BioMed Research International

BioMed Research International / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 8105735 | https://doi.org/10.1155/2020/8105735

Quangdon Tran, Hyunji Lee, Chaeyeong Kim, Gyeyeong Kong, Nayoung Gong, So Hee Kwon, Jisoo Park, Seon-Hwan Kim, Jongsun Park, "Revisiting the Warburg Effect: Diet-Based Strategies for Cancer Prevention", BioMed Research International, vol. 2020, Article ID 8105735, 9 pages, 2020. https://doi.org/10.1155/2020/8105735

Revisiting the Warburg Effect: Diet-Based Strategies for Cancer Prevention

Academic Editor: Cristiano Capurso
Received13 Apr 2020
Revised15 Jul 2020
Accepted18 Jul 2020
Published05 Aug 2020

Abstract

It is widely acknowledged that cancer cell energy metabolism relies mainly on anaerobic glycolysis; this phenomenon is described as the Warburg effect. However, whether the Warburg effect is caused by genetic dysregulation in cancer or is the cause of cancer remains unknown. The exact reasons and physiology of this abnormal metabolism are unclear; therefore, many researchers have attempted to reduce malignant cell growth in tumors in preclinical and clinical studies. Anticancer strategies based on the Warburg effect have involved the use of drug compounds and dietary changes. We recently reviewed applications of the Warburg effect to understand the benefits of this unusual cancer-related metabolism. In the current article, we summarize diet strategies for cancer treatment based on the Warburg effect.

1. Introduction

Unlike normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells rely on aerobic glycolysis, in a phenomenon termed the Warburg effect. In the 1920s, Warburg discovered enhanced oxygen uptake and subsequent rapid cell division upon fertilization; he hypothesized that cancer cells might also take up more O2 than normal cells [1]. In 1956, Warburg reported that cancer cells exhibit high rates of glucose uptake and lactic acid production, even in the presence of oxygen [2], with cancer cells appearing to prefer aerobic glycolysis to oxidative phosphorylation (OXPHOS). Warburg also initially suspected impaired respiration in cancer cells due to functional defects in mitochondria [3]; however, findings from his own laboratory [4] and those of others [5, 6] indicated otherwise. The mitochondria were found to be necessary for tumor growth [7]. However, cancer glycolysis produces only two moles of ATP per one mole of glucose [8]. This context is still controversial. In many cancers, aerobic glycolysis is upregulated without mitochondrial dysfunction (no identifiable mitochondrial gene mutations) or OXPHOS disruption [911]. In these cancers, OXPHOS continues normally, producing as much ATP as OXPHOS in normal tissue under the same oxygen pressures [911]. In a new model of cancer metabolism, Kim reported that cancer cell mitochondria exhibit active oxidative phosphorylation [8]. NADH production from glutamine in the cytosol plays a key role of ATP production through the mitochondrial electron transport chain in cancer cells, while NADH production is mostly occupied inside the mitochondria in normal cells [8]. This hypothesis contradicts Warburg’s claim for mitochondrial defects in cancer, but after more than half a century of research, Warburg’s observations have been applied to most cancer cells, becoming the seventh feature of cancer cells: (1) persistent growth signals, (2) evasion of apoptosis, (3) insensitivity to antigrowth signals, (4) unlimited replicative potential, (5) angiogenesis, and (6) invasion and metastasis [1214]. Aerobic glycolysis has also been observed in rapidly proliferating normal cells such as stimulated lymphocytes and mitotic and proliferating fibroblasts [1520], suggesting the association of aerobic glycolysis and rapid growth and proliferation. Upregulation of glycolysis occurs not only in ATP synthesis but also in the synthesis of biomass, including ribonucleotide [21] and nicotinamide adenine dinucleotide phosphate (NADPH) production [22], which can remove reactive oxygen species (ROS) generated by accelerated cancer cell metabolism under hypoxic conditions [22, 23]. Thus, the Warburg effect appears to be strategically driven by cancer cells, while they simultaneously meet several urgent requirements for proliferation in an ever-changing microenvironment under numerous material limitations such as the lack of oxygen and nutrients and proper control of ROS production.

The exact reason and physiological value of abnormal metabolism in cancer should still be revealed. The Warburg effect is generally thought to confer growth advantages to tumor cells including the rapid supply of ATP, amino acids for protein synthesis, nucleic acids for DNA duplication, and lipids for cell biomembrane synthesis, which may be needed in cell proliferation. These processes generate an acidic environment, which is harmful to normal cells but has no effect to tumor cells [24]; fewer ROS are produced, such that the cancer cell genome may elude damage due to a high ROS concentration, leading to apoptosis resistance in tumor subjects [25, 26]. The Warburg effect is now more attractive to scientists. The cause of the Warburg effect caught the attention of scientists, because understanding the cause of the Warburg effect can make more effective treatment for cancer. Indeed, numerous studies have proposed different models of the Warburg effect, which may lead to the identification of its underlying mechanism. In addition, some anticancer drugs have been developed by using the transition from oxidative phosphorylation to glycolytic metabolism in cancer [27], besides diagnosis and detection of metastasis by using F-18 fluorodeoxyglucose- (FDG-) positron emission tomography (PET).

