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A Metabolic Explanation of

Cancer: The Bio-Energetic Theory


of Carcinogenesis
by Michael J. Gonzalez¹, DSc, NMD, PhD, FACN, and
Jorge Duconge², PhD
the modulation of respiratory rate and oxygen (oxidative energy production)
Abstract
Cancer is considered a genetic on the production of hydrogen peroxide with a concurrent increase in energy
disease involving nuclear mutations. and other oxidative species released generation without oxygen. In other
This view has persisted despite into the cytosol. words, this theory states that cancer is
numerous inconsistencies with the All cancer cells regardless of not of genetic origin but rather a disease
somatic mutation theory. In contrast, their tissue origin express a defect in of metabolism.
emerging evidence advocates cancer mitochondrial energy metabolism. The This theory is based on the ideas
as a mitochondrial metabolic disease, view of cancer as a genetic disease proposed in 1924 by the Nobel Prize-
in accordance to the original theory has been an issue of confusion and winning German biochemist Otto
of Otto Warburg. In this paper, we
is largely responsible for the failure Warburg. These ideas were subsequently
discuss the evidence that favors
cancer as a metabolic derangement in treating the disease. This view of discarded when it was discovered that
instead of a genetic disease. This cancer as a genetic disease is based on cancer cells had mutations to their DNA.
paradigm changing concept can also the flawed assumption that somatic So, it was concluded that if cancer cells
influence how we treat cancer with mutations cause cancer—although we have mutations to the molecule that
hope in improving outcomes. should state that genomic instability is dictates all cellular functions, then that
linked to respiratory insufficiency. The must be the cause of the disease.
Introduction mitochondrial oxidative rate has to A healthy cell produces 89% of its
Eukaryotic mitochondria resulted remain depressed for cell proliferation energy using oxygen, and 11% through
from symbiotic incorporation of to occur; even in the presence of non-oxidative metabolism (non-
α-proteobacteria into ancient oxygen, energy is obtained from oxidative metabolism is also known
archaea species. During evolution, increased glycolysis (Warburg effect) as fermentation). Oxidative energy
mitochondria lost most of the (Antico-Arciuch et al, 2012). production is far more efficient than
prokaryotic bacterial genes and only It is likely that the major impediment fermentation. Almost 20 times more
conserved a small fraction, including to the effective treatment of cancer energy is released when glucose is
the encoding 13 proteins of the has been the confusion surrounding completely oxidized, as opposed to
respiratory chain. In this process, many its origin. Most of the confusion arises when it is just fermented.
functions were transferred to the from the absence of a unifying theory The Bio-Energetic Theory of
host cells, but mitochondria gained a that integrates all aspects of the disease. Carcinogenesis explains that the disease
central role in the regulation of cell We propose the Bio-Energetic Theory of begins with damage to the mitochondria.
proliferation and apoptosis, and in the Carcinogenesis as the main theory to The cell is then forced to shift energy
modulation of metabolism. Defective fill this gap in the understanding of the production to fermentation in order to
mitochondria may contribute to cell origin of cancer (Gonzalez et al, 2012). survive. So, two main characteristics of
transformation and cancer, diabetes, In general, the Bio-Energetic cancer are (1) damaged mitochondria
and neurodegenerative diseases. Many Theory of Carcinogenesis states that and (2) increased fermentation, which
effects of the mitochondria depend on cancer originates from damage to the are present in all cancer types. Also,
University of Puerto Rico, Medical Sciences Campus,
mitochondria that impairs the cell’s the greater the degree of fermentation
School of Public Health¹ and School of Pharmacy² capacity to generate energy with displayed by a given cancer, the more
RECNAC 2 Project (San Juan, Puerto Rico)

