The black-or-white extremism of conventional medicine needs to be redacted in favor of a more nuanced view of oncogenesis—one where cancer represents a spectrum of deviation from the norm, where carcinogenesis is an adaptive response to a radically divergent environment from the one in which we evolved.

Instead of a cell gone rogue, where cancer is caused by the accumulation of point mutations in genes controlling the cell cycle and proliferation, cancer represents a reincarnation of a more ancient survival mechanism whereby cells coordinate their behavior to survive in an increasingly harsh cellular milieu. In this view, cancer represents a regression to a pre-programmed ancestral time, before the evolution of complex, highly differentiated eukaryotic organisms, where the hostile environment would have selected for traits favoring cellular immortalization, or resistance to apoptosis, as a primitive form of survival mode emphasizing replication, self-repair, and metastasis (1). In particular, the bio-energetic and metabolic theories of carcinogenesis, advanced by the luminaries Dr. Michael Gonzalez, Dr. Dominic D’Agostino, Dr. Garth Nicolson, and Dr. Thomas Seyfried, are perfectly situated to explain the role of mitochondria, our energetic cellular powerhouses, in cancer (2).

Mitochondria: The Conductors of the Physiological Orchestra

Mitochondria are rod-shaped, double-membrane organelles responsible for production of adenosine triphosphate (ATP), the cellular energy currency that powers metabolic reactions (3). In addition to transforming organic material into ATP, mitochondria are intimately involved in heme, amino acid, lipid, and steroid synthesis, in optimal functioning of the energetically demanding immune and nervous systems, and in dictating cell fates (4). Mitochondria mediate cellular proliferation, and regulate the energetically intensive process of apoptosis, or cell suicide, via release of cytochrome c through the mitochondrial permeability transition pore (mtPTP) (5).

Apoptosis, or the coordinated collapse of the cell, is accompanied by energy-dependent signaling cascades that result in predictable morphological changes, cellular dismantling, and engulfment of the cellular corpses by neighboring phagocytes (6). Although aberrant apoptosis is implicated in disease pathophysiology, apoptosis is essential to development and homeostasis (7). In contrast, necrosis occurs secondary to cellular injury, and results in cellular swelling, membrane fracture, and complement-mediated lysis, causing release of intracellular components and consequent inflammation. Mitochondrial function is so inextricably tied to apoptosis that tissue necrosis is one of the clinical features of mitochondrial diseases, such that extensive tissue damage can be incurred (8).

Via their production of reactive oxygen species (ROS) as metabolic byproducts, mitochondria also regulate the cellular redox state. Although often vilified for perpetuating the inflammatory molecular mechanisms underlying the pathogenesis of disease, elevated levels of ROS also serve adaptive and hormetic roles as signaling molecules in redox biology for maintenance of homeostasis (9). In fact, it is theorized that ROS evolved as a signal transduction mechanism to activate transcription factors that enable adaptation to changes in accessibility of environmental nutrients and in the oxidative environment (10, 11).

Although somatic cells can contain anywhere from two hundred to two thousand mitochondria, energy requirements dictate how many mitochondria each cell contains (12, 13). The most metabolically active cells, such as those within the brain, liver, skeletal muscle, and cardiac muscle, contain the largest number of mitochondria, whereas mature erythrocytes, or red blood cells, are the only cells devoid of mitochondria (14, 15).

The Evolutionary Origins of Mitochondria

The inner mitochondrial membrane contains the metabolic machinery for aerobic metabolism, an evolutionary adaptation to oxygen-rich environments, which coincided with the endosymbiosis, or engulfment, of the ancient autotrophic bacteria that were the predecessors of these eukaryotic organelles. One to three billion years ago, aerobic bacteria colonized an ancient prokaryote, generating energy for the host cell in return for shelter and a reliable supply of food, which was the genesis of intracellular mitochondria (5, 16).

