Is there a role for carbohydrate restriction in the treatment and prevention of cancer
TL;DR: The possible beneficial effects of low CHO diets on cancer prevention and treatment are addressed, with emphasis on the role of insulin and IGF1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.
Abstract: Over the last years, evidence has accumulated suggesting that by systematically reducing the amount of dietary carbohydrates (CHOs) one could suppress, or at least delay, the emergence of cancer, and that proliferation of already existing tumor cells could be slowed down. This hypothesis is supported by the association between modern chronic diseases like the metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to which more complex carbohydrates are ultimately digested, can have direct and indirect effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells depend on steady glucose availability in the blood for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction. Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic ingestion of CHO-rich Western diet meals, can directly promote tumor cell proliferation via the insulin/IGF1 signaling pathway. Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have been found to negatively affect proliferation of different malignant cells in vitro or not to be usable by tumor cells for metabolic demands, and a multitude of mouse models have shown antitumorigenic properties of very low CHO ketogenic diets. In addition, many cancer patients exhibit an altered glucose metabolism characterized by insulin resistance and may profit from an increased protein and fat intake. In this review, we address the possible beneficial effects of low CHO diets on cancer prevention and treatment. Emphasis will be placed on the role of insulin and IGF1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.
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TL;DR: The objective of this review is to present the most recent research on the cancer-specific role of glycolysis including their non-glycolytic functions in order to explore the potential for therapeutic opportunities.
Abstract: Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the “hallmarks of cancer”. This metabolic phenotype is characterized by preferential dependence on glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.
760 citations
Cites background from "Is there a role for carbohydrate re..."
...carbohydrate-restricted diets to treat cancer patients have been reported to have therapeutic benefits [84]....
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TL;DR: The meaning of physiological ketosis is revisited and whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician's hand are questioned.
Abstract: Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician’s hand.
582 citations
TL;DR: GLUTs represent attractive targets for cancer therapy and this review summarizes recent studies in which GLUT1, GLUT3,GLUT5 and others are inhibited to decrease cancer growth.
Abstract: It is long recognized that cancer cells display increased glucose uptake and metabolism. In a rate-limiting step for glucose metabolism, the glucose transporter (GLUT) proteins facilitate glucose uptake across the plasma membrane. Fourteen members of the GLUT protein family have been identified in humans. This review describes the major characteristics of each member of the GLUT family and highlights evidence of abnormal expression in tumors and cancer cells. The regulation of GLUTs by key proliferation and pro-survival pathways including the phosphatidylinositol 3-kinase (PI3K)-Akt, hypoxia-inducible factor-1 (HIF-1), Ras, c-Myc and p53 pathways is discussed. The clinical utility of GLUT expression in cancer has been recognized and evidence regarding the use of GLUTs as prognostic or predictive biomarkers is presented. GLUTs represent attractive targets for cancer therapy and this review summarizes recent studies in which GLUT1, GLUT3, GLUT5 and others are inhibited to decrease cancer growth.
272 citations
TL;DR: This review aimed to present the most recent data on the emerging drug candidate targeting enzymes and intermediates involved in glucose metabolism to provide therapeutic opportunities and challenges for antiglycolytic cancer therapy.
255 citations
TL;DR: Evidence highlighting recent advances in understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity are discussed, as well as those areas where there remains a paucity of data.
Abstract: Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary conserved factors well known as key regulators of energy metabolism and growth, with crucial roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2 diabetes mellitus, as well as associated immune deregulations. A growing body of evidence suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation, differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream through insulin receptor substrate molecules and thus play a pivotal role in cell fate determination. Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms that might account for this relationship remains incompletely understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which has been proposed as the key mechanism bridging insulin resistance and cancer. The present review summarizes and discusses evidence highlighting recent advances in our understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity, as well as those areas where there remains a paucity of data. It is anticipated that issues discussed in this paper will also recover new therapeutic targets that can assist in diagnostic screening and novel approaches to controlling tumor development.
216 citations
Cites background from "Is there a role for carbohydrate re..."
...Unlike IGFs, local production of insulin by tumors is uncommon (Venkateswaran et al. 2007, Klement & Kammerer 2011)....
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...Notably, IGFs originate from both local and systemic productions in cancer (Fagin et al. 1988, Foulstone et al. 2003) and are commonly expressed by cancer cells (Venkateswaran et al. 2007, Klement & Kammerer 2011)....
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References
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Journal Article•
TL;DR: It is concluded that tumor lactate content may be used as a prognostic parameter in the clinic and in accordance with data from the literature showing that the presence of hypoxia in cervical tumors is associated with a poorer patient survival.
