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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TL;DR: Insight is provided on the coupling of glucose metabolism and the cell cycle in c-Myc-transformed cells and may in the future be exploited for cancer therapeutics.
Abstract: The lactate dehydrogenase A (LDH-A) gene, whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, has been identified as a c-Myc-responsive gene. It was of interest, therefore, to compare the effect of glucose deprivation in c-Myc-transformed and nontransformed cells. We observed that glucose deprivation or treatment with the glucose antimetabolite 2-deoxyglucose caused nontransformed cells to arrest in the G0/G1 phase of the cell cycle. In contrast, c-Myc-transformed fibroblasts, lymphoblastoid, or lung carcinoma cells underwent extensive apoptosis. Ectopic expression of LDH-A alone in Rat1a fibroblasts was sufficient to induce apoptosis with glucose deprivation but not with serum withdrawal, suggesting that LDH-A mediates the unique apoptotic effect of c-Myc when glycolysis is blocked. The apoptosis caused by glucose deprivation was blocked by Bcl-2 expression but appeared to be independent of wild-type p53 activity. These studies provide insights on the coupling of glucose metabolism and the cell cycle in c-Myc-transformed cells and may in the future be exploited for cancer therapeutics.
283 citations
"Is there a role for carbohydrate re..." refers background in this paper
...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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TL;DR: Research advances supporting the clinicobiological rationale for dose painting are reviewed as are studies of the technical feasibility of optimizing and delivering realistic dose painted radiation therapy plans.
276 citations
"Is there a role for carbohydrate re..." refers background in this paper
...uptake have been consistently linked to poor prognosis [55,56] and are now being considered as important biological target volumes to receive dose escalations in radiation treatment [57]....
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TL;DR: Over a 3-month study period, a Paleolithic diet improved glycemic control and several cardiovascular risk factors compared to a Diabetes diet in patients with type 2 diabetes.
Abstract: Our aim was to compare the effects of a Paleolithic ('Old Stone Age') diet and a diabetes diet as generally recommended on risk factors for cardiovascular disease in patients with type 2 diabetes not treated with insulin. In a randomized cross-over study, 13 patients with type 2 diabetes, 3 women and 10 men, were instructed to eat a Paleolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts; and a Diabetes diet designed in accordance with dietary guidelines during two consecutive 3-month periods. Outcome variables included changes in weight, waist circumference, serum lipids, C-reactive protein, blood pressure, glycated haemoglobin (HbA1c), and areas under the curve for plasma glucose and plasma insulin in the 75 g oral glucose tolerance test. Dietary intake was evaluated by use of 4-day weighed food records. Study participants had on average a diabetes duration of 9 years, a mean HbA1c of 6,6% units by Mono-S standard and were usually treated with metformin alone (3 subjects) or metformin in combination with a sulfonylurea (3 subjects) or a thiazolidinedione (3 subjects). Mean average dose of metformin was 1031 mg per day. Compared to the diabetes diet, the Paleolithic diet resulted in lower mean values of HbA1c (-0.4% units, p = 0.01), triacylglycerol (-0.4 mmol/L, p = 0.003), diastolic blood pressure (-4 mmHg, p = 0.03), weight (-3 kg, p = 0.01), BMI (-1 kg/m2, p = 0.04) and waist circumference (-4 cm, p = 0.02), and higher mean values of high density lipoprotein cholesterol (+0.08 mmol/L, p = 0.03). The Paleolithic diet was mainly lower in cereals and dairy products, and higher in fruits, vegetables, meat and eggs, as compared with the Diabetes diet. Further, the Paleolithic diet was lower in total energy, energy density, carbohydrate, dietary glycemic load, saturated fatty acids and calcium, and higher in unsaturated fatty acids, dietary cholesterol and several vitamins. Dietary GI was slightly lower in the Paleolithic diet (GI = 50) than in the Diabetic diet (GI = 55). Over a 3-month study period, a Paleolithic diet improved glycemic control and several cardiovascular risk factors compared to a Diabetes diet in patients with type 2 diabetes. ClinicalTrials.gov NCT00435240.
272 citations
"Is there a role for carbohydrate re..." refers background in this paper
...Maybe more importantly, even moderate CHO restriction has been shown to effectively target several important markers of atherosclerosis and type II diabetes, both of which are associated with chronic inflammation [151-157]....
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TL;DR: It is proposed that the adoption of diet and lifestyle that mimic the beneficial characteristics of the preagricultural environment is an effective strategy to reduce the risk of chronic degenerative diseases.
Abstract: Correspondence: Pedro Carrera-Bastos R. Gorgel do Amaral, No. 5, 1 e; Lisbon 1250-119, Portugal Tel +351 967 088 799 email pedro.carrera_bastos@med.lu.se Abstract: It is increasingly recognized that certain fundamental changes in diet and lifestyle that occurred after the Neolithic Revolution, and especially after the Industrial Revolution and the Modern Age, are too recent, on an evolutionary time scale, for the human genome to have completely adapted. This mismatch between our ancient physiology and the western diet and lifestyle