The cancer cell’s “power plants” as promising therapeutic targets: An overview.pdf

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J Bioenerg Biomembr (2007) 39:1–12
DOI 10.1007/s10863-007-9070-5
The cancer cell’s “power plants” as promising therapeutic
targets: An overview
Peter L. Pedersen
Published online: 3 April 2007
Abstract This introductory article to the review series
entitled “The Cancer Cell’s Power Plants as Promising
Therapeutic Targets” is written while more than 20 million
people suffer from cancer. It summarizes strategies to de-
stroy or prevent cancers by targeting their energy production
factories, i.e., “power plants.” All nucleated animal/human
cells have two types of power plants, i.e., systems that make
the “high energy” compound ATP from ADP and P i .One
type is “glycolysis,” the other the “mitochondria.” In contrast
to most normal cells where the mitochondria are the major
ATP producers (
much effort is being focused on identifying agents that
induce “necrotic,” “apoptotic” or apoptotic plus necrotic cell
death only in cancer cells. Regardless how death is inflicted,
every cancer cell must die, be it fast or slow.
Keywords Bioenergetics
Warburg effect
Anti-cancer agents
Cancer therapy
3-BrPA, Cell death
Energy metabolism
Power plants
Cytochrome c
90%) in fueling growth, human cancers
detected via Positron Emission Tomography (PET) rely on
both types of power plants. In such cancers, glycolysis may
contribute nearly half the ATP even in the presence of oxygen
(“Warburg effect”). Based solely on cell energetics, this
presents a challenge to identify curative agents that destroy
only cancer cells as they must destroy both of their power
plants causing “necrotic cell death” and leave normal cells
alone. One such agent, 3-bromopyruvate (3-BrPA), a lactic
acid analog, has been shown to inhibit both glycolytic
and mitochondrial ATP production in rapidly growing
cancers (Ko et al., Cancer Letts., 173, 83–91, 2001), leave
normal cells alone, and eradicate advanced cancers (19 of
19) in a rodent model (Ko et al., Biochem. Biophys. Res.
Commun., 324, 269–275, 2004). A second approach is to
induce only cancer cells to undergo “apoptotic cell death.”
Here, mitochondria release cell death inducing factors (e.g.,
cytochrome c). In a third approach, cancer cells are induced
to die by both apoptotic and necrotic events. In summary,
Despite the enormous amount of funding targeted for cancer
research during the past half century by funding agencies
throughout the world and by private donors, particularly in
the U.S.A., a major victory in our ongoing war against this
frequently fatal disease does not appear imminent. Thus,
some reports predict even today that one in two men and
one in three women are likely to die of cancer. Consid-
ering there are about 6.5 billion people in the world to-
day (World Fact Book, Central Intelligence Agency, Of-
fice of Public Affairs Washington, D.C., July 2006), and
about half are men and half are women, it can be estimated
that if anti-cancer agents with long-term curative effects are
not found soon, particularly for advanced “metastatic” can-
cers, that the cause of death for about 2.7 billion people,
i.e., about 42% of the world’s current population, will be
Although during the past century, a number of diseases
have been seriously curtailed including those related to
bacterial infection, polio, smallpox, and even heart disease,
cancer is rapidly becoming “public enemy number one.”
Despite this, there is historical solace in the fact that bacterial
Department of Biological Chemistry, Johns Hopkins University,
School of Medicine, 725 North Wolfe Street, Baltimore,
Maryland 21205-2185, USA
Springer Science + Business Media, LLC 2007
P. L . P e d e r s e n (
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J Bioenerg Biomembr (2007) 39:1–12
infections that had posed a constant death threat to humans
for at least 5,000 years were finally curtailed following the
discovery in 1928 of penicillin in a laboratory mold by a
single scientist, Sir Alexander Fleming (Fleming, 1929).
This led to the isolation/manufacture of penicillin on a
large scale and the discovery of other anti-bacterial agents
that collectively have greatly benefited the whole world.