2. Targeting Metabolic Mediators

Previous reviews have described several compounds that mediate characteristics of the Warburg effect [28] including (i) increased expression of glucose transporters and thus increased glucose uptake; (ii) increased pentose phosphate pathway-catalyzed NADPH production; (iii) altered activity of glycolytic or glycolysis-related enzymes such as hypoxia-inducible factors/MYC-induced activation of hexokinase 2, lactate dehydrogenase A, and pyruvate dehydrogenase kinase-1 and the switch from pyruvate kinase isozymes M1 to the less active pyruvate kinase isozymes M2; and (iv) increased lactate production. Some of these characteristics have been or could potentially be targeted to develop cancer therapeutics (Table 1, [28]). For example, inhibiting glucose transport slows glucose supply to cancer cells, slowing cancer metabolism and biomass synthesis. As a result, cancer cells fail to grow and instead undergo apoptosis [29]. Many glucose transporter (GLUT) inhibitors have been previously studied [30, 31]. The principle and the use of 2-deoxy-D-glucose (2-DG), dichloroacetate (DCA), and 3-bromopyruvate (3-BP) in cancer therapy has also been addressed in our previous review (Table 2, [28]). Targeting Warburg effect mediators is thus emerging as a promising strategy for cancer treatment.


Physiological changeMechanisms for antitumor effect

Reduce insulin level and signalingLower insulin levels reduce oncogenic signaling pathways: PI3K-PKB-mTOR, RAS-RAF-MAPK.
Decrease blood glucoseGlucose restriction sensitizes tumor cells to radiotherapy and chemotherapy.
Enhance fatty acids and ketone bodiesPreclinical inhibition of glycolysis through fatty acids and ketone bodies (Randle cycle) is problematic for tumor cells with dysfunctional mitochondria that rely on glycolysis for energy and antioxidant production.
Increase β-hydroxybutyrateβ-Hydroxybutyrate is an endogenous histone deacetylase inhibitor with the potential to epigenetically alter protein expression in tumors towards a less aggressive phenotype.
Increase decanoic acid (if medium chain triglyceride oil is part of the ketogenic diet)Decanoic acid is a PPARg agonist and inhibits AMPA glutamate receptors, which are overexpressed by human glioblastoma cells.

Adapted from [77].

TargetCompoundEffectStatusReferences

GLUT1WZB117, STF-31Inhibits CLUT1
Induces cell cycle arrest and inhibits cancer cell growth
Preclinical[30, 31]
HK2DGInhibits HK
Tolerable adverse effects
Clinical trials discontinued[78]
PKM2TEPP-46Activates PKM2
Tetramer formation and suppress tumorigenesis
Preclinical[79] [80]
LDHAFX11Inhibits LDHA
Oxidative stress and inhibits tumor progression
Preclinical[81]
G6PD6-ANInduces oxidative stress
Induces cell cycle arrest and apoptosis selectively in irradiated human malignant cells
Preclinical[82]
MCT1AZD3965Inhibits uptake of extracellular lactatePhase I[83]
PDK1DCAInhibits PDK1Phase I-II[84] [85]
PKBAZD5363Inhibits PKB activityPhase I-II[86]
GDC0068Phase I[87]
GSK2141795Phase I completed[88]
GSK2110183Phase I-II completed
Phase II
[88]
MK-2206Akt inhibitor enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivoPhase I-II[89]

Adapted from [90].

3. Modulating Metabolite Flow

3.1. Less Is More: Calorie Restriction (CR) and Cancer Therapy Response

Proposed in 1914, CR was the first method offered for cancer prevention by reducing tumor blood supply [32]. The impact of CR on cancer suppression has since been replicated in studies of brain, prostate, and breast tumors [3340]. The effect of CR on cancer prevention is based on the Warburg theory, by regulating several metabolic mediators. The reduction of lower circulating glucose, in turn, lowers insulin levels and increases transcription of insulin-like growth factor binding protein- (IGFBP-) 1, consequently decreasing the bioavailability of insulin-like growth factor-1 (IGF-1) [41]. By binding to specific tyrosine kinase receptors, insulin and free IGF-1 activate the phosphatidylinositol-3 kinase- (PI3K-) protein kinase B- (PKB-) mammalian target of rapamycin complex 1 (mTORC1) pathways, which promote proliferative signaling, protect against cell death, and alter cellular metabolism including increased fermentation of glucose and glutamine [42]. CR activates the nuclear factor erythroid 2-related factor 2 (Nrf2) gene [43], an energy-sensing network consisting of adenosine monophosphate-activated protein kinase (AMPK), NAD-dependent deacetylase sirtuin-1 (SIRT1) [44], peroxisome proliferator-activated receptor-alpha (PPARα), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which counteract the insulin/IGF-1/PI3K/PKB/mTORC1 pathway and promote mitochondrial function.

Interestingly, metabolic responses to CR differ between normal and cancer cells. Effectively, CR shuts off the energy source of the cancer. As described earlier, normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, whereas cancer cells rely on aerobic glycolysis. In normal cells, abundant acetyl-CoA from the breakdown of ketone bodies (acetoacetate and β-hydroxybutyrate) and fatty acids due to starvation inhibits glycolysis to ensure stable ATP levels, and subsequent oxidation of ketone bodies in peripheral tissue decreases the NADP+/NADPH ratio [45]. Mitochondria in tumor cells were initially thought to be dysfunctional [3, 13]. However, several cancer cells also lack the mitochondrial enzymes necessary to metabolize ketone bodies [4649]. Theoretically, the drop in glycolytic ATP production achieved by CR cannot be compensated for via oxidative phosphorylation; thus, ATP depletion, cell growth inhibition [50], and death ensue [5153]. Although cancer mitochondrial dysfunction is still under debate, CR has great potential as a cancer therapy simply because of glycolysis depletion, eliminating the advantages conferred to tumor cells by the Warburg effect such as the synthesis of biomass including ribonucleotides [21], amino acids [54], and NADPH [22] (Figures 1(c) and 1(d)).

To date, many studies of the tumor-suppressive effects of CR have focused on its ability to prevent cancer, as an intervention rather than as an application as an anticancer therapy. Recent interest has focused on the potential of CR as an adjunct therapy for various cancers, in tandem with traditional chemotherapy or radiation therapy. CR increases radiation efficacy in breast cancer [55]. Similarly, fasting-based intervention has been demonstrated to protect normal cells while keeping cancer cells vulnerable to high-dose chemotherapy in both cell culture and neuroblastoma-bearing mice [5659]. However, it remains unknown whether these observations are caused by the Warburg effect.