82 TOWNSEND LETTER – AUGUST/SEPTEMBER 2018


aggressive the cancer is. Because a Respiratory insufficiency precedes definitely responsible for the origin of
tumor cell’s mitochondria are damaged the genomic instability that further the disease. To make this issue even
and, therefore, are forced to generate contributes to tumor development. more confusing, the mutational profile is
energy by an inefficient pathway, Once established, this genomic different from cell to cell within the same
they need to consume much more derangement also contributes to further tumor, rendering drug development to
glucose to remain viable. A glance at respiratory impairment, mutability, target mutations next to impossible. No
a PET scan, which uses a radioactive- and tumor progression. Metabolic mutation has yet been identified that is
labeled glucose analog to image cancer, derangements precede genetic changes. reliably diagnostic of any type of cancer.
provides stunning visual evidence of It is, in essence, a process that starts So, we definitely see genetic changes in
the necessity that tumor cells have for as an epigenetic phenomenon that cancer progression but secondary to the
glucose compared to normal cells. eventually changes the genotype. metabolic problem, which contributes
It is interesting that since 1885, The genetic mutations acquired to perpetuate the malignant state.
when Freund observed that patients following mitochondrial impairment To achieve real therapeutic progress,
with malignant disease can develop
spontaneous hyperglycemia (Freund
et al, 1885), there has been episodic
While it’s true that most of the agents known to cause cancer…can
interest in the association of the cause mutations to DNA, it is also true these agents damage cell
altered glucose metabolism in nutrition membranes and especially the mitochondria.
and neoplasia (Marks et al, 1957). As
early as 1924, Händel and Tadeuma
summarized the findings in those days unquestionably contribute to the tumor the true origin of the disease needs
by the following statement: “A diet rich cell’s features and aggressiveness but to be determined. All therapeutic
in carbohydrates has a pronounced are not the cause of the disease. They progress, from prevention to treatment,
stimulating impact on tumor growth” appear to be of secondary consequence must arise from a foundation of
(Händel et al, 1924). or an epiphenomenon to the metabolic understanding of the disease.
Emerging evidence reveals that all dysfunction. While it’s true that most A series of nuclear/cytoplasm
hallmarks of cancer can be explained of the agents known to cause cancer transfer experiments are exceptionally
by mitochondrial damage followed – chemical carcinogens, viruses, important in revealing the true nature
by a shift to non-oxidative energy radiation, and inflammation – can cause of the disease. In brief, the experiments
metabolism. Once the oxidative energy mutations to DNA, it is also true these consist of transferring the nucleus of
generating capacity of the cell is agents damage cell membranes and a cancer cell into a healthy cell that
impaired, the cell undergoes a dramatic especially the mitochondria. Once the has had its nucleus removed prior.
transformation; it is when oncogenes are mitochondrion is damaged, the cell The newly created hybrid cell has
switched on, initiating and propagating reverts to fermentation to obtain energy, the genetic material of a cancer cell,
the uncontrolled proliferation that is the we can state that the cancer has begun. with all of its defects, but now has
main hallmark of cancer. It is subsequent to the shift in energy the healthy mitochondria of a normal
metabolism that genomic instability cell. Intuitively, if the origin of cancer
Genetics and Cancer and mutations occur (Seyfried et al, is indeed due to mutations to DNA,
Most genetic changes in tumor 2010). Genetic sequencing data the newly created hybrid cells that still
cells are irrelevant to the origin of has been unable to implicate genetic retain all of the mutations of the cancer
cancer. They can be described as an mutations as the cause of cancer; cell nucleus should be tumorigenic. But
epiphenomenon of the metabolic/ in contrast metabolic dysfunction they were not.
physiological chaos due to the less has been shown to be present in These experiments were carefully
availability of cellular energy. every type of cancer, regardless of executed with strict controls and
Genomic instability has been tissue of origin. In an attempt to were found to be very reproducible.
assumed to elicit the large number of explain the random complexity of the Experiments like these provide
mutations found in tumor cells, thus thousands of mutations reported in irrefutable evidence that DNA
supporting the idea that cancer is a cancer, researchers claim that cancer mutations are not the origin of cancer;
genetic disease. While genome changes is a collection of over 200 different the damaged mitochondria are. All cells
participate in disease progression, they diseases. We believe that cancer is just require regulated energy homeostasis
do not cause the disease. Cancer is a one disease, a metabolic one. It is not a to maintain their differentiated state
disease of defective cellular energy collection of over 200 different diseases (Elliott et al, 2012). It should be stated
metabolism. Most genomic effects as the genetic theory proposes. that mitochondrial dysfunction leads to
found in cancer arise as secondary The genetic mutational profile of nuclear genome instability.