Therefore, optimistically, if we view cancerous cells as
sophisticated types of “infectious-like” cells that have
developed and gone awry in our own bodies, i.e., exhibit the
capacity to multiply, mutate, invade, spread (metastasize),
and kill, we can believe also that natural agents may already
exist, or synthetic agents can be made, that will selectively
and repeatedly kill the major types of cancer regardless of
Although in the U.S. alone, such success may impact
negatively on some major pharmaceutical companies, reduce
the size of the National Cancer Institute, and make the newly
built, or to be built, Comprehensive Cancer Centers in almost
all 50 states in the United States available for other health
purposes, it would most importantly reduce greatly human
suffering, increase life expectancy and the quality of that
increased life, and hopefully also reduce income taxes on
the general population who are supporting our never ending
losing war on cancer.
Despite everyone’s desire for one or more proven cancer
cures/preventions in the immediate future, our continuing
36 year war with cancer in the United States, formally de-
clared by President Richard Nixon upon signing the National
Cancer Act (U.S. Govt. Print, 1971) shows no signs of end-
ing soon. When applying this prognosis to the rest of the
world, the situation is no better and in fact in many cases
much worse. Thus, in the United States and in the rest of
the world, we are still looking for our first “Magic Bul-
let” that will consistently destroy in different patients both
primary and metastatic cancers regardless of their tissue of
origin while exhibiting minimal toxicity to the human host.
The major challenge is not to find agents that kill cancer
cells. Rather, the real challenge is to find agents that kill
cancer cells while leaving normal cells alone. To do this,
one must target one or more phenotypes unique to cancer
synthesis that will be up-regulated or subjected to different
patterns of regulation than in normal cells. Likewise, it is ex-
pected in cancer cells that the two energy (ATP) producing
power plants “glycolysis” and the oxygen dependent “mito-
chondria” will be altered such that tumors comprised of such
cells will be able to survive when oxygen is either plentiful
or limiting.
In fact, the normal to cancer cell metabolic shifts sug-
gested above do occur (Warburg, 1930; Weber and Lea,
1966; Weber, 2001), and are most evident in the more
rapidly growing (more malignant types of cancers). Thus,
enzymes involved in nucleic acid synthesis have been up-
regulated whereas those involved in nucleic acid degrada-
tion have been down-regulated. This helps assure more rapid
cell division. Likewise, in the most malignant, rapidly grow-
ing cancer cells the mitochondria have been down-regulated
frequently resulting in fewer of these organelles (Schreiber
et al., 1970; Reviewed in Pedersen, 1978), whereas enzymes
involved in glycolysis have been up-regulated (Weber, 1968;
Weinhouse, 1972; Bustamante and Pedersen, 1977). This
“shift” allows cancer cells to assume an energetic advantage
over normal cells in the sense that cancer cells can remain
alive either when ample oxygen is present or when oxygen
becomes limiting. Thus, cancer cells within tumors that have
a limited blood supply (therefore less oxygen) or cancer cells
close to a tumor’s inner core, i.e., where blood vessels may
not reach will remain viable for a longer period of time by
relying more on ATP produced by glycolysis. It should be
noted also that glycolysis (via intermediates like glucose-
6-phosphate) plays a major role in biosynthesis of the cell’s
building blocks (i.e., proteins, phospholipids, fat, and nucleic
acids). Thus, when a cancer cell’s glycolysis is enhanced, it
not only gains an advantage over normal cells in being able
to produce ATP should oxygen become limiting, but also
provides increased numbers of building blocks to help make
more cancer cells (Arora and Pedersen, 1988).
Although the molecular biological and bioenergetic-
related phenotypes in cancers seemed to be the most obvious
two phenotypes to target in the middle of the last century, it
will be noted below that the former was almost exclusively
championed, and the latter almost completely ignored. Even
when it was clear near the end of the last century that the
almost exclusive focus on potential anticancer agents that tar-
get molecular biological phenotypes was not winning the war
on cancer, the shift in focus was to signal transduction targets
(Reviewed in Dancy and Sausville, 2003) rather than targets
related to bioenergetics. Only very recently, after it has been
learned that cell death pathways (particularly those involv-
ing apoptosis), have a close relationship to the cell’s bioen-
ergetic machinery (Reviewed in Jiang and Wang, 2004) has
there been an overwhelming interest in seriously considering
bioenergetic or bioenergetic-related phenotypes as potential
anticancer drug targets.