3.2. The Emerging Role of Ketogenic Diets (KDs) in Cancer Treatment

In a KD, fats account for about 90% or more of total energy intake. The KD simulates fasting, increasing ketones in the blood and reducing glucose; fatty acid oxidation and acetyl-CoA production are also increased at high rates. KDs have recently attracted attention, with a broad-spectrum approach aimed at lowering blood sugar and insulin levels, targeting the Warburg effect and fundamental genetic changes [60]. This dietary approach exploits the main metabolic differences between micronutrient loss or limitation, mimicking fasting to some extent by lowering and stabilizing insulin levels, mildly elevating cortisol levels, and raising fatty acid oxidation. Together, these adaptions promote hepatic ketogenesis, raising the concentration of ketones. KDs are therefore attractive for long-term application during cancer treatment. Many studies have revealed pleiotropic effects of KDs on malignant tumors due to changes in systemic and cellular metabolism (Table 1).

Thus, the basis for providing a fat-rich and low-carbohydrate diet in cancer therapy is to lower circulating glucose levels and cause ketosis, which depletes the energy of cancer cells, while normal cells use ketone bodies through metabolism. Reducing blood sugar also reduces the levels of insulin and insulin-like growth factors, which are important drivers of cancer cell proliferation. Due to the Warburg effect, glucose in dietary carbohydrates acts as a primary metabolic fuel for many tumors. This observation prompted early research into KD as a cancer treatment, and carbohydrate restriction-induced glucose deprivation was thought to be the main mechanism by which KD slows tumor progression. KD and CR target the same molecular pathways including PI3K, PKB, mTORC, and AMPK. Several preclinical models have reported that ketosis is associated with tumor growth inhibition either by direct action or as an indicator of the effect of maximal insulin inhibition [6164]. KD has been shown to delay human gastric cancer cell growth in nude mice [65] and in a xenograft model of prostate cancer [66]. Changes in gene expression suggest that KD can inhibit the IGF-1, platelet-derived growth factor (PDGF), and epidermal growth factor receptor (EGFR) signaling pathways, as shown in various CR and KD studies [34, 53, 67].

3.3. Clinical Experience in Humans

The first clinical attempts to control tumor growth by reducing glucose supply to cancer cells were performed in 1987 [68], after the original concept was developed by Gold [69] and by Ray et al. [70]. These researchers found that hydrazine sulphate administration significantly reduced amino acid flux and may favorably influence metabolic abnormalities in cancer cachexia.

However, recent nutritional therapy approaches have been tailored to tumor metabolic properties. In 2005, Breitkreutz et al. [71] investigated gastrointestinal carcinomas in a randomized trial of 23 moderately malnourished patients and found that a high-fat diet may support the maintenance of both body weight and body cell mass, while decreasing lymphocyte numbers; several aspects of quality of life were rated as improved by patients consuming a fat-enriched artificial liquid diet. Although these results do not indicate direct tumor reduction by diet, they may offer a supportive strategy for cancer therapy.

Since the first known applications of KDs to target the Warburg effect specifically were published in 1941/1942, there has been only sporadic interest in KDs for cancer treatment [60, 72]. Clinical results have included a case report of two female pediatric patients with advanced-stage malignant astrocytoma, who demonstrated a 21.8% decrease in glucose uptake at the tumor site when fed a KD, as determined by FDG–PET [73]. Although a KD diet does not replace conventional antineoplastic treatments, these preliminary results suggest that potential clinical application of KDs merits further research.

A recent case report showed improvement in a 65-year-old female patient with glioblastoma multiform treated with a CR-KD, together with standard treatment [74]. Studies of cancer patient quality of life have found that KDs produce no serious side effects, improve emotional functioning, and reduce insomnia [75]. At present, 62 trials are being performed to evaluate low-carbohydrate diets as potential therapies for various diseases, among which 11 are evaluating KDs as adjuvant cancer therapies. At Würzburg University in Germany, KDs are being tested in patients for whom traditional cancer treatment has failed and no other remedy options remain. Preliminary reports indicate that these patients were able to continue the KD therapy for over 3 months and showed improvement, including stable physical condition, tumor shrinkage, and/or slowed tumor growth [75].

Most studies have suggested that CR and KD combined with other clinical therapies can improve cancer treatment. The clinical evidence for CR and KD curing cancer as a conventional anticancer treatment is very poor and is a subject of continuing study (NCT00575146). Previous clinical studies of CR and/or KD treatment of cancer patients are summarized in Table 3. Overall, these studies show that CR and KD are safe for long periods in cancer patients.


