects. Preclinical studies have already shown that inhibition of HIF-1 activity has marked effects on tumor growth [17].
HIF-1 is considered a potential target for cancer chemoprevention
[19] and therapy [17] and, recently, many efforts to develop new
HIF-1-targeting agents have been made by both academic and
pharmaceutical industry laboratories [17, 18, 96, 97]. As a result,
several FDA-approved anticancer drugs (e.g. topotecan, imatinib
(4), trastuzumab, NS398, celecoxib, ibuprofen) have been found to
inhibit HIF-1 activity [18]. Several natural products (e.g. resveratrol, genistein, apigenin, berberin) have also been found to inhibit
the activity of this transcription factor [18, 97].
Several other drugs have shown ability to inhibit glycolysis,
including oxythiamine, genistein, 5-thioglucose, mannoheptulose,
!-chlorohydrin, ornidazole, glufosfamide, or arsenic compounds
(see references [7, 8]). Oxamate (an analogue of pyruvate that
blocks the step of glycolysis that converts pyruvate to lactic acid)
and iodoacetate (an inhibitor of glyceraldehyde 3-phosphate dehydrogenase) may also produce anticancer effects [98-100]. Bisphosphonates [101] or tubercidin [102] may also inhibit glycolysis in
cancer cells. As mentioned before, the activity of the Na+/K+ATPase pump has also been associated with the activation of aerobic glycolysis [67, 68]. Cardiac glycosides, such as ouabain (8) or
digitoxin, are known inhibitors of the Na+/K+-ATPase pump that
have shown anticancer effects [103-105].
Finally, Fig. (3) implies that the glycolytic capacity of cancer
cells may be restricted by preventing or reducing excessive cellular
levels of O2! and H2O2. It has been demonstrated that the use of
antioxidants, such as the enzyme catalase, prevents the activation of
HIF-1 induced by hypoxia and non-hypoxic stimuli [44-46]. Since
HIF-1 plays a key role in the activation of glycolysis, the use of
antioxidants would prevent HIF-1 activation; this would attenuate
the glycolytic capacity of tumor cells and would prevent the development of invasive cancers [23].
5. CONCLUSIONS
Cells can obtain energy through the oxygen-dependent pathway
of OXPHOS and through the oxygen-independent pathway of glycolysis. Since glycolysis is less efficient in generating ATP than
OXPHOS, it is comprehensible that glycolysis is inhibited in cells
under aerobic conditions (Pasteur effect). It is not well understood,
however, why cancer cells and non-malignant proliferating cells

310 Anti-Cancer Agents in Medicinal Chemistry, 2008, Vol. 8, No. 3

OH

Miguel Lpez-Lzaro

HO

HO
HO

Cl

OH

Br

OH

3-bromopyruvate
(3-BrPA) (2)

lonidamine (1)
Cl

2-deoxyglucose (2-DG) (3)

N
H
N

O
N

Cl

N
HN
N

HO

NH2
N

NH2

NH2

Cl

HO
O

SB-204990 (6)

Cl

HO

Cl

Cl

HO
HO
OH

O
OH OH

5,5-dimethylamiloride (DMA) (5)

imatinib (4)

OH
Rha - O

dichloroacetate (DCA) (7)

OH

ouabain (8)

Fig. (4). Selected gycolysis inhibitors. These drugs have been shown to inhibit glycolysis and produce anticancer effects.

have increased rates of glycolysis in the presence of an adequate O 2

supply (aerobic glycolysis or Warburg effect). Established biochemical evidence indicates that the activation of glycolysis is essential for cell proliferation. This suggests that, if glycolysis were
always inhibited in the presence of O2, cell proliferation would be
restricted under aerobic conditions. The necessity that cells proliferate under aerobic conditions seems a powerful reason to justify
the presence of aerobic glycolysis in cancer cells and non-malignant
proliferating cells. The possible mechanisms by which these cells
evade O2-induced glycolysis inhibition (Pasteur effect) are not welldefined. The present report has discussed evidence that supports
that the key mechanism involved in the activation of aerobic glycolysis may be a switch in O2 metabolism from the route that generates ATP to the route that produces O2 and H2O2 (dysoxic metabolism). This switch in O2 metabolism has already been proposed to
mediate other key aspects of the carcinogenesis process, including
HIF-1 activation, tumor growth, invasion and metastasis. Finally,
possible strategies and drugs that may be used for reducing the
increased glycolytic capacity of cancer cells have been shown. This
knowledge may help develop anticancer strategies, as a growing
body of research suggests that the increased glycolytic metabolism
of tumor cells plays a crucial role in cancer development.
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Received: 22 May 2007

Revised: 22 June 2007

Accepted: 25 June 2007

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