Cancers’ major phenotypes as rational drug targets
Although cancer cells have many phenotypic differences
from normal cells, two general categories stand out, i.e.,
those related directly to enhanced cell division ( molecular
biological phenotypes ) and those related to fueling this en-
hanced cell division ( bioenergetic phenotypes ). Because can-
cer cells divide more rapidly than normal cells, it is expected
that there will be certain enzymes involved in DNA and RNA
J Bioenerg Biomembr (2007) 39:1–12
Therapy for cancer, part I: An initial and persistent
half century focus on targeting molecular
biological phenotypes
mechanism of hormone action discovered cyclic AMP (Rall
and Sutherland, 1958; Sutherland and Rall, 1958). Subse-
quently, many signal transduction pathways were discovered
that commenced via either hormone binding or other types
of induction. This led eventually to the additional discovery
that the human genome encodes over 500 protein kinases
that can be grouped into approximately 20 known families
(Manning et al., 2002), thus revealing the extent to which
signal transduction pathways are involved in modulating key
events occurring in human cells.
Now, over 30 clinical trials are under way to defeat sev-
eral types of cancers with either small molecule inhibitors
of selected protein kinases or monoclonal antibodies to one
or more of their domains (Fischer et al., 2003). Of these
novel anticancer agents, Gleevec (Imatinib mesylate) and
Herceptin (Trastuzumab) have received the greatest atten-
tion (Fischer et al., 2003). Gleevec is a small molecule
ATP analogue that targets protein kinase domains in the
proteins named BCR-Abl, ckit, and the platelet-derived
growth factor receptor while Herceptin is a monoclonal
antibody that targets the receptor tyrosine kinase named
HER2. Remarkably, Gleevec has been approved by the FDA
( on 9
different occasions in this new century for different cancers.
Among these are chronic myelogenous leukemia (CML),
malignant gastrointestinal stromal tumors (GIST), and newly
diagnosed Ph
Following World War II, the thrust of cancer research focused
primarily on the development of new anticancer agents that
targeted molecular biological phenotypes that were accentu-
ated in cancer cells. Among these were derivatives of folic
acid, a member of the vitamin B complex that is required
for DNA synthesis via an enzyme named thymidylate syn-
thase (Reviewed in McGuire, 2003). Such derivatives were
first used by Sidney Farber and colleagues (Farber, 1950)
at Harvard to treat acute lymphoblastic leukemia in chil-
dren. This initial thrust into targeting DNA related processes
was likely accelerated immensely after 1962 by the award-
ing of the Nobel Prize to James Watson, Francis Crick, and
Maurice Wilkins for their work on the “double helix.” Thus,
many other agents were later either synthesized or isolated
from natural sources to target nucleic acid synthesis/function
in cancers. The NCI website (
cancer/searches/standard mechanism.html) list these agents
under 6 different categories: Alkylating agents (e.g., cis-
platinum, mitomycin c), Antimitotic Agents (e.g., taxol
(paclitaxel), colchicines, vincristine), DNA Antimetabolites
(e.g., ara c, hydroxyurea, and thioguanine), RNA/DNA
Antimetabolites (e.g., 5-fluorouracil, methotrexate), Topoi-
somerase I inhibitors (e.g., campothecin and deriva-
tives), and Topoisomerase II inhibitors (e.g., doxorubincin,
Although a detailed analysis of the literature will certainly
reveal many success stories with such agents either alone or
in combination, cancer has continued to be a major health
problem worldwide, the U.S. being no exception. This is
despite other notable advances that include earlier detection
methods, improved treatment centers, and more knowledge
about the disease. Therefore, there has been a continued
search for newer, more powerful, and specific agents, and
hopefully one or more agents that might be called “the peni-
cillin for cancer,” or at the minimum “the penicillin” for one
or more cancer types.
chronic myelogenous leukemia. Herceptin,
approved earlier by the FDA in 1998, is used in the treatment
of metastatic breast cancer. Other signal transduction based
drugs in clinical development are targeting pancreatic, lung,
colorectal, stomach, ovarian, and prostate cancer (Fisher
et al., 2003).