CancerStudy groupDietOutcomeReferences

Malignant astrocytoma tumors2 (8 wks)↓PET, 1 patient alive at 4 years and 1 at 10 years[73]
A partial gastrectomy and total colectomy for familial adenomatous polyposis1Parenteral nutrition 28 kcal/kg/d carbohydrates 45 g (5 months)Treatment well tolerated[91]
Mix: breast, lung, prostate, ovary…10CR (20-140 h pretherapy) (8-56 h posttherapy)Low chemotherapy side effects[92]
Glioblastoma1Patient conducted water-only therapeutic fasting and a restricted 4 : 1 (fat : carbohydrate+protein) ketogenic diet that delivered about 600 kcal/dayComplete response with radio chemotherapy[74]
Mix: ovarian, breast, thyroid…16KD (less than 70 g carbohydrates per day) 3-month intervention period1/3 completed CR, 3/4 tolerated well, few side effects from CR[75]
Mix: breast, lung, colorectum, ovary…10KD 17 kcal/kg/d (4 wks)Level of ketosis (not weight loss) correlated with tumor response[93]
Advanced stagePediatric patientsMedium chain triglyceride- (MCT-) based KD (60% MCT, 20% protein, 10% carbohydrate, and 10% other dietary fats)Blood ketone levels increased 20- to 30-fold; blood glucose levels declined[94]
Gastrointestinal tract27Parental feeding with lipid-based diet (80% of total caloric requirement were fat, 20% dextrose) or glucose-based diet (100% dextrose)Number of replicating cells increased in average 32.2% in the glucose-based diet group and decreased by 24.3% in the lipid-based diet but the results were not statistically significant[95]
Glioblastoma20 patients with recurrent diseaseKD (calories: 77% fat, 8% carbohydrates, and 15% protein) for 3–9 months in combination with temozolomide (TMZ) or chemoradiationFour patients were alive at median follow-up of 14 months; one of the four patients was under carbohydrate-restricted KD (4.5% carbohydrates) post radiation and TMZ treatment and had no recurrence after 12 months from treatment; the other three had recurrence and started alternative chemotherapy treatments[96]
Malignant disease5 patients with severe weight lossKD (70% MCT supplemented with β-hydroxybutyrate (BHB))Increased body weight after 7 days (∼2 kg), presence of ketosis already after 24 h in association with a reduction of blood glucose, pyruvate, and lactate levels[97]

4. Conclusion and Perspectives

In the presence of oxygen, normal cells undergo glycolysis and oxidative phosphorylation, whereas proliferating cancer cells exhibit an increased glucose uptake and glycolysis rate and, predominantly, undergo lactic acid fermentation. The physiology of cancer metabolism remains to be elucidated, although several drug compounds and therapeutic strategies have been proposed for cancer treatment based on the Warburg effect, which is generally thought to confer growth advantages to tumor cells by increasing ATP and biomass production, generating tumor-promoting environments by increasing lactic acid [24], and decreasing ROS production [25, 26]. Therefore, anticancer strategies are being developed to eliminate these benefits to cancer cells. To target cancer metabolic processes, diet-based strategies can be used in pushbike with drug treatments as an emerging and promising cancer therapy. CR and/or KD can starve cancer cells, while maintaining normal cells. CR and KD reduce glucose levels, eliminating the benefits of glycolysis to cancer cells. These dietary strategies enhance ketones and other metabolites that normally interact with the mitochondrial ATP generation process. OXPHOS was initially thought to be dysfunctional in cancer cells, which lack the mitochondrial enzymes necessary to metabolize ketone bodies.

Theoretically, CR and KD can completely remove the ATP sources of cancer cells but not those of normal cells. These strategies have been applied in both preclinical and clinical studies; however, much stronger effects on cancer proliferation are required to cure cancer. It is necessary to determine whether cancer mitochondria are actually dysfunctional, as well as the exact role of such abnormal mitochondria in cancer cell function. Other aspects, is there any side effect caused by KD? Is there any impairment in rapidly proliferating normal cells (lymphocytes, fibroblasts) that have active aerobic glycolysis [1520]? Moreover, in a study, Ozsvari et al. demonstrated that mitoketoscins, novel mitochondrial inhibitors for targeting ketone metabolism, could inhibit cancer stem cell activity and propagation [76]. Thus, could KD block cancer stem cell itself? Addressing these questions is critical for the development of new diet-based tools for the improvement of recent therapies by targeting cancer cell metabolism.

Abbreviations

OXPHOS:Oxidative phosphorylation
ATP:Adenosine triphosphate
NAD:Nicotinamide adenine dinucleotide
ROS:Reactive oxygen species
FDG-PET:F-18 fluorodeoxyglucose-positron emission tomography
GLUT:Glucose transporter
2-DG:2-Deoxy-D-glucose
DCA:Dichloroacetate
3-BP:3-Bromopyruvate
CR:Calorie restriction
IGF-1:Insulin-like growth factor-1
PI3K:Phosphatidylinositol-3 kinase
PKB:Protein kinase B
mTORC1:Mammalian target of rapamycin complex 1
Nrf2:Nuclear factor erythroid 2-related factor 2
AMPK:Adenosine monophosphate-activated protein kinase
PPARα:Peroxisome proliferator-activated receptor-alpha
PGC1α:Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
KD:Ketogenic diet.

Conflicts of Interest

The authors declare that they have no competing interests.

Authors’ Contributions

GK, HL, JiP, SHK, and JoP contributed to the conception and design of the study; GK, QT, NG, JiP, and CK organized the database; GK wrote the first draft of the manuscript; GK, HL, QT, SK, and JiP wrote sections of the manuscript. All authors contributed to manuscript revision and read and approved the submitted version. All authors gave consent for publication.

Acknowledgments

This work was financially supported by a research fund from Chungnam National University (grant to SH Kim) and by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (NRF-2020R1F1A1049801).