Abstract: Pathophysiological parameters such as vascular density and tissue oxygen pressure can influence tumor malignancy and patient survival. Observations from our group showed that metastatic spread of carcinomas of the uterine cervix and of head and neck cancers was closely correlated with the lactate concentration in the primary lesion. Because these results were obtained in a low number of patients, the present investigation was performed to verify such a correlation in a larger population. Cryobiopsies were taken at first diagnosis of cervical cancer from 34 patients. Tissue concentrations of ATP, glucose, and lactate in viable tumor regions of these biopsies were measured microscopically using the technique of imaging bioluminescence. There was no correlation between stage or grade and any of the metabolic parameters measured. ATP and glucose concentrations were not significantly different in metastatic and nonmetastatic primary tumors (P>0.05). However, lactate concentrations were significantly higher (P = 0.001) in tumors with metastatic spread (mean +/- SD, 10.0+/-2.9 micromol/g; n = 20) compared with malignancies in patients without metastases (6.3+/-2.8 micromol/g; n = 14). The majority of patients who suffered a recurrence of the disease (17 of a total of 22 patients) or died (15 of 20) within the observation period of up to 8 years belonged to the metastatic, i.e., high lactate group. A Kaplan-Meier analysis of the data showed that the overall and disease-free survival probabilities of patients having low tumor lactate values were significantly higher compared with patients with high tumor lactate concentrations (P = 0.015 and 0.014, respectively). We conclude that tumor lactate content may be used as a prognostic parameter in the clinic. Furthermore, these findings are in accordance with data from the literature showing that the presence of hypoxia in cervical tumors is associated with a poorer patient survival.
716 citations
"Is there a role for carbohydrate re..." refers background in this paper
...Fourth, high glycolytic activity produces high levels of lactate and H ions which get transported outside the cell where they directly promote tumor aggressiveness [68] through invasion and metastasis, two other hallmarks of cancer....
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TL;DR: This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function.
Abstract: The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more at...
697 citations
"Is there a role for carbohydrate re..." refers background in this paper
...Recent evidence suggests that overstimulation of zonulin in susceptible individuals could dysregulate intercellular communication promoting tumorigenesis at specific organ sites [161]....
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TL;DR: Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism.
Abstract: Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention.
606 citations
"Is there a role for carbohydrate re..." refers background in this paper
...In addition, most malignant cells lack key mitochondrial enzymes necessary for conversion of ketone bodies and fatty acids to ATP [40,113,114], while myocytes retain this ability even in the cachectic state [107]....
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...Indeed, several studies have shown that malignant cells in vitro quickly lose ATP and commit apoptosis when starved of glucose [78-80]....
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...Seyfried TN, Shelton LM: Cancer as a metabolic disease....
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...Berwick DC, Hers I, Heesom KJ, Moule SK, Tavare JM: The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes....
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...It is clear that the high proliferative phenotype can only be sustained as long as a steady supply of substrates for ATP production is available....
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TL;DR: Control of mRNA translation constitutes a critical step in the control of gene expression, and consequently cell growth, proliferation and differentiation, and thus cap-dependent translation are emerging as promising therapeutic options for the treatment of cancer.
Abstract: Control of mRNA translation plays a fundamental role in many aspects of cell metabolism. It constitutes a critical step in the control of gene expression, and consequently cell growth, proliferation and differentiation. Translation is regulated in response to nutrient availability, hormones, mitogenic and growth factor stimulation and is coupled with cell cycle progression and cell growth. Signaling by the PI3K/Akt/mTOR pathway profoundly affects mRNA translation through phosphorylation of downstream targets such as 4E-BP and S6K. Inhibitors of this pathway and thus cap-dependent translation are emerging as promising therapeutic options for the treatment of cancer.
594 citations
"Is there a role for carbohydrate re..." refers background in this paper
...Akt also activates mTOR, a key regulator of cell growth and proliferation that integrates signaling from insulin and growth factors, amino acid availability, cellular energy status and oxygen levels [49,50]....
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TL;DR: There is increasing evidence that the resulting mismatch fosters "diseases of civilization" that together cause 75 percent of all deaths in Western nations, but that are rare among persons whose lifeways reflect those of the authors' preagricultural ancestors.
594 citations
"Is there a role for carbohydrate re..." refers background in this paper
...This observation makes sense from an evolutionary perspective from which it is reasonable to assume that the lifestyle factors that protect our genome against tumorigenesis have been selected for early in the history of the genus homo when humans lived as hunter-gatherers [5]....
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