Despite the success today with Gleevec as an anticancer
agent, particularly in patients with CML, it now seems clear
that this agent in some patients can cause cardiotoxicity, i.e.,
left ventricle dysfunction (Kerkela et al., 2006; Strebhardt
and Ullrich, 2006).
Therapy for cancer, part III: Targeting phenotypes
related to bioenergetics
Therapy for cancer, part II: A shift toward agents
that target signal transduction pathways
Death by necrosis
The end of the 20th century and our entry into the 21st cen-
tury has seen some significant movement away from molec-
ular biological phenotypes as the almost exclusive targets for
anticancer drug development and some rather significant fo-
cus on signal transduction phenotypes (Dancy and Sausville,
2003). This new direction had its origin more than 3 decades
earlier following the awarding of the Nobel Prize in 1971 to
Earl Sutherland who while working with T. W. Rall on the
Necrosis is a term that has been associated more in the lit-
erature to death of normal cells as a consequence of tissue
injury than to cancer therapy. Such injury to normal tissues
may result because of a lack of oxygen, e.g., to the heart re-
sulting in cardiac arrest or to the brain resulting in stroke. In
either case, the mitochondria become compromised, glycol-
ysis cannot fully compensate, cell ATP levels drop precip-
itously and death results. Death by necrosis is a quick way
to die. To understand the targeting of cancer via agents that
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J Bioenerg Biomembr (2007) 39:1–12
induce necrosis requires some understanding of the bioen-
ergetics/metabolism of cancers, particularly those that are
referred to as “PET positive.”
One of the problems with cancer as a disease in humans is
that it is frequently asymptomatic and not detected until an
advanced stage. At this stage such tumors are likely poorly
differentiated and have undergone many changes. The most
well known bioenergetic change (phenotype) of such can-
cers is their capacity to catabolize glucose at elevated rates
to pyruvic acid, a significant portion of which is then con-
verted to lactic acid and transported out of the cell (Warburg,
1930). This metabolic property of many cancers occurs even
in the presence of oxygen and is referred to as the “ Wa r bu rg
effect ”or“ high glycolytic phenotype ,” the former des-
ignation after its discoverer, the German scientist Otto
Warburg. In fact, PET analysis for cancer (Reviewed in
Shields, 2006; Cherry, 2006) monitors the “Warburg effect”
and is one of the most common detection methods for can-
cer used clinically throughout the world. Warburg received
the Nobel Prize in 1931 for his pioneering studies on cell
respiration but never lived to fully appreciate the clinical
applications of his work.
It is important to note that in PET scan positive tumors
not all the pyruvate derived from glucose catabolism is con-
verted to lactic acid. Some enters the mitochondria and
becomes oxidized, at least in part, to carbon dioxide and
water, a process that involves the tricarboxylic acid cycle
and the electron transport chain. In fact, in those advanced
“highly glycolytic” cancer cells that have been examined
carefully, it is found that significant energy (ATP) is derived
from both glycolytic and mitochondrial events (Aisenberg,
1961) . In one of the most extreme cases studied, mitochon-
drial ATP production was estimated at about 40% and gly-
colytic ATP production at about 60% (Nakashima et al.,
1984). This is in sharp contrast to most normal cells where
the mitochondria are responsible for over 90% of the ATP
From the above, one can see clearly why the “high gly-
colytic phenotype” serves the advanced cancer cell well and
gives it an energetic advantage over those normal cells re-
siding in its tissue of origin. Thus, the advanced cancer
cell thrives when oxygen is either plentiful or reduced, and
because of its rapid division can “crowd out” surrounding
normal cells while subjecting them to a constant stream of
acid (“chemical warfare”). In addition, once a solid tumor is
formed within one human organ, some of its cancer cells can
separate, sometimes as clusters, travel (metastasize) through
the blood stream (Elshimali and Grody, 2006) where “food”
(glucose) is plentiful, and eventually settle into a comfortable
environment in one or more other body organs. Here, it will
undergo multiple divisions until a new tumor is developed
that will become vascularized and receive both oxygen and
glucose from the blood of the human host. Thus, the new
tumor in its new body organ will be using also both of its
power plants (glycolysis and mitochondria) to provide the
ATP essential for its survival and rapid growth (Fig. 1A).