References

  1. O. Warburg, “Notizen zur Entwicklungsphysiologie des seeigeleies,” Pflüger's Archiv für die Gesamte Physiologie des Menschen und der Tiere, vol. 160, no. 4-6, pp. 324–332, 1915. View at: Publisher Site | Google Scholar
  2. O. Warburg, “On the origin of cancer cells,” Science, vol. 123, no. 3191, pp. 309–314, 1956. View at: Publisher Site | Google Scholar
  3. O. Warburg, “On respiratory impairment in cancer cells,” Science, vol. 124, no. 3215, pp. 269-270, 1956. View at: Google Scholar
  4. O. Warburg, “Verbesserte methode zur messung der atmung und glykolyse,” Biochemische Zeitschrift, vol. 152, pp. 51–63, 1924. View at: Google Scholar
  5. B. Chance and L. N. Castor, “Some patterns of the respiratory pigments of ascites tumors of mice,” Science, vol. 116, no. 3008, pp. 200–202, 1952. View at: Publisher Site | Google Scholar
  6. S. Weinhouse, O. Warburg, D. Burk, and A. L. Schade, “On respiratory impairment in cancer cells,” Science, vol. 124, no. 3215, pp. 267–272, 1956. View at: Publisher Site | Google Scholar
  7. M. T. Villanueva, “Metabolism: the mitochondria thief,” Nature Reviews Cancer, vol. 15, no. 2, pp. 70-71, 2015. View at: Publisher Site | Google Scholar
  8. S. Y. Kim, “Cancer energy metabolism: shutting power off cancer factory,” Biomolecules & Therapeutics, vol. 26, no. 1, pp. 39–44, 2018. View at: Publisher Site | Google Scholar
  9. W. H. Koppenol, P. L. Bounds, and C. V. Dang, “Otto Warburg’s contributions to current concepts of cancer metabolism,” Nature Reviews Cancer, vol. 11, no. 5, pp. 325–337, 2011. View at: Publisher Site | Google Scholar
  10. V. R. Fantin, J. St-Pierre, and P. Leder, “Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance,” Cancer Cell, vol. 9, no. 6, pp. 425–434, 2006. View at: Publisher Site | Google Scholar
  11. R. Moreno-Sanchez, S. Rodriguez-Enriquez, A. Marin-Hernandez, and E. Saavedra, “Energy metabolism in tumor cells,” The FEBS Journal, vol. 274, no. 6, pp. 1393–1418, 2007. View at: Publisher Site | Google Scholar
  12. D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000. View at: Publisher Site | Google Scholar
  13. S. J. Yeung, J. Pan, and M. H. Lee, “Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer,” Cellular and Molecular Life Sciences, vol. 65, no. 24, pp. 3981–3999, 2008. View at: Publisher Site | Google Scholar
  14. J. Jung, “Role of G protein-coupled estrogen receptor in cancer progression,” Toxicology Research, vol. 35, no. 3, pp. 209–214, 2019. View at: Publisher Site | Google Scholar
  15. S. Y. Lunt and M. G. Vander Heiden, “Aerobic glycolysis: meeting the metabolic requirements of cell proliferation,” Annual Review of Cell and Developmental Biology, vol. 27, no. 1, pp. 441–464, 2011. View at: Publisher Site | Google Scholar
  16. S. Christen and U. Sauer, “Intracellular characterization of aerobic glucose metabolism in seven yeast species by 13C flux analysis and metabolomics,” FEMS Yeast Research, vol. 11, no. 3, pp. 263–272, 2011. View at: Publisher Site | Google Scholar
  17. Z. Darzynkiewicz, L. Staiano-Coico, and M. R. Melamed, “Increased mitochondrial uptake of rhodamine 123 during lymphocyte stimulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 4, pp. 2383–2387, 1981. View at: Publisher Site | Google Scholar
  18. C. J. Hedeskov, “Early effects of phytohaemagglutinin on glucose metabolism of normal human lymphocytes,” The Biochemical Journal, vol. 110, no. 2, pp. 373–380, 1968. View at: Publisher Site | Google Scholar
  19. T. Wang, C. Marquardt, and J. Foker, “Aerobic glycolysis during lymphocyte proliferation,” Nature, vol. 261, no. 5562, pp. 702–705, 1976. View at: Publisher Site | Google Scholar
  20. W. H. Munyon and D. J. Merchant, “The relation between glucose utilization, lactic acid production and utilization and the growth cycle of L strain fibroblasts,” Experimental Cell Research, vol. 17, no. 3, pp. 490–498, 1959. View at: Publisher Site | Google Scholar
  21. X. Tong, F. Zhao, and C. B. Thompson, “The molecular determinants of de novo nucleotide biosynthesis in cancer cells,” Current Opinion in Genetics & Development, vol. 19, no. 1, pp. 32–37, 2009. View at: Publisher Site | Google Scholar
  22. D. Anastasiou, G. Poulogiannis, J. M. Asara et al., “Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses,” Science, vol. 334, no. 6060, pp. 1278–1283, 2011. View at: Publisher Site | Google Scholar
  23. R. B. Hamanaka and N. S. Chandel, “Warburg effect and redox balance,” Science, vol. 334, no. 6060, pp. 1219-1220, 2011. View at: Publisher Site | Google Scholar
  24. R. A. Gatenby and R. J. Gillies, “Why do cancers have high aerobic glycolysis?” Nature Reviews Cancer, vol. 4, no. 11, pp. 891–899, 2004. View at: Publisher Site | Google Scholar
  25. K. A. Brand and U. Hermfisse, “Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species,” The FASEB Journal, vol. 11, no. 5, pp. 388–395, 1997. View at: Publisher Site | Google Scholar
  26. D. R. Spitz, J. E. Sim, L. A. Ridnour, S. S. Galoforo, and Y. J. Lee, “Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism?” Annals of the New York Academy of Sciences, vol. 899, pp. 349–362, 2000. View at: Publisher Site | Google Scholar
  27. S. E. Elf and J. Chen, “Targeting glucose metabolism in patients with cancer,” Cancer, vol. 120, no. 6, pp. 774–780, 2014. View at: Publisher Site | Google Scholar