Mitochondria produce over ninety percent of cellular energy via oxidative phosphorylation, a process that couples glucose oxidation to an electron transport chain and to the flow of protons down a gradient, which results in ATP synthesis via a rotary engine of the cell called ATP synthetase (4). Pyruvate, a downstream product of cytosol-based glycolysis, along with fatty acids, are imported into the mitochondria and processed via the tricarboxylic acid (TCA) or citric acid cycle into high-energy reduced coenzymes, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which consequently donate electrons into the electron transport chain (ETC) in the production of ATP (17). Electrons are successively passed down an electrochemical gradient to the final electron acceptor, diatomic oxygen (O2), via a chain of respiratory proton pumps embedded in the inner mitochondrial membrane, which is why humans need oxygen to survive (18).

The fact that mitochondria have distinct, bacteria-like circular genomes that are functionally and structurally disparate from the chromosomal assemblies residing in the nucleus supports the endosymbiosis hypothesis (19). Because most of the mitochondrial genome is scattered throughout chromosomal DNA, the mitochondria is referred to as a semi-autonomous organelle, as it relies on communication with the nucleus for expression of all its enzyme complexes and molecular constituents (5). Mitochondria, which are inherited in maternal fashion, “divide by binary fission and propagate distinct ‘lineages’ within each cell” (19, p. 269). However, unlike nuclear DNA, mitochondrial DNA (mtDNA) lacks protective histones, and hence is particularly susceptible to DNA damage from free radicals (20).

Thus, mitochondrial dysfunction has been increasingly linked to almost all pathologic and toxicologic conditions, including, “A wide range of seemingly unrelated disorders, such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis” (3, 15, p. 84). Recently, however, pioneering researchers such as Michael Gonzalez and colleagues have elucidated a unified theory of carcinogenesis where mitochondria are at the nexus of dysfunction in cancer pathogenesis (2).

Cancer As A Pre-Symbiotic, Primordial State

Emerging data, which considers malignancy through an ecological lens, recognizes cancer not as a predetermined genetic time bomb due to defective genes, but rather as an evolutionary throwbackto a time where more rudimentary cooperation between free-floating cells existed, which allowed their survival in nutrient depleted, increasingly uninhabitable environments. This view is articulated by Davies and Lineweaver (2011), who state,

“We hypothesize that cancer is an atavistic condition that occurs when genetic or epigenetic malfunction unlocks an ancient 'toolkit' of pre-existing adaptations, re-establishing the dominance of an earlier layer of genes that controlled loose-knit colonies of only partially differentiated cells, similar to tumors” (1).

This is similarly articulated by Davila and Zamorano (2013), who discuss how, “Some of the hallmarks of cancer such as uncontrolled cell proliferation, lack of apoptosis, hypoxia, fermentative metabolism and free cell motility (metastasis) are akin to a prokaryotic lifestyle, suggesting a link between cancer disease and evolution” (21). They note that cancer represents a phenotypic reversion to the most preliminary stage of eukaryotic evolution, that of a heterotrophic, facultative anaerobe that is suited for survival and replication in oxygen-poor, hypoxic environments (21). The authors state that this occurs due to cumulative oxidative damage to both maternally inherited mtDNA and nuclear DNA and to mitochondrial insufficiency, or uncoupling between electron transfer and chemiosmotic ATP synthesis (21).

In particular, the bioenergetic theory of carcinogenesis proposed by Gonzalez and colleagues proposes that the replacement of oxygen-dependent aerobic respiration by aerobic glycolysis and lactic-acid producing fermentation, phenomena first characterized in cancer cells over ninety years ago by Nobel Laureate Otto Warburg, favors carcinogenesis (2). In the hypoxic micro-environment in which cancer develops, a metabolic transition from obligate anaerobe to partial anaerobe, accompanied by enhanced glycolytic flux, takes place, which ensures survival in oxygen-poor conditions (22).

The switch from mitochondrial-based glucose oxidation to cytosol-based aerobic glycolysis, or glycolysis in the presence of oxygen, is why positron emission tomography (PET) scans can be used to localize tumors and metastases, since the labeled glucose gravitates towards malignant tissue with a high rate of glycolysis (2). The propensity of tumor cells for increased glycolytic flux also confers resistance to apoptosis, or programmed cell death, which allows cancer cells to evade cell suicide signals (23, 24). Without electron flow down the ETC, mitochondria also lack the energy for depolarization and synthesis of reactive oxygen species (ROS), which are crucial redox signals required for apoptosis (25, 26).