To quickly arrest the growth of a tumor characterized by
the “high glycolytic” phenotype where it is in fact fueled
by significant amounts of ATP derived from both glycolysis
and the mitochondria (See above discussion), it is essen-
tial to have an agent that will “selectively” destroy both
“power plants” of the tumor while leaving the power plants
in the surrounding normal tissue alone. That is, to subject
the tumor to a quick death it is important to induce necro-
sis in each of its cells while doing minimal harm to normal
One approach (“Trojan Horse”) is to screen for and iden-
tify an agent that will preferentially enter tumor cells, and
once inside destroy both its “power plants,” i.e., glycoly-
sis and mitochondria. This would cause a rapid decline in
cell ATP levels inducing death mainly by “necrosis” (Fig.
1A). The second approach (“Backdoor Block”) is to iden-
tify an agent that will selectively block the exit of lactic
acid from the tumor cells (i.e., inhibit the lactate transporter)
without doing the same to normal cells. By blocking the
exit of lactic acid, the tumor cells’ internal pH will be low-
ered and this increased acidity will have a deleterious effect
on both power plants resulting in death predominantly by
The first approach (“Trojan Horse”) noted above, i.e., “to
identify an agent that will preferentially enter tumor cells but
not normal cells, and once inside the tumor cells destroy both
power plants (Fig. 1A),” has been accomplished. Thus, fol-
lowing the discovery by Ko et al. (2001) that the lactic acid
analog 3-bromopyruvic acid (3-BrPA) inhibits hepatocellu-
lar carcinoma cells in tissue culture, advanced cancers (hepa-
tocellular carcinomas) were completely eradicated (Fig. 1B)
with this agent in 19 out of 19 animals without harm to the
animals (Ko et al., 2004; Also see Supplement to Ko et al.,
2004). Moreover, all animals lived thereafter a normal life
without tumor recurrence. [A unique aspect of this study that
is rarely presented in published work to verify therapeutic
success over a given type of cancer is that photographs of
animals bearing healthy growing tumors to be treated are
presented followed by photographs of the same animal at
different stages of treatment. In addition, photographs of the
tumor free animals are shown after the tumors have disap-
peared. Finally, photographs revealing the results of PET, the
analysis that monitors the high glycolytic cancer phenotype,
are shown before and after treatment. Significantly, these
two types of visual data verify tumor eradication. What is
more common to see in many animal studies with a poten-
tial anticancer agent is the absence of such photographs/data
during the treatment process. Rather, a Kaplan-Meier sur-
vival curve (Allison, 1995) is shown that reveals, relative
to untreated controls, how many of the animals’ lives have
J Bioenerg Biomembr (2007) 39:1–12
been extended and for how long. Unfortunately, this survival
curve also reveals for most, if not all cases, that the agent
being tested rarely “cured” the animal of its cancer, unlike
3-BrPA in the study noted above by Ko et al., 2004]. Fi-
nally, it should be noted also that an earlier study involving
the use of 3-BrPA to treat liver implanted dermatoid tumors
in rabbits also showed impressive results, although animal
survival was not monitored (Geschwind et al., 2002).
The potent anticancer agent 3-BrPA has been called an
“energy blocker” (Foubister, 2002) for highly malignant
cancer cells as it inhibits both of their “power plants”
(glycolysis and mitochondria) while leaving normal cells
alone. Like a “Trojan horse” 3-BrPA likely enters cancer
cells through the same “gates,” i.e., lactic acid transporters,
that lactic acid goes out (Fig. 1A). Normal cells are spared
as they have a much lower number of such transporters.
(The transporter for lactic acid is in the “mono-carboxylic
acid transporter family”).