downstream effects of defective energy any given cancer type looks different
metabolism (Seyfried et al, 2010). from person to person, rendering it
impossible to claim that mutations are

TOWNSEND LETTER – AUGUST/SEPTEMBER 2018 83


Carcinogenesis efficiency of aerobic glycolysis is low, normal respiration and fermentation;
since two ATP are produced, which this particular issue can bring light to

represents eighteen times less than much of the controversy surrounding
the complete degradation of glucose this hypothesis, since it can give a false
Cell Energetics
producing 36 ATP. impression of mitochondrial oxidative
In order for cells to remain viable
Aerobic fermentation involves phosphorylation.
and to perform their programmed
elevated glucose uptake with lactic acid Cancer cells not only consume
function, they must produce energy.
production in the presence of oxygen. glucose in excess but also amino
Membrane pumps require constant
Warburg stated that irreversible damage acids, especially glutamine, derived
energy to maintain functionality.
to respiration was the prime cause of from muscle proteolysis. Glutamine,
Most cell functions are linked to the
cancer (Warburg et al, 1931; Warburg et which is the preferential mode of
membrane potential and to the Na+/K+/
al 1956; Warburg et al, 1969). Warburg transportation of blood nitrogen,
Ca+ gradients. Availability of ATP to the
was the first to describe in detail the provides amine groups for several
pumps maintains these ionic gradients.
dependence of cancer cells on glucose biosynthetic processes, such as purine
If these pumps are disrupted, cellular
and glycolysis in order to maintain and pyrimidine bases synthesis.
Cancer cells that rely on glutamine for
energy production are able to produce
Lipids may have a further relevant role in carcinogenesis related to ATP through non-oxidative processes
the mitochondrial membrane…. Mitochondrial lipid abnormalities are in the mitochondria. Glutamine
common in all tumors. metabolism increases ammonia in the
extracellular environment. Ammonia
can neutralize acidity from glycolytic
dysfunction will ensue. Regardless of viability following respiratory damage lactate production (Baggetto et al,
cell type or tissue origin, cancer cells (Warburg et al, 1931; Warburg et al 1992; Kelly et al, 1974). So, caution
share a singular characteristic and 1956; Warburg et al, 1969). Warburg is therefore necessary in using pH
that is abnormal energy metabolism. considered energy as the central issue as an indicator of lactate production
Energy dysregulation is the hallmark of of carcinogenesis. Warburg considered (fermentation) in cancer cells that
malignant cells. Tumor cells differ from fermentation as the formation of lactate use glutamine as fuel. This type of
normal cells in the origin of the energy from glucose in the absence of oxygen. pseudo-respiration has the biochemical
produced rather than in the amount of This type of energy pathway is also characteristics of normal respiration but
energy produced. utilized in mammalian embryos and does not involve ATP synthesis through
We truly believe that targeting muscle cells during strenuous exercise. oxidative phosphorylation (OxPhos).
the defective energy metabolism of Here, pyruvate instead of entering the The energy is derived from amino acid
tumor cells will eventually become TCA cycle is reduced to lactate in the fermentation. Glucose and glutamine
the most effective approach to cancer absence of oxygen. Lactate fermentation interact synergistically to drive tumor
management. generates NAD+ that can be used as cell fermentation (Seyfried et al, 2010;
Another important characteristic of an electron acceptor. In cancer cells, Seyfried et al, 2011).
cell energetics is that at physiological this fermentation occurs even in the The external pH of solid tumors is
levels reactive oxygen species (ROS), a presence of oxygen. acidic as a consequence of increased
product of oxidative phosphorylation, Lactate is basically a metabolic waste metabolism of glucose and poor
function as cellular messengers in from incomplete oxidation of glucose; perfusion. Acid pH has been shown to
intracellular signaling and regulation. It nevertheless, it can be recycled at a stimulate tumor cell growth, invasion,
is feasible that these molecules have a high energetic cost in the Cori cycle. and metastasis.
role in gene regulation, especially cell The Cori cycle produces two ATPs at a
division. cost of six ATPs, which in part explains Mitochondrial Uncoupling and Cancer
the cachexia syndrome in patients with Uncoupling involves dissipation of
Warburg Hypothesis advanced cancer. Most lactate enters the mitochondrial proton gradient.
The shift by cancer cells from the blood stream where it is used to Uncoupling produces heat instead of
OxPhos (oxidative phosphorylation) synthesize glucose in the liver. Warburg ATP. Heat production is greater in less
to glycolysis, even under normoxic attributed this aerobic fermentation in differentiated tumor cells (Seyfried et
conditions, is called the Warburg effect. tumor cells to respiratory damage or al, 2010). The greater heat production
ATP production by glycolysis can be respiratory insufficiency. In other words, in the less differentiated cells supports
more rapid than by OxPhos, but it is damaged mitochondria. the hypothesis that mitochondrial
less efficient in terms of molecules One relevant issue pertaining uncoupling is greater in cancer cells that
of ATP generated per unit of glucose. to the Warburg hypothesis is that are more malignant. Moreover, heat
Therefore, tumor cells must increment mitochondrial amino acid fermentation production is correlated with increased
the rate of glucose uptake. The energy confuses the boundaries between glucose consumption and lactic acid