  28. Q. Tran, H. Lee, J. Park, S. H. Kim, and J. Park, “Targeting cancer metabolism - revisiting the Warburg effects,” Toxicology Research, vol. 32, no. 3, pp. 177–193, 2016. View at: Publisher Site | Google Scholar
  29. T. Higashi, N. Tamaki, T. Torizuka et al., “FDG uptake, GLUT-1 glucose transporter and cellularity in human pancreatic tumors,” Journal of Nuclear Medicine, vol. 39, no. 10, pp. 1727–1735, 1998. View at: Google Scholar
  30. Y. Liu, Y. Cao, W. Zhang et al., “A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo,” Molecular Cancer Therapeutics, vol. 11, no. 8, pp. 1672–1682, 2012. View at: Publisher Site | Google Scholar
  31. D. A. Chan, P. D. Sutphin, P. Nguyen et al., “Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality,” Science Translational Medicine, vol. 3, no. 94, p. 94ra70, 2011. View at: Publisher Site | Google Scholar
  32. P. Rous, “The influence of diet on transplanted and spontaneous mouse tumors,” The Journal of Experimental Medicine, vol. 20, no. 5, pp. 433–451, 1914. View at: Publisher Site | Google Scholar
  33. P. Mukherjee, M. M. El-Abbadi, J. L. Kasperzyk, M. K. Ranes, and T. N. Seyfried, “Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model,” British Journal of Cancer, vol. 86, no. 10, pp. 1615–1621, 2002. View at: Publisher Site | Google Scholar
  34. P. Mukherjee, L. E. Abate, and T. N. Seyfried, “Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors,” Clinical Cancer Research, vol. 10, no. 16, pp. 5622–5629, 2004. View at: Publisher Site | Google Scholar
  35. C. Yang, J. Sudderth, T. Dang, R. M. Bachoo, J. G. McDonald, and R. J. DeBerardinis, “Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling,” Cancer Research, vol. 69, no. 20, pp. 7986–7993, 2009. View at: Publisher Site | Google Scholar
  36. L. M. Shelton, L. C. Huysentruyt, P. Mukherjee, and T. N. Seyfried, “Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse,” ASN Neuro, vol. 2, no. 3, article e00038, 2010, AN20100002. View at: Publisher Site | Google Scholar
  37. P. Mukherjee, A. V. Sotnikov, H. J. Mangian, J. R. Zhou, W. J. Visek, and S. K. Clinton, “Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression,” Journal of the National Cancer Institute, vol. 91, no. 6, pp. 512–523, 1999. View at: Publisher Site | Google Scholar
  38. M. S. De Lorenzo, E. Baljinnyam, D. E. Vatner, P. Abarzua, S. F. Vatner, and A. B. Rabson, “Caloric restriction reduces growth of mammary tumors and metastases,” Carcinogenesis, vol. 32, no. 9, pp. 1381–1387, 2011. View at: Publisher Site | Google Scholar
  39. K. N. Phoenix, F. Vumbaca, M. M. Fox, R. Evans, and K. P. Claffey, “Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy,” Breast Cancer Research and Treatment, vol. 123, no. 2, pp. 333–344, 2010. View at: Publisher Site | Google Scholar
  40. H. J. Thompson, J. N. McGinley, N. S. Spoelstra, W. Jiang, Z. Zhu, and P. Wolfe, “Effect of dietary energy restriction on vascular density during mammary carcinogenesis,” Cancer Research, vol. 64, no. 16, pp. 5643–5650, 2004. View at: Publisher Site | Google Scholar
  41. S. Rajaram, D. J. Baylink, and S. Mohan, “Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions,” Endocrine Reviews, vol. 18, no. 6, pp. 801–831, 1997. View at: Publisher Site | Google Scholar
  42. D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011. View at: Publisher Site | Google Scholar
  43. K. N. Lewis, J. Mele, J. D. Hayes, and R. Buffenstein, “Nrf2, a guardian of healthspan and gatekeeper of species longevity,” Integrative and Comparative Biology, vol. 50, no. 5, pp. 829–843, 2010. View at: Publisher Site | Google Scholar
  44. D. A. Sinclair, “Toward a unified theory of caloric restriction and longevity regulation,” Mechanisms of Ageing and Development, vol. 126, no. 9, pp. 987–1002, 2005. View at: Publisher Site | Google Scholar
  45. R. L. Veech, “The determination of the redox states and phosphorylation potential in living tissues and their relationship to metabolic control of disease phenotypes,” Biochemistry and Molecular Biology Education, vol. 34, no. 3, pp. 168–179, 2006. View at: Publisher Site | Google Scholar
  46. M. J. Tisdale and R. A. Brennan, “Loss of acetoacetate coenzyme A transferase activity in tumours of peripheral tissues,” British Journal of Cancer, vol. 47, no. 2, pp. 293–297, 1983. View at: Publisher Site | Google Scholar
  47. R. Skinner, A. Trujillo, X. Ma, and E. A. Beierle, “Ketone bodies inhibit the viability of human neuroblastoma cells,” Journal of Pediatric Surgery, vol. 44, no. 1, pp. 212–216, 2009, discussion 216. View at: Publisher Site | Google Scholar
  48. G. D. Maurer, D. P. Brucker, O. Bähr et al., “Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy,” BMC Cancer, vol. 11, no. 1, 2011. View at: Publisher Site | Google Scholar
  49. H. T. Chang, L. K. Olson, and K. A. Schwartz, “Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: implication for ketogenic diet therapy,” Nutrition & Metabolism (London), vol. 10, no. 1, p. 47, 2013. View at: Publisher Site | Google Scholar
  50. E. J. Fine, A. Miller, E. V. Quadros, J. M. Sequeira, and R. D. Feinman, “Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2,” Cancer Cell International, vol. 9, no. 1, p. 14, 2009. View at: Publisher Site | Google Scholar
