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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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Journal ArticleDOI
TL;DR: Transduction of the CIT3 mammary epithelial cell line with a recombinant human adenovirus encoding myr-Akt resulted in an increase in glucose transport and lipid biosynthesis, suggesting that Akt plays an important role in regulation of lipid metabolism.

137 citations


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

  • ...Akt suppresses b-oxidation of fatty acids [46], but enhances de novo lipid synthesis in the cytosol [47,48]....

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Journal Article
TL;DR: Peripheral tissues are of importance for the disturbed glucose metabolism in cancer disease since skeletal muscles showed specifically lowered capacity for glucose utilization with and without insulin stimulation in vitro.
Abstract: Disturbed glucose metabolism is a well-recognized feature in cancer. This study was designed to elucidate the role of peripheral tissues for glucose metabolism in this disease. Ten cancer patients and 11 appropriate controls were subjected to insulin challenge (0.10 unit/kg body weight) and i.v. glucose tolerance test. The fractional uptake or release of insulin, glucose, free fatty acids, glycerol, acetoacetate, and lactate in the forearm was determined. In isolated skeletal muscle fibers obtained from biopsies from the rectus abdominal muscle, the incorporation rate of glucose carbon into glycogen and CO2 and the incorporation of palmitic acid carbon and leucine carbon into CO2 as well as insulin stimulation of the incorporation of glucose carbon into glycogen and leucine carbon into proteins were determined. In cancer patients the response of blood glucose to insulin challenge was smaller than in controls. Neither the elimination rate of insulin from plasma nor the fractional uptake of glucose in the forearm was significantly changed in these patients. The incorporation rate of glucose carbon into glycogen and CO2 was significantly decreased, and the insulin stimulation of this incorporation was smaller in cancer patients than in controls. The incorporation rate of palmitic acid and leucine into CO2 did not differ between the groups. Peripheral tissues are of importance for the disturbed glucose metabolism in cancer disease since skeletal muscles showed specifically lowered capacity for glucose utilization with and without insulin stimulation in vitro. All of these results were compatible with an insulin resistance in the liver and in the skeletal muscles in cancer.

137 citations


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

  • ...Since 1885, when Ernst Freund described signs of hyperglycemia in 70 out of 70 cancer patients [99], it has been repeatedly reported that glucose tolerance and insulin sensitivity are diminished in cancer patients even before signs of cachexia (weight loss) become evident [100-102]....

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Journal ArticleDOI
TL;DR: In this paper, the morphological changes, increasing gracilization of the mandible and increasing brain size have been interpreted as the move from plants to higher quality, more digestible, animal meat, although this is debated.
Abstract: Knowledge of our ancestor's diets is becoming increasingly important in evolutionary medicine, as researchers have argued that we have evolved to specific type of 'Palaeolithic' diet, and many modern nutritional disorders relate to the mismatch between the diet to which we have evolved, and the relatively newer agricultural-based 'Neolithic' diets. However, what is the archaeological evidence for pre-agricultural diets and how have they changed over the four million years of hominid evolution? This paper briefly introduces the three lines of evidence we have for Palaeolithic and Neolithic diets; morphological changes, archaeological material evidence, and direct measurement of diet from bone chemistry. The morphological changes, increasing gracilization of the mandible and increasing brain size have been interpreted (based on analogies with living primates) as the move from plants to higher-quality, more digestible, animal meat, although this is debated. The archaeological evidence is especially weak, as many organic materials, especially plants, do not survive well, and are therefore invisible in the archaeological record. Artefacts, such as stone tools which are likely to be used for hunting and animal bones with evidence of human processing and butchering do indicate that hunting did occur at many times in the past, but it is impossible to judge the frequency. Direct evidence from bone chemistry, such as the measurement of the stable isotopes of carbon and nitrogen, do provide direct evidence of past diet, and limited studies on five Neanderthals from three sites, as well as a number of modern Palaeolithic and Mesolithic humans indicates the importance of animal protein in diets. There is a significant change in the archaeological record associated with the introduction of agriculture worldwide, and an associated general decline in health in some areas. However, there is an rapid increase in population associated with domestication of plants, so although in some regions individual health suffers after the Neolithic revolution, as a species humans have greatly expanded their population worldwide.