84 TOWNSEND LETTER – AUGUST/SEPTEMBER 2018


production (Nittinger et al, 1990). The are producing ATP through respiration Carcinogenesis
greater the uncoupling, the greater will (Seyfried et al, 2010). The failure to
be the need to produce energy through recognize this type of ATP production
substrate level phosphorylation (aerobic by a non-oxidative process in tumor various metabolic pathways in the
glucose fermentation). mitochondria contributes to the mitochondrial matrix (Scarpulla,2002,
While reduced oxygen uptake confusion surrounding the Warburg Scarpulla,2002 (B)). Communication and
may be indicative of reduced OxPhos, hypothesis of cancer and explains the signaling pathways from mitochondria
increased oxygen uptake may or may basis of its rejection (Denny et al, 2010). to nucleus evolved as a cellular
not be indicative of increased OxPhos Stem cells are described to have adaptation to factors and conditions that
and ATP production (Jahnke et al, 2010; minimal mitochondrial structures with impair mitochondrial functions. When
Samudio et al, 2009; Ramanathan few cristae. Increased mitochondrial mitochondria emit such a signal to the
et al, 2005). In this sense, oxygen function is important for differentiation. nucleus, the cell can switch on repair
consumption in tumor cells could programs and reorganize metabolism
provide misinformation of the true Cellular Communication Between the to keep energetic homeostasis (Guha
respiratory capacity of these cells. Mitochondrion and the Nucleus and and Avadhani, 2013). This pathway can
Mitochondrial dysfunction can be Cancer be induced by defects in the respiratory
characterized by any of three ways: 1) There is a development of chain, accumulation of mtDNA
by not having enough mitochondria, bidirectional signaling mechanisms mutations, alterations in mtDNA copy
2) by not having adequate substrate or between the mitochondrion and number, or loss of membrane potential.
nutrient co-factors needed for oxidative nucleus. Communication and
phosphorylation, or 3) by acquired signaling pathways from nucleus to Lipids and Cancer
dysfunction in the ATP synthesis the mitochondria are ancient, early Lipids may have a further relevant
machinery. developed communication routes role in carcinogenesis related to the
that coordinate the mitochondrial mitochondrial membrane. OxPhos
Mitochondria and Differentiation response to changing intracellular capability is linked to the structural
Mitochondria provide the microenvironment and act as sensor integrity of mitochondrial cristae (Frey
energy needed to maintain cellular mechanisms governing the cellular et al, 2000; Putignani et al, 2008;
differentiation. The total number response to external stimuli (Grabacka Paumard et al, 2008). Lipids maintain
of mitochondria in tumor cells is et al, 2014). Evolution had led to the the integrity of these bio-membranes.
significantly lower that the number of transfer of increasing numbers of Abnormalities in lipids can compromise
mitochondria in normal cells (Seyfried genes encoding the proteins crucial mitochondrial function. Mitochondrial
et al, 2010). The total respiratory for respiration to nuclear genome. lipid abnormalities are common in
capacity of tumor mitochondria is lower Mitochondrial DNA encodes only 13 all tumors. Altered mitochondrial
than that of mitochondria of normal subunits of respiratory complexes lipids reduce the efficiency of
cells (Seyfried, 2010; Seyfried et al, I, III, IV, and V, although they are OxPhos, requiring increased energy
2014). Abnormalities in mitochondrial indispensable for electron transport production through substrate level
size and shape are correlated with and respiration. Nuclei have taken phosphorylation.
mitochondrial dysfunction (Benard over the significant control expression
et al, 2008; Shapovalov et al, 2011; of respiratory complexes but also Phospholipids and Cancer
Matés et al, 2009). Highly malignant numerous proteins involved in the Cardiolipin is known as the signature
tumors do not have mitochondria maintenance and replication of mtDNA phospholipid of mitochondria. It
of normal morphology and number or enzymatic machinery driving is responsible for a wide range of