Studies involving the second approach (“Backdoor”)
noted above to selectively arrest the growth of highly gly-
colytic cancers had its roots three decades ago in studies by
Spencer and Lehninger (1976). These investigators showed
that lactic acid transport could be inhibited by alpha-cyano-4-
hydroxycinnamate (ACCA), alpha-cyano-3-hydroxycinna-
mate, or DL-p-hydroxyphenyl-lactate. Subsequent studies
pursued by Johnson et al. (1980) showed that lactic acid
transport could be inhibited also by isobutylcarbonyl lactayl
anhydride (iBCLA) resulting in a decrease in intracellular
pH. Although these early studies focused on identifying
inhibitors of lactate transport out of tumor cells, more recent
work has applied this approach to cancer therapy. In these
studies one first inhibits lactic acid exit (“Backdoor”) from
highly glycolytic cancer cells and then allows time for the
acid concentration to rise inside the cell, lower the pH,
and induce cell death. Specific examples are the recent
studies of Mathupala et al. (2004) who were able to inhibit
dramatically (92%) the viability of malignant glioma cells
(U-87) using small interfering ribonucleic acids specific
for monocarboxylic acid transporters 1 and 2 (i.e., MCT1
and MCT2), and the studies of Fang et al. (2006) who
were able to diminish cell viability in neuroblastoma cells
using the lactic acid transport inhibitor (ACCA) noted
of cell death from that which results from “necrosis.” In bio-
chemical terms the author of the current article has already
defined necrotic cell death above as death that results when a
living cell is deprived of both its ATP sources (Fig. 1A), i.e.,
glycolysis and mitochondria. Apoptotic cell death is quite
different (Fig. 1A). In this case, the cell suicide program
of events commences with a death signal (i.e., “it’s time to
die”) that may originate either within the cell or from ex-
ternal signals acting on membrane receptors. Whatever the
case, i.e ., an intrinsically initiated pathway for cell death or
an extrinsically initiated pathway (Fig. 1A), central players
in the death events include mitochondrial proteins, in partic-
ular cytochrome c that is released, and a number of proteins
that reside outside the mitochondria that include proteases
referred to collectively as caspases (Reviewed in Jiang and
Wang, 2004).
During cell life cytochrome c is required in our mito-
chondria to participate in the final stages of the biological
oxidation of food that we consume (Reviewed in Hosler
et al., 2006). Interestingly, it is loosely bound to the outer
surface of the inner membrane where it transfers electrons
from complex III (b-c 1 complex) of the mitochondrial elec-
tron transport chain to complex IV (cytochrome oxidase),
the terminal complex that reduces the oxygen that we con-
sume to water. This overall process of electron transport to
molecular oxygen via the mitochondrial electron transport
chain yields the free energy necessary to drive the synthesis
of ATP that is needed for cell growth and development. If
cytochrome c is not “in place” within the mitochondrial elec-
tron transport chain, the critical process of electron transport
to molecular oxygen will come to a screeching halt, and no
ATP will be synthesized by the ATP synthase. If glucose is
present, which it usually is in a living system, the cells lack-
ing the capacity to make ATP via their mitochondria may
still survive, at least temporarily from ATP that is produced
by glycolysis. However, to assure that the cell does not sur-
vive indefinitely when cytochrome c is released, a number
of proteases are present called caspases, and with the help
of cytochrome c facilitate the cell death process via what is
referred to as the caspase cascade (Jiang and Wang, 2004).
Numerous publications (Jiang and Wang, 2004; Neuzil et al.,
2006; Cereghetti and Scorrano, 2006; Goodsell, 2004) have
dealt with how cytochrome c is released from mitochon-
dria in the initial stages of the cell death program, its in-
teraction with a complex called the apoptosome, and sub-
sequent activation of the caspase cascade leading to cell
In contrast to normal cells which turnover, and in so do-
ing must undergo cell death on a programmed schedule,
cancer cells have become immortalized. Although there are
likely a number of factors involved in this process, one of
the most critical is Type II hexokinase (hexokinase II). This
crucial metabolic enzyme was first shown in a collaborative
Death by apoptosis
“Apoptosis” is defined as the process of programmed cell
death. Unlike necrosis, apoptosis is not a quick way to die.
The pioneers in the discovery of this process were Sydney
Brenner, H. Robert Horvitz, and John E. Sulston all of whom
shared a Nobel Prize in 2002. The term “apoptosis” was used
by Kerr et al. (1972) in order to distinguish this natural type
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