Cancer Thrives in An Acidic Body

As a corollary, cancer cells lack superoxide dismutase (SOD), one of the endogenous antioxidant defense systems that protects mitochondrial genes and proteins from the free radical byproducts of the citric acid cycle (27). As a result, free radicals impair the citric acid cycle and pyruvate is instead shuttled into lactic acid, perpetuating lactic acidosis. In fact, when succinate, a tricarboxylic acid (TCA) cycle intermediate, is added to cancer cell lines, the rate of respiration remains stagnant, which demonstrates that cancer cells cannot utilize the citric acid cycle (17).

In particular, fermentation by malignant cells facilitates the generation of acidic pH in cancerous tissues due to lactic acid production, a hallmark of aggressive cancer growth (22, 28). Production of lactate begins to dwarf that of pyruvate, which results in less activity of the TCA cycle, and less generation of the energized intermediates NADH and FADH2 to fuel oxidative phosphorylation (2). What’s more, lactate accumulation promotes tumor growth by activating angiogenesis, or the formation of new blood cells to supply the tumor with nutrients, and by degrading extracellular matrix, which allows tumor expansion and augments potential for metastasis (29).

In addition, the adverse change in pH engender voltage differences in cell membranes, which may disrupt communication, cause electrical uncoupling, induce mitosis, and lead to further derangements in proton and electron efflux (2). Further, membrane potential disruption and consequent accumulation of a surplus of negative ions in the extracellular milieu repels erythrocytes and lymphocytes, shielding cancer cells from oxygen- and immune-mediated destruction, respectively (2). This sequestering effect and decrease in immune reactivity is compounded by the formation of coagulated proteins around transformed cells, which in turn prohibits access of host immune defenses to combat cancer (2).

Compared to the complete aerobic oxidation of glucose, which generates 38 ATP per mole of glucose, substrate-level phosphorylation via glycolysis is relatively energy inefficient, yielding only 2 ATP per mole of glucose (2). In addition to diminished internal resources of the malignant cell due to preferential use of glycolysis, cancer interferes with electrical impedance, sodium-potassium membrane pump function, and the enzymes of the respiratory complexes embedded within the inner mitochondrial membrane, such that intercellular communication and membrane dynamics are jeopardized (2, 30).

These metabolic limitations, in concert with the decreased mitochondrial content, lead to an enormous reduction in energy reserve, with the average cancer cell having less than one-twentieth the energy of a healthy cell (2). Hypoxia-inducible factor (HIF), which is activated as a consequence of the hypoxic microenvironment in which cancer develops, up-regulates expression of glucose receptors and glycolytic enzymes in attempt to reflexively compensate for the diminished efficiency of glycolysis compared to oxidative phosphorylation (31).

In sum, incessant cellular insult, as a result of the micronutrient depletion, sedentary lifestyle, psychosocial stress, and toxicant exposure to which most of us are subjected, culminates in a transformed cell phenotype where cellular apoptotic mechanisms are compromised and cellular metabolism becomes deranged. Hence, cancer arrives on the scene as an adaptation to the traumatic living circumstances of modernity.

Mitochondrial Metabolic Correction

Restoration of mitochondrial function is of the utmost importance, since mitochondrial remodeling, or mitochondrial dysbiosis, defined as the process whereby “mitochondria can dissolve their symbiosis with the cell host, and no longer function in harmony with the cell,” is a distal molecular pathway common to all cancer cells (29, 2, p. 436). Instead of treating cancer like a foreign entity to be eradicated, cancer should be re-conceptualized as cells that have lost their way, and have begun operating as unicellular, independent entities, profligately replicating and forming a protista colony of sorts as a survival mechanism (2). In this model, cells need to be supplied with the proper conditions to be coaxed back to their normal phenotype, re-differentiate, and regain local tissue communication and architecture.

Dr. Michael Gonzalez and colleagues reiterate these foundational principles of Nobel laureate Szent-Györgyi with, “Efficient oxidative energy production is associated with organized cell structure, whereas fermentation is associated with lack of structure and the inclination to cell division” (2, p. 437). Because the cardinal difference between normal and cancer cells is the use of fermentation by the latter to meet energy demands, restoring aerobic respiration, or correcting mitochondrial function to promote induction of apoptosis in cancer cells, should be clinical priorities, rather than decimating the very immune defenses that fight cancer with radiation and chemotherapy.