129 citations


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

  • ...This is consistent with stable isotope studies of human fossils [8,9]....

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Journal ArticleDOI
TL;DR: This is the first example of an attempt to reverse cachexia by a diet based on metabolic differences between tumour and host tissues, which aims to selectively feed the host at the expense of the tumour.
Abstract: An attempt has been made to reverse cachexia and to selectively deprive the tumour of metabolic substrates for energy production by feeding a ketogenic regime, since ketone bodies are considered important in maintaining homeostasis during starvation. As a model we have used a transplantable mouse adenocarcinoma of the colon (MAC 16) which produces extensive weight loss without a reduction in food intake. When mice bearing the MAC16 tumour were fed on diets in which up to 80% of the energy was supplied as medium chain triglycerides (MCT) with or without arginine 3-hydroxybutyrate host weight loss was reduced in proportion to the fat content of the diet, and there was also a reduction in the percentage contribution of the tumour to the final body weight. The increase in carcass weight in tumour-bearing mice fed high levels of MCT was attributable to an increase in both the fat and the non-fat carcass mass. Blood levels of free fatty acids (FFA) were significantly reduced by MCT addition. The levels of both acetoacetate and 3-hydroxybutyrate were elevated in mice fed the high fat diets, and tumour-bearing mice fed the normal diet did not show increased plasma levels of ketone bodies over the non-tumour-bearing group despite the loss of carcass lipids. Both blood glucose and plasma insulin levels were reduced in mice bearing the MAC16 tumour and this was not significantly altered by feeding the high fat diets. The elevation in ketone bodies may account for the retention of both the fat and the non-fat carcass mass. This is the first example of an attempt to reverse cachexia by a diet based on metabolic differences between tumour and host tissues, which aims to selectively feed the host at the expense of the tumour.

125 citations


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

  • .../80 2 MCT emulsion 8 20 ↑ - 50% less weight loss ; left35% less tumor weight [121]...

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  • ...While the diet had no effect on rats bearing the Walker 256 sarcoma [120], it decreased the cachectic weight loss in proportion to its fat content in mice bearing the mousespecific colon carcinoma MAC16 [121]....

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  • ...This stability of blood glucose, independent of ketosis, was subsequently confirmed in studies in which mice were fed ad libitum on a KD [84,114,121-123,130] although two studies reported a drop in blood glucose concentrations compared with the control group [116,131]....

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Journal ArticleDOI
TL;DR: Using a 3D-migration assay, it is shown that high glucose concentrations caused increased motility rates of the tumour cells, which could help to understand how hyperglycaemia and hyperinsulinemia might trigger tumour cell proliferation and motility in patients, too.
Abstract: During the last decade, epidemiological studies uncovered the tremendous impact of metabolic syndrome/diabetes mellitus type 2 (DM T2) as risk factors of the progression of cancer. Therefore, we studied the impact of diabetogenic glucose and insulin concentrations on the activities of tumour cells, because little is known about how high glucose and insulin levels are influencing gene activities causing changes in the signal cascade activities with respect to kinases involved in the proliferation and migration of cancer cells. To address this question we analysed the activity of more than 400 gene signatures related to (i) cell cycle, (ii) cell movement as well as (iii) signal transduction. We examined transcriptoms of kinases (PKCα, PI3K), cadherins (E-, N- VE-), integrins and cyclins by comparing physiological (5.5 mM) vs diabetogenic (11 mM) glucose concentrations (without and with insulin). Proliferation assays revealed that high levels of glucose (11 mM) and insulin (100 ng ml−1) did promote the proliferation of the tumour cell lines HT29, SW480, MCF-7, MDA MB468, PC3 and T24. Using a 3D-migration assay, we have shown that high glucose concentrations caused increased motility rates of the tumour cells. The increase in migratory activity at high glucose and insulin concentrations was mediated by an activation of PI3K, PKCα and MLCK, as figured out by the pharmacological inhibitors wortmannin, Go6976 and ML-7. We present molecular and functional data, which could help to understand how hyperglycaemia and hyperinsulinemia might trigger tumour cell proliferation and motility in patients, too.

124 citations


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

  • ...These results support the epidemiological [25,29,31,32] and in vitro [81,144] findings that high CHO diets, in particular those including high GI foods, promote mammary tumorigenesis via the sustained action of insulin....

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