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Journal ArticleDOI

Is there a role for carbohydrate restriction in the treatment and prevention of cancer

26 Oct 2011-Nutrition & Metabolism (BioMed Central)-Vol. 8, Iss: 1, pp 75-75
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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Citations
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Journal ArticleDOI
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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Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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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01 Jan 2011
TL;DR: Glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet.
Abstract: BackgroundEven in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells.MethodsTo investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model.ResultsThe ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival.ConclusionIn summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways.

151 citations


"Is there a role for carbohydrate re..." refers background in this paper

  • ...demonstrated that glioma cells - although not negatively influenced by b-hydroxybutyrate - are not able to use this ketone body as a substitute for glucose when starved of the latter, contrary to benign neuronal cells [128]....

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  • ...Foxn1nu mice 12 LNT-229 glioma cells ad libitum 0/13/ 36 flaxseed and hempseed oil 1 > 63 - no significant differences in survival, tumor growth and plasma IGF1 levels [128]...

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Journal Article
TL;DR: In this paper, a tracer technique was used to study the conversion of the carbon skeleton of alanine to glucose in patients with progressive malignant disease and found that uncontrolled gluconeogenesis from alanines is probably not significant in terms of energy expenditure.
Abstract: We have studied by tracer technique the conversion of the carbon skeleton of alanine to glucose in patients with progressive malignant disease. These data have been compared to similar studies done in patients with chronic undernutrition from other causes. The results show increased conversion of alanine to glucose in the overnight fasting state as compared to the control group. Whereas the percentage increases are comparable to those found with pyruvate-glucose cycling in such subjects, the total amount of carbon conversion is considerably less (alanine carbon, 5.6 mmol/hr, versus pyruvate carbon, 39 mmol/hr). Exogenous glucose resulted in good suppression of alanine-to-glucose conversion as it does in normal subjects. It did, however, result in increased glucose-to-alanine conversion, increased alanine levels, and increased flux of alanine from the circulation. Although these latter data may not have specificity for the patient with advanced cancer, a strong dependence for carbohydrate and protein metabolism is suggested. We conclude that uncontrolled gluconeogenesis from alanine is probably not significant in terms of energy expenditure in the patient with uncontrolled cancer.

149 citations


"Is there a role for carbohydrate re..." refers background in this paper

  • ...In the liver, the inflammatory process leads to increased gluconeogenesis that is fuelled by lactate secreted from the tumor as well as glycerol from fatty acid breakdown and the amino acid alanine [106] from muscle proteolysis....

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Journal ArticleDOI
TL;DR: This work tested whether a no‐carbohydrate ketogenic diet (NCKD) would delay prostate cancer growth relative to Western and low‐fat diets in a xenograft model.
Abstract: BACKGROUND Recent evidence suggests carbohydrate intake may influence prostate cancer biology. We tested whether a no-carbohydrate ketogenic diet (NCKD) would delay prostate cancer growth relative to Western and low-fat diets in a xenograft model.

147 citations


"Is there a role for carbohydrate re..." refers background or result in this paper

  • ...This contrasts with other studies showing growth-inhibitory effects of unrestricted or higher-caloric KDs despite neither decreases in blood glucose concentration nor body weight loss compared with a control group [130,134,135]....

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  • ...observed that a diet rich in corn oil might stimulate prostate cancer growth to a greater extent than one rich in saturated fat [134]....

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  • ...SCID mice 25 LAPC-4 human prostate cancer 9% more energy than control 0/16/ 84 milk fat + lard -24 > 40 ↑ c longer survival b [134]...

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  • ...indeed reported that the mice with the highest levels of ketone bodies had the longest survival times in a human prostate cancer xenograft model [134]....

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Journal ArticleDOI
TL;DR: Changes in fatty acid synthase, Spot 14, Akt, and DecR1 may underlie altered lipid metabolism in tumor cells and contribute to the ability of tumor cells to proliferate or metastasize.
Abstract: Tumor cells exhibit an altered metabolism, characterized by increased glucose uptake and elevated glycolysis, which was first recognized by Otto Warburg 70 years ago. Warburg originally hypothesized that these metabolic changes reflected damage to mitochondrial oxidative phosphorylation. Although hypoxia and hypoxia inducible factor can induce transcriptional changes that stimulate glucose transport and glycolysis, it is clear that these changes can occur in cultured tumor or transformed cells cultured under normoxic conditions, and thus there must be genetic alterations independent of hypoxia that can stimulate aerobic glycolysis. In recent years it has become clear that loss of p53 and activation of Akt can induce all or part of the metabolic changes reflected in the Warburg effect. Likewise, changes in expression of lactate dehydrogenase and other glycolytic control enzymes can contribute to increased or altered glycolysis. It is also clear that changes in lipid biosynthesis occur in tumor cells to support increased membrane biosynthesis and perhaps the altered energy needs of the cells. Changes in fatty acid synthase, Spot 14, Akt, and DecR1 (2,4-dienoylcoenzyme A reductase) may underlie altered lipid metabolism in tumor cells and contribute to the ability of tumor cells to proliferate or metastasize. Although these advances provide new therapeutic targets that merit exploration, there remain critical questions to be explored at the mechanistic level; this work may yield insights into tumor cell biology and identify additional therapeutic targets.

146 citations


"Is there a role for carbohydrate re..." refers background in this paper

  • ...In tumor cells, Akt plays a major role in resisting apoptosis and promoting proliferation, and it does so by reprogramming tumor cell metabolism [43-45]....

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  • ...In principle, hyperactivation of this pathway can occur at several points from alterations in either upstream (receptor) or downstream (transducer) proteins and/or disruption of negative feedback loops via loss-of-function mutations in suppressor genes [44,45,54]....

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01 Jan 2008
TL;DR: The Warburg effect of increased glucose uptake and elevated glycolysis in tumor cells was first recognized by Warburg 70 years ago as mentioned in this paper, and it has been shown that loss of p53 and activation of Akt can induce all or part of the metabolic changes reflected in the Warburg Effect.
Abstract: Tumor cells exhibit an altered metabolism, characterized by increased glucose uptake and elevated glycolysis, which was first recognized by Otto Warburg 70 years ago. Warburg originally hypothesized that these metabolic changes reflected damage to mitochondrial oxidative phosphorylation. Although hypoxia and hypoxia inducible factor can induce transcriptional changes that stimulate glucose transport and glycolysis, it is clear that these changes can occur in cultured tumor or transformed cells cultured under normoxic conditions, and thus there must be genetic alterations independent of hypoxia that can stimulate aerobic glycolysis. In recent years it has become clear that loss of p53 and activation of Akt can induce all or part of the metabolic changes reflected in the Warburg effect. Likewise, changes in expression of lactate dehydrogenase and other glycolytic control enzymes can contribute to increased or altered glycolysis. It is also clear that changes in lipid biosynthesis occur in tumor cells to support increased membrane biosynthesis and perhaps the altered energy needs of the cells. Changes in fatty acid synthase, Spot 14, Akt, and DecR1 (2,4-dienoyl-coenzyme A reductase) may underlie altered lipid metabolism in tumor cells and contribute to the ability of tumor cells to proliferate or metastasize. Although these advances provide new therapeutic targets that merit exploration, there remain critical questions to be explored at the mechanistic level; this work may yield insights into tumor cell biology and identify additional therapeutic targets.

140 citations