(Seyfried et al, 2010). The greater the
degree of mitochondrial morphological
abnormality, the greater the degree
of malignancy (Pedersen et al, 1978).
Respiratory impairment requires
enhanced fermentation to prevent
apoptosis (Seyfried et al, 2010).
Moreover, enhanced fermentation
prevents differentiation and is linked to
uncontrolled cell proliferation (Seyfried
et al, 2010).
ATP synthesis through mitochondrial
fermentation involving substrate level
phosphorylation could give the false
impression that tumor mitochondria

TOWNSEND LETTER – AUGUST/SEPTEMBER 2018 85


Carcinogenesis rates have slowed dramatically. It A strategic problem in cancer therapy
appears that the ketogenic diet is able is how to selectively activate apoptosis

to put cancer cells under significant in transformed cells. A successful way to
mitochondrial functions. Abnormalities metabolic stress allowing additional eliminate cancer cells can be based on
in the structure of cardiolipin have been non-toxic therapies, like intravenous the ability of anti-cancer treatment to
identified in tumor cells (Seyfried et al, vitamin C, hyperbaric oxygen, and activate apoptotic pathways, which are
2014). mitochondrial correction to push suppressed in tumor cells. This may be
It is important to clarify that the in- the cells further over the edge. We achieved by partially restoring damaged
vitro growth environment produces lipid propose that combining these non-toxic mitochondria.
and electron transport abnormalities treatments would provide a powerful, Mitochondrial dysfunction is a
in mitochondria in both tumorigenic synergistic anti-cancer effect. primary cause of cancer, and biochemical
and non-tumorigenic cells (Kiebish et Potential concern may arise and genetic deviations develop as
al, 2009). A failure to recognize this regarding the use of a diet therapy for consequent events. Cancer therapeutic
fact could confuse data interpretation cancer patients susceptible to cachexia. strategy targeting mitochondria may
related to energy metabolism. Caution While low carbohydrate or ketogenic restore normal physiological functions
should be taken when comparing diets promote weight loss in overweight of mitochondria and open the apoptotic
energy metabolism of malignant vs individuals, they are also known to pathway.
non-malignant cells in tissue culture spare muscle wasting during conditions
environments since they do not truly of energy restriction and starvation Mitochondrial Enhancers (Co-Factors)
replicate the in vivo environmental (Manninen et al, 2006; Cahill et al, 2006; for Mitochondrial Correction
growth conditions. This could have Veech et al, 2004; Volek et al, 2002). If the mitochondria are denied the
been the problem interpreting key The anti-cachexia effects of the basic nutrition they need to function,
experiments defining the metabolic ketogenic diet are not surprising when they cease to function normally. For
origin of cancer. considering a metabolic switch to fat their functioning, mitochondria need
metabolism and subsequent ketosis energy substrates and oxygen, but also
Mitochondrial Oncology: The Next evolved as a method of sparing protein cofactors (non-protein compounds,
Frontier during prolonged fasting or starvation vitamins, and minerals needed for
Once considered exclusively the (Veech et al, 2001; Wu et al, 1988). enzyme activity) to perform essential
cell’s powerhouse, mitochondria are It makes sense that dietary-induced biochemical tasks. Insufficiencies
now recognized to perform multiple therapeutic ketosis in a cancer patient in these cofactors are associated
essential functions beyond energy would prevent muscle wasting similarly with diseases including cancer; this
production, impacting most areas of cell as it does with athletes undergoing may result from their role in energy
biology and medicine especially cancer. intense exercise (Paoli et al, 2012). metabolism but also from specific
The customary cancer therapeutic Human studies of high-dose metabolic alterations, such as the
strategy is based on cancer cell killing, intravenous vitamin C in patients formation of toxic metabolites, altered
which has not proven to be successful. with cancer have shown improved mechanisms that protect against
Treatment of cancer should be based quantity and quality of life, as well reactive oxygen species, etc. Among
on essential and specific differences as improvements in physical, mental, the essential cofactors facilitating
between healthy cells and cancer cells. and emotional functions, symptoms of energy metabolism are B vitamins and
fatigue, nausea and vomiting, pain, and minerals such as magnesium. Additional
Protocol for Cancer appetite loss (Gonzalez et al, 2014). important cofactors are acetyl-L-
If we are correct that cancer is truly In relation to hyperbaric oxygen carnitine, r-alpha-lipoic-acid, coenzyme
a metabolic disease, the therapeutic (HBO2T), there are a substantial number Q10, phospholipids, vitamin C, vitamin
implications are huge. First, if we are of studies indicating that HBO2T can D, mixed tocopherols and tocotrienols,
correct, it would explain why virtually induce marked anti-cancer effects in creatine, NADH, NAC, omega-3,
no progress has been made in reducing vitro and in animal and human studies resveratrol, arginine, quercetin, Shilajit,
the death rates from cancer since 1950. alike (Daruwalla et al, 2006; Moen et al, PQQ, and curcumin.
Second, it opens up many possibilities 2012; Al-Waili et al, 2005).
for new avenues of treatment. The Considering mitochondria a possible Conclusion
first place to start is manipulating therapeutic target, two different In summary, the information
the macromolecules of our diet by approaches can be suggested: a) to presented herein supports the concept
implementing a low carbohydrate diet stimulate mitochondrial activity, in that cancer originates from damage
(Paleo or ketogenic diet), starving the order to restore metabolic pathways to the mitochondria rather than from
cancer cells of glucose. In virtually every characteristic of nonmalignant cells, damage to the genome. The genomic
experiment in which the ketogenic diet and/or b) to stimulate mitochondrial damage in tumor cells follows, rather
has been tested in mice, tumor growth dependent cell death pathways. Both than precedes, the disturbances in
ways suppress cancer. cellular respiration.

