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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TL;DR: It is suggested that diets containing MCT would provide the best ketogenic regime to reverse the weight loss in cancer cachexia with a concomitant reduction in tumour size.
Abstract: A comparison has been made between the ability of long-chain triglycerides (LCT) and medium-chain triglycerides (MCT) to prevent weight loss induced by the cachexia-inducing colon adenocarcinoma (MAC16) and to reduce tumour size. There was no difference in calorie consumption or nitrogen intake between the various groups. When compared with a normal control high carbohydrate, low fat diet, animals fed MCT showed a reduced weight loss and a marked reduction in tumour size. In contrast neither weight loss nor tumour size differed significantly from the controls in animals fed the LCT diet. An elevated plasma level of 3-hydroxybuturate was found only in the animals fed the MCT diets. Administration of LCT caused an increase in the plasma level of FFA, which was not observed in the MCT group. These results suggest that diets containing MCT would provide the best ketogenic regime to reverse the weight loss in cancer cachexia with a concomitant reduction in tumour size.
30 citations
"Is there a role for carbohydrate re..." refers background or result in this paper
...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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...For the latter, they further proved an anti-cachectic effect of a ketogenic diet in which the MCTs were replaced with long chain triglycerides (LCTs), although to a somewhat lesser extent [122]....
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TL;DR: This study was undertaken to determine the metabolic effects of an exogenous caloric mixture of constituents similar to the endogenous calories mixture of fasting.
Abstract: Introduction The fasting subject has elevated ketones, 1-3 elevated nonesterified fatty acids ( NEFA), 4,5 negative nitrogen balance, 6,7 lowered blood suger, 6 salt loss, 7,8 water loss, and weight loss 6,8-10 In the fasting man, the glycogen reserves 6,11 are soon depleted, and fat and protein fcatabolism supplies the body's caloric needs since new carbohydrate is only available in minimal amount Thus, at a cellular level, the major characteristic of fasting is limitation of available carbohydrate as an energy source 12 Since fat and protein are the energy sources in fasting, there should be little difference in cellular metabolism whether the fat and protein come from endogenous or exogenous sources This study was undertaken to determine the metabolic effects of an exogenous caloric mixture of constituents similar to the endogenous caloric mixture of fasting Method The subjects in this study were normal healthy volunteers placed on a diet of normal
28 citations
"Is there a role for carbohydrate re..." refers background in this paper
...Indeed, it has been shown in healthy subjects that CHO restriction induces hormonal and metabolic adaptions very similar to fasting [63-66]....
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TL;DR: This data indicates that conventional chemotherapy may be a viable option to treat central giant cell granuloma, but the use of either chemotherapy or a combination of the two is likely to be beneficial.
Abstract: Comment on: Zha X, et al. Cancer Res 2011; 71:13-8.
28 citations
"Is there a role for carbohydrate re..." refers background in this paper
...HIF-1a is further important for the adaption to hypoxia by increasing the expression of glycolytic enzymes including GLUT1 and hexokinase (HK)II as well as several angiogenic factors [49,52]....
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TL;DR: Interference with insulin-glucagon balance by sepsis and disease is suggested as a possible explanation for the failure of three-quarters of the patients to become starvation-adapted and its implications on the parenteral feeding of undernourished patients.
Abstract: Hormonal and substrate profiles and urinary nitrogen and urea excretion were measured in 78 underweight patients admitted for surgical investigation, who were placed into either a normo- or a hyperketonemic group, depending upon their levels of acetoacetate and beta-hydroxybutyrate. The two groups were otherwise similar in terms of weight loss, arm muscle circumference, triceps skinfold thickness, and serum protein levels. Before surgery only one-quarter of them were hyperketonemic displaying mean glucose, insulin, and glucagon levels characteristic of starvation-adaption, and excreted significantly less urinary nitrogen than in normoketonemic group. Those patients who underwent surgery tended to retain their presurgery hormonal and substrate profile. The normoketonemic group excreted significantly greater amounts of urinary nitrogen, depleted body protein to a greater extent as evidenced by larger changes in arm muscle circumference and serum protein levels, and mortality was greater. Interference with insulin-glucagon balance by sepsis and disease is suggested as a possible explanation for the failure of three-quarters of the patients to become starvation-adapted. The implications of this finding on the parenteral feeding of undernourished patients are discussed.
26 citations