Therefore, undertaking a program of mitochondrial correction, including a nutrient-dense, paleolithic diet to which our physiology is accustomed, and nutraceuticals needed for aerobic respiration, repolarization, and membrane repair, could potentially reverse cancer (2). This phenomenon is illustrated by the observation that suppression of mitochondria promotes cancer growth in normal cells, whereas inhibition of glycolysis leads to rapid death of cancer cells (2). Likewise, animal models and in vitro studies have illuminated decreased rates of tumor growth with normalization of mitochondrial function (32).

Dietary Considerations for Mitochondrial Renewal

A primarily plant-based paleo diet rich in fruits and vegetables and devoid of processed foods, high-glycemic foods, flour, sugar, coffee, and alcohol, will promote blood alkalinity, which is important since alkaline solutions favor oxygen absorption, whereas acidic solutions favor oxygen release (2). Mitochondrial matrix enzymes operate best in an alkaline environment, whereas acidity disturbs membrane potential, resulting in cellular malfunction, compromised energy production, and carcinogenesis (33, 34, 35). A nutrient-dense, phytonutrient-replete diet will provide the blood with the minerals to maintain an alkaline pH and to retain oxygen (2).

A high fat, low carbohydrate ketogenic paleo template diet is ideal, since ketogenic diets increase circulating ketone bodies while decreasing blood glucose levels, thus restricting energy supplied to cancer cells (36). Ketones, which bypass glycolysis and enter the mitochondria directly for oxidation, are a viable alternative energy source for wild-type cells with normal mitochondrial function, but cannot be utilized by cancer cells since they lack metabolic flexibility (37, 38, 39). Furthermore, ketone bodies are inherently anti-inflammatory, reducing ROS while augmenting activity of glutathione peroxidase, one of the endogenous antioxidant defense systems (37, 40).

In addition, ketogenic diets are often accompanied by dietary energy reduction (DER), which elicits anti-cancer effects through inhibition of the IGF-1/PI3K/Akt/HIF-1alpha pathway that cancer cells hijack to suppress apoptosis and to engender proliferation and angiogenesis (36). DER induces apoptosis in astrocytoma cells and has demonstrated anti-tumor effects in brain, colon, gastric, lung, mammary, prostate, and pancreatic cancer (36). The ketogenic diet administered in restricted amounts also significantly improves health and longevity of mice with malignant brain tumors relative to controls receiving a low fat high carbohydrate diet (40). The calorie-restricted ketogenic diet likewise decreases micro-vessel density in tumors and has been shown to lead to 65% and 35% lower orthotropic growth rates of implanted malignant mouse astrocytoma and human malignant gliomas, respectively, in animal models (40).

Hyperbaric Oxygen Therapy

In light of the observations that white blood cells kill cancer cells by injecting them with oxygen in the form of hydrogen peroxide, and that depleting oxygen induces cellular mutation, one of the clinical objectives of cancer treatment should be increasing cellular oxygenation (2). Promoting oxygenation, and hence better detoxification, through therapies such as hyperbaric oxygen therapy (HBOT), will promote down-regulation of the expression of cancer-related genes such as HIF-1 (41).

Poff and colleagues (2013) elucidate how, “Abnormal tumor vasculature creates hypoxic pockets which promote cancer progression and further increase the glycolytic-dependency of cancers” (36, p. e65522). Tumor hypoxia not only renders cancer cells three-times as resistant to radiation therapy than well-oxygenated cells, but it also stimulates oncogenic biochemical pathways that facilitate tumor growth, angiogenesis, metastasis, and inhibition of apoptosis via the transcription factor HIF-1 (42, 43, 44). Saturating the tumors with hyperbaric oxygen chamber therapy, in contrast, enables adequate tissue perfusion, effectively reversing the cancer-permissive effects of hypoxia (36).