  51. S. K. N. Marie and S. M. O. Shinjo, “Metabolism and brain cancer,” Clinics, vol. 66, Supplement 1, pp. 33–43, 2011. View at: Publisher Site | Google Scholar
  52. A. M. Puzio-Kuter, “The role of p53 in metabolic regulation,” Genes & Cancer, vol. 2, no. 4, pp. 385–391, 2011. View at: Publisher Site | Google Scholar
  53. Y. S. Jiang and F. R. Wang, “Caloric restriction reduces edema and prolongs survival in a mouse glioma model,” Journal of Neuro-Oncology, vol. 114, no. 1, pp. 25–32, 2013. View at: Publisher Site | Google Scholar
  54. J. W. Locasale, A. R. Grassian, T. Melman et al., “Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis,” Nature Genetics, vol. 43, no. 9, pp. 869–874, 2011. View at: Publisher Site | Google Scholar
  55. A. Saleh, B. Simone, J. Palazzo et al., “Caloric restriction augments radiation efficacy in breast cancer,” Cell Cycle, vol. 12, no. 12, pp. 1955–1963, 2014. View at: Publisher Site | Google Scholar
  56. L. Raffaghello, C. Lee, F. M. Safdie et al., “Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 24, pp. 8215–8220, 2008. View at: Publisher Site | Google Scholar
  57. C. Lee, F. M. Safdie, L. Raffaghello et al., “Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index,” Cancer Research, vol. 70, no. 4, pp. 1564–1572, 2010. View at: Publisher Site | Google Scholar
  58. C. Lee, L. Raffaghello, S. Brandhorst et al., “Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy,” Science Translational Medicine, vol. 4, no. 124, p. 124ra27, 2012. View at: Publisher Site | Google Scholar
  59. F. Safdie, S. Brandhorst, M. Wei et al., “Fasting enhances the response of glioma to chemo- and radiotherapy,” PLoS One, vol. 7, no. 9, article e44603, 2012. View at: Publisher Site | Google Scholar
  60. R. J. Klement, “Wilhelm Brünings’ forgotten contribution to the metabolic treatment of cancer utilizing hypoglycemia and a very low carbohydrate (ketogenic) diet,” Journal of Traditional and Complementary Medicine, vol. 9, no. 3, pp. 192–200, 2019. View at: Publisher Site | Google Scholar
  61. M. J. Tisdale, R. A. Brennan, and K. C. Fearon, “Reduction of weight loss and tumour size in a cachexia model by a high fat diet,” British Journal of Cancer, vol. 56, no. 1, pp. 39–43, 1987. View at: Publisher Site | Google Scholar
  62. B. A. Magee, N. Potezny, A. M. Rofe, and R. A. J. Conyers, “The inhibition of malignant cell growth by ketone bodies,” The Australian Journal of Experimental Biology and Medical Science, vol. 57, no. 5, pp. 529–539, 1979. View at: Publisher Site | Google Scholar
  63. G. E. Demetrakopoulos and M. F. Brennan, “Tumoricidal potential of nutritional manipulations,” Cancer Research, vol. 42, 2 Suppl, pp. 756s–765s, 1982. View at: Google Scholar
  64. S. A. Beck and M. J. Tisdale, “Effect of insulin on weight loss and tumour growth in a cachexia model,” British Journal of Cancer, vol. 59, no. 5, pp. 677–681, 1989. View at: Publisher Site | Google Scholar
  65. C. Otto, U. Kaemmerer, B. Illert et al., “Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides,” BMC Cancer, vol. 8, no. 1, 2008. View at: Publisher Site | Google Scholar
  66. S. J. Freedland, J. Mavropoulos, A. Wang et al., “Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis,” Prostate, vol. 68, no. 1, pp. 11–19, 2008. View at: Publisher Site | Google Scholar
  67. I. Urits, P. Mukherjee, J. Meidenbauer, and T. N. Seyfried, “Dietary restriction promotes vessel maturation in a mouse astrocytoma,” Journal of Oncology, vol. 2012, Article ID 264039, 10 pages, 2012. View at: Publisher Site | Google Scholar
  68. J. A. Tayek, D. Heber, and R. T. Chlebowski, “Effect of hydrazine sulphate on whole-body protein breakdown measured by 14C-lysine metabolism in lung cancer patients,” Lancet, vol. 2, no. 8553, pp. 241–244, 1987. View at: Publisher Site | Google Scholar
  69. J. Gold, “Proposed treatment of cancer by inhibition of gluconeogenesis,” Oncology, vol. 22, no. 2-3, pp. 185–207, 1968. View at: Publisher Site | Google Scholar
  70. P. D. Ray, R. L. Hanson, and H. A. Lardy, “Inhibition by hydrazine of gluconeogenesis in the rat,” The Journal of Biological Chemistry, vol. 245, no. 4, pp. 690–696, 1970. View at: Google Scholar
  71. R. Breitkreutz, K. Tesdal, D. Jentschura, O. Haas, H. Leweling, and E. Holm, “Effects of a high-fat diet on body composition in cancer patients receiving chemotherapy: a randomized controlled study,” Wiener Klinische Wochenschrift, vol. 117, no. 19-20, pp. 685–692, 2005. View at: Publisher Site | Google Scholar
  72. B. G. Allen, S. K. Bhatia, C. M. Anderson et al., “Ketogenic diets as an adjuvant cancer therapy: history and potential mechanism,” Redox Biology, vol. 2, pp. 963–970, 2014. View at: Publisher Site | Google Scholar
  73. L. C. Nebeling, F. Miraldi, S. B. Shurin, and E. Lerner, “Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports,” Journal of the American College of Nutrition, vol. 14, no. 2, pp. 202–208, 1995. View at: Publisher Site | Google Scholar
  74. G. Zuccoli, N. Marcello, A. Pisanello et al., “Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: case report,” Nutrition & Metabolism (London), vol. 7, no. 1, p. 33, 2010. View at: Publisher Site | Google Scholar
  75. M. Schmidt, N. Pfetzer, M. Schwab, I. Strauss, and U. Kammerer, “Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: a pilot trial,” Nutrition & Metabolism (London), vol. 8, no. 1, p. 54, 2011. View at: Publisher Site | Google Scholar