86 TOWNSEND LETTER – AUGUST/SEPTEMBER 2018


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Dr. Michael J. Gonzalez, CNS, DSc, NMD, PhD, is professor at the nutrition program, School of Public Health in the
medical sciences campus, University of Puerto Rico, and adjunct faculty at the University of Western States And
EDP University. He is currently co-director of RECNAC II project, and research director of the InBioMed Project
Initiative, leaders in the development of non-toxic chemotherapy treatments for cancer. The findings of their work
with intravenous vitamin C as an anti-cancer agent, published in 2002, were confirmed by the NIH in 2005. They
published the first Phase I clinical study utilizing intravenous vitamin C for treatment of terminal cancer patients in
2005, and also published in 2005 the most comprehensive review on vitamin C and cancer, as a follow-up on the
work of Dr. Linus C. Pauling.
Dr. Gonzalez is a Fellow of the American College of Nutrition and has authored over 200 scientific publications as well
as the books I Have Cancer: What Should I Do? (2009) and New Insights on Vitamin C and Cancer (2014). He serves
as a member on multiple scientific editorial boards. He has also served as consultant for several companies where he
has been responsible for designing formulations of nutritional supplements and pharmaceutical products.
Dr. Gonzalez has obtained several research awards for his work on nutrition and cancer.
He is one of the first Hispano-Americans and Puerto Rican to be inducted to the
International Hall of Fame of Orthomolecular Medicine in April 2016.

Jorge Duconge, PhD, is professor at the School of Pharmacy, University of Puerto Rico, with more than 15 years of experience
in teaching and scholarly activities. He performs research in the area of pharmacogenomics and DNA-guided personalized
medicine. He also has experience in conducting pharmacokinetics and pharmacodynamic studies.

TOWNSEND LETTER – AUGUST/SEPTEMBER 2018 87