In addition to inhibiting tumor growth, depleting blood vessel density within mutated cells, and promoting expression of anti-cancer genes in animal models, hyperbaric oxygen therapy up-regulates production of ROS by tumor cells to enhance efficacy of the standards of care (36). In a mouse model of metastatic cancer, the ketogenic diet in concert with hyperbaric oxygen therapy led to significant decreases in blood glucose and tumor growth rate and produced a 77.0% average increase in survival time compared to controls (36). Quintessentially, by increasing delivery of oxygen to tissues independent of hemoglobin oxygen saturation, hyperbaric oxygen therapy has the potential to restore aerobic respiration over the substrate-level phosphorylation that occurs in glycolysis (45).

Targeted Nutraceuticals

Furthermore, a cancer-mitigating diet should be rich in micronutrients needed to sustain the biochemical pathways that extract and convert energy from organic molecules into biologically accessible forms (4). Restoration of oxidative respiration will cause the synthesis of oxidation byproducts, which normally translocate from the cytosol to the nucleus, influencing gene expression in a way favoring re-differentiation away from the primitive mutagenic phenotype (46).

Targeted orthomolecular use of mitochondrial support, such as alpha lipoic acid, acetyl-L-carnitine, coenzyme Q10, magnesium, D-ribose, PQQ, creatine, and B complex may also be warranted (4). Phospholipids replacement therapy is also integral to mitochondrial repair since damage to the lipid bilayer and to the dual-layered mitochondrial membrane precedes mitochondrial damage (47).  Further, ascorbate, or vitamin C, administered intravenously in particular, may restore normal apoptosis in cancer cells by augmenting electron flux, increasing generation of ATP, and facilitating re-differentiation to a normal phenotype (4, 33).\

Removal of Offending Agents

Lastly, exposure to mitochondrial toxicants, such as xenobiotics and persistent organic pollutants which damage the mitochondrial membrane, should be minimized (4). Importantly, medications such as psychotropic drugs, analgesics, anti-inflammatory agents, antibiotics, anticonvulsants, statins, steroids, chemotherapy, and drugs for diabetes and HIV/AIDS are major contributors to mitochondrial damage (4). Although many medication side effects and drug-induced toxicities are a direct consequence of mitochondrial dysfunction, the U.S. Food and Drug Administration (FDA) still does not mandate mitochondrial toxicity testing for pharmaceuticals (48).

According to Neustadt and Pieczenik (2007), medications can directly disable elements of the electron transport chain, inhibit transcription of electron transport chain complexes, or inhibit the enzymatic processes involved in beta-oxidation or glycolysis. Pharmaceutical drugs can also deplete endogenous antioxidants or nutrients required for mitochondrial function, or generate free radicals which damage mitochondrial structures (3).

Where Oncology is Failing, Mitochondrial Regeneration Can Succeed

The decision to use toxic chemotherapy, radiation, or trauma-inducing surgery—the only legally sanctioned cancer therapies, fraught with conflicts of interest and vested fiscal agendas—is a personal one, and should be made in concert with a licensed physician and your intuition as a guide. However, studies have shown that the percentage increase in five-year survival rate due to adjuvant and curative cytotoxic chemotherapy is only 2.1% in the United States and 2.3% in Australia (49). Another comprehensive analysis of over 3,000 clinical trials determined that there is no direct evidence that chemotherapy prolongs survival in advanced carcinoma, apart from small-cell lung cancer (50).

Researchers state, “Many oncologists take it for granted that response to therapy prolongs survival, an opinion which is based on a fallacy and which is not supported by clinical studies” (50). In other words, tumor shrinkage does not translate into survival advantages over ‘watch and wait’ approaches in many cancers (51). Further, because chemotherapy and radiation do not target the self-renewing cancer progenitor cells known as cancer stem cells, secondary cancers that re-emerge are usually more aggressive and fatal. In fact, radiation generates therapy-resistant cancer stem cells, such that lingering cancer cells become more malignant (52).

A more holistic vantage point should be adopted regardless of the therapies a cancer patient employs, addressing latent infections, micronutrient and fatty acid deficiencies, hormonal imbalances, toxicant exposures, dysbiosis, inflammatory underpinnings, psychospiritual stress, and mitochondrial insufficiency, all of which contribute to a hostile, threatening environment which cause cells to harken back to a pathological, undifferentiated, cancerous phenotype.