  76. B. Ozsvari, F. Sotgia, K. Simmons, R. Trowbridge, R. Foster, and M. P. Lisanti, “Mitoketoscins: novel mitochondrial inhibitors for targeting ketone metabolism in cancer stem cells (CSCs),” Oncotarget, vol. 8, no. 45, pp. 78340–78350, 2017. View at: Publisher Site | Google Scholar
  77. R. J. Klement, “The emerging role of ketogenic diets in cancer treatment,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 22, no. 2, pp. 129–134, 2019. View at: Publisher Site | Google Scholar
  78. L. E. Raez, K. Papadopoulos, A. D. Ricart et al., “A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors,” Cancer Chemotherapy and Pharmacology, vol. 71, no. 2, pp. 523–530, 2013. View at: Publisher Site | Google Scholar
  79. D. Anastasiou, Y. Yu, W. J. Israelsen et al., “Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis,” Nature Chemical Biology, vol. 8, no. 10, pp. 839–847, 2012. View at: Publisher Site | Google Scholar
  80. C. Kung, J. Hixon, S. Choe et al., “Small molecule activation of PKM2 in cancer cells induces serine auxotrophy,” Chemistry & Biology, vol. 19, no. 9, pp. 1187–1198, 2012. View at: Publisher Site | Google Scholar
  81. A. Le, C. R. Cooper, A. M. Gouw et al., “Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 5, pp. 2037–2042, 2010. View at: Publisher Site | Google Scholar
  82. R. Bhardwaj, P. K. Sharma, S. P. S. Jadon, and R. Varshney, “A combination of 2-deoxy-D-glucose and 6-aminonicotinamide induces cell cycle arrest and apoptosis selectively in irradiated human malignant cells,” Tumour Biology, vol. 33, no. 4, pp. 1021–1030, 2012. View at: Publisher Site | Google Scholar
  83. P. Sonveaux, F. Végran, T. Schroeder et al., “Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice,” The Journal of Clinical Investigation, vol. 118, no. 12, pp. 3930–3942, 2008. View at: Publisher Site | Google Scholar
  84. E. D. Michelakis, L. Webster, and J. R. Mackey, “Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer,” British Journal of Cancer, vol. 99, no. 7, pp. 989–994, 2008. View at: Publisher Site | Google Scholar
  85. S. B. Strum, O. Adalsteinsson, R. R. Black, D. Segal, N. L. Peress, and J. Waldenfels, “Case report: sodium dichloroacetate (DCA) inhibition of the “Warburg effect” in a human cancer patient: complete response in non-Hodgkin’s lymphoma after disease progression with rituximab-CHOP,” Journal of Bioenergetics and Biomembranes, vol. 45, no. 3, pp. 307–315, 2013. View at: Publisher Site | Google Scholar
  86. M. Addie, P. Ballard, D. Buttar et al., “Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin -4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases,” Journal of Medicinal Chemistry, vol. 56, no. 5, pp. 2059–2073, 2013. View at: Publisher Site | Google Scholar
  87. J. Lin, D. Sampath, M. A. Nannini et al., “Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models,” Clinical Cancer Research, vol. 19, no. 7, pp. 1760–1772, 2013. View at: Publisher Site | Google Scholar
  88. M. Dumble, M. C. Crouthamel, S. Y. Zhang et al., “Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor,” PLoS One, vol. 9, no. 6, article e100880, 2014. View at: Publisher Site | Google Scholar
  89. H. Hirai, H. Sootome, Y. Nakatsuru et al., “MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo,” Molecular Cancer Therapeutics, vol. 9, no. 7, pp. 1956–1967, 2010. View at: Publisher Site | Google Scholar
  90. X. Chen, Y. Qian, and S. Wu, “The Warburg effect: evolving interpretations of an established concept,” Free Radical Biology & Medicine, vol. 79, pp. 253–263, 2015. View at: Publisher Site | Google Scholar
  91. F. Bozzetti, L. Cozzaglio, C. Gavazzi et al., “Total nutritional manipulation in humans: report of a cancer patient,” Clinical Nutrition, vol. 15, no. 4, pp. 207–209, 1996. View at: Publisher Site | Google Scholar
  92. F. M. Safdie, T. Dorff, D. Quinn et al., “Fasting and cancer treatment in humans: a case series report,” Aging, vol. 1, no. 12, pp. 988–1007, 2009. View at: Publisher Site | Google Scholar
  93. E. J. Fine, C. J. Segal-Isaacson, R. D. Feinman et al., “Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients,” Nutrition, vol. 28, no. 10, pp. 1028–1035, 2012. View at: Publisher Site | Google Scholar
  94. L. C. Nebeling and E. Lerner, “Implementing a ketogenic diet based on medium-chain triglyceride oil in pediatric patients with cancer,” Journal of the American Dietetic Association, vol. 95, no. 6, pp. 693–697, 1995. View at: Publisher Site | Google Scholar
  95. S. Järvinen and L. Lehtinen, “Prevalence of extracted primary canines and molars in children aged 3 to 6 years in the city of Lahti,” Proceedings of the Finnish Dental Society. Suomen Hammaslaakariseuran toimituksia, vol. 74, no. 1-2, pp. 27–30, 1978. View at: Google Scholar
  96. C. E. Champ, J. D. Palmer, J. S. Volek et al., “Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme,” Journal of Neuro-Oncology, vol. 117, no. 1, pp. 125–131, 2014. View at: Publisher Site | Google Scholar
  97. K. C. Fearon, W. Borland, T. Preston, M. J. Tisdale, A. Shenkin, and K. C. Calman, “Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism,” The American Journal of Clinical Nutrition, vol. 47, no. 1, pp. 42–48, 1988. View at: Publisher Site | Google Scholar

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