Researcher and clinician Dr. Michael Gonzalez, who is using some of these targeted therapies in his clinic, has witnessed better quality of life and increased survival time in cancer patients compared to use of conventional therapies alone. He states, “I truly believe that the bioenergetic theory of carcinogenesis describe the root of cancer…and will pave the way for a new understanding of cancer as a metabolic mitochondrial disease, leading to more effective, less toxic, and user-friendly treatments”.

References

1. Davies, P.C.W., & Lineweaver, C.H. (2011). Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Physical Biology, 8(1), https://doi.org/10.1088/1478-3975/8/1/015001.

2. Gonzalez, M.J. et al. (2012). The bio-energetic theory of carcinogenesis. Medical hypotheses, 79(4), 433-439.’

3. Neustadt, J., & Pieczenik, S.R. (2008). Medication-induced mitochondrial damage and disease. Molecular Nutrition and Food Research, 52, 780-788.

4. Zeviar, D.D. et al. (2014). The role of mitochondria in cancer and other chronic diseases. Journal of Orthomolecular Medicine, 29(4), 157-166.

5. Wallace, D. C. (2005). A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annual Reviews in Genetics, 39, 359 – 407.

6. Hacker, G. (2000). The morphology of apoptosis. Cell and Tissue Research, 301, 5–17. doi: 10.1007/s004410000193

7. Benjamin, I.J., & Schneider, M.D. (2005). Learning from failure: congestive heart failure in the postgenomic age. Journal of Clinical Investigation, 115, 495–499.

8. Rustin, P. (2002). Mitochondria, from cell death to proliferation. Nature, 30, 352-353.

9. Schieber, M., & Chandel, N.S. (2014). ROS Function in Redox Signaling and Oxidative Stress. Current Biology, 24(10), R453-R462.

10. Wood, Z.A., Poole, L.B., & Karplus, P.A. (2003). Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science, 300, 650–653.

11. Kiley, P.J., & Storz, G. (2004). Exploiting thiol modifications. PLoS Biology, 2, e400.

Kim, J.W., & Dang, C.V. (2006). Cancer’s molecular sweet tooth and the Warburg effect. Cancer Research, 66, 8927–8930.

12. Gray, M.W. (1989). Origin and evolution of mitochondrial DNA. Annual Reviews in Cell Biology, 5, 25–50.

13. Veltri, K.L., Espiritu, M., & Singh, G. (1990). Distinct genomic copy number in mitochondria of different mammalian organs. Journal of Cell Physiology, 143(1), 160–164.

14. Cohen, B.H., & Gold, D.R. (2001). Mitochondrial cytopathy in adults: what we know so far. Cleveland Clinic Journal of Medicine, 68(7):625–626.

15. Pieczenik, S.R., & Neustadt, J. (2007). Mitochondrial dysfunction and molecular pathways of disease. Experimental and Molecular Pathology, 83, 84-92.

16. Margulis, L., & Bermudes, D. (1985). Symbiosis as a mechanism of evolution: Status of cell symbiosis theory. Symbiosis, 1, 101-124.

17. Kidd, J.G., Winzler, R.J., & Burk, D. (1944). Comparative glycolytic and respiratory metabolism of homologous normal, benign and malignant rabbit tissues. Cancer Research, 4, 655.

18. Brookes et al. (2004). Calcium, ATP, and ROS: a mitochondrial love–hate triangle. American Journal of Physiology and Cell Physiology, 287(4), C817–C833.

19. Kidd, P.M. (2005). Neurodegeneration from mitochondrial insufficiency: Nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. Alternative Medicine Review, 10(4), 268-293.

20. Croteau, D.L., & Bohr, V.A. (1997). Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. Journal of Biological Chemistry, 272(41), 25409-25412.

21. Davila, A.F., & Zamorano, P. (2013). Mitochondria and the evolutionary roots of cancer. Physical Biology, 10(2).

22. Moreno-Sánchez, R., Rodríguez-Enríquez, S., Marín-Hernández, A., & Saavedra, E. (2007). Energy metabolism in tumor cells. FEBS Journal, 274(6), 1393–418.

23. Plas, D.R., & Thompson, C.B. (2002). Cell metabolism in the regulation of programmed cell death. Trends in Endocrinology and Metabolism, 13, 75–78.

24. Kim, J.W., & Dang, C.V. (2005). Multifaceted roles of glycolytic enzymes. Trends in Biochemistry, 30, 142–150.

25. Halestrap, A. (2005). Biochemistry: a pore way to die. Nature, 434, 578–579.

26. Zamzami, N., & Kroemer, G. (2001). The mitochondrion in apoptosis: how Pandora’s box opens. National Reviews in Molecular and Cellular Biology, 2, 67–71.

27. Oberley, L.W., & Buettner, G.R. (1979). Role of superoxide dismutase in cancer: a review. Cancer Research, 39, 1141–1149.

28. Hsu, P.P., & Sabatini, D.M. (2008). Cancer cell metabolism: Warburg and beyond. Cell, 134, 703–707.

29. Michelakis, E. D., Webster, L., & Mackey, J. R. (2008). Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. British Journal of Cancer, 99(7), 989-994.

30. Cone, C.D. (1975). The role of surface electrical transmembrane potential in normal and malignant mitogenesis. Annals of the New York Academy of Science, 238, 420–435.

31. Semenza, G.L., Roth, P.H., Fang, H.M., & Wang, G.L. (1994). Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. Journal of Biological Chemistry, 269, 23757–23763.

32. Gogvadze, V., Orrennius, S., & Zhivotovsky, B. (2008). Mitochondria in cancer cells: what is so special about them? Trends in Cell Biology, 18(4), 165–173.

33. Gonzalez et al. (2010). Mitochondria, energy and cancer: The relationship with ascorbic acid. Journal of Orthomolecular Medicine, 25, 29-38.

34. Hansen et al. (2010. A role for taurine in mitochondrial function. Journal of Biomedical Science, 17(Suppl 1), S23.

35. Minich, D., & Bland, J. (2007). Acid-alkaline balance: Role in chronic disease and detoxification. Alternative Therapies in Health and Medicine, 13, 62-65.

36. Poff et al. (2013). The ketogenic diet and hyperbaric oxygen prolong survival in mice with systemic metastatic cancer. PLoS One, 8(6), e65522. doi: 10.1371/journal.pone.0065522

37. Veech, R. (2004). The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 70, 309-328.

38. Vantallie, T.B., & Nufert, T.H. (2003). Ketones: metabolism’s ugly duckling. Nutrition Reviews, 2003, 61, 327-341.

39. Maurer et al. (2011). Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer, 11, 315.

40. Zhou et al. (2007). The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutrition and Metabolism, 4(5), 1-15.

41. Macfarlane, C.M. (2000). Sublethal oxygen deficiency—the primary cause of cancer. Medical Hypotheses, 54(2), 323–325.

42. Gray et al. (1953). The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. The British Journal of Radiology, 26, 638-648.

43. Le, Q-T., Denko, N., & Giaccia, A. (2004). Hypoxic gene expression and metastasis. Cancer Metastasis Reviews, 23, 293-310.

44. Wouters, B. et al. (2004). Targeting hypoxia tolerance in cancer. Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy, 7, 25-40.

45. Gill, A.L., & Bell, C.N.A. (2004). Hyperbaric oxygen: its uses, mechanisms of action and outcomes. QJM., 97(7), 385-395.

46. Apell, H.J. (1989). Electrogenic properties of the Na/K pump. Journal of Membrane Biology, 110(2), 103-114.

47. Nicolson, G.L., & Ellithorpe, R. (2006). Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses. Journal of Chronic Fatigue Syndrome, 13(1), 57-68.

48. Dykens, J.A., & Will, Y. (2007). The significance of mitochondrial toxicity testing in drug development. Drug Discoveries of Today, 12, 777-785.

49. Morgan, G., Ward, R., & Barton, M. (2004). The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clinical Oncology, 16, 549-560.

50. Abel, U. (1992). Chemotherapy of advanced epithelial cancer: a critical review. Biomedicine & Pharmacotherapy, 46, 439-352.

51. Huff, C.A. et al. (2006). The paradox of response and survival in cancer therapeutics. Blood, 107, 431-434. doi: https://doi.org/10.1182/blood-2005-06-2517

52. Printz, C. (2012). Radiation treatment generates therapy-resistant cancer stem cells from less aggressive breast cancer cells. Cancer, 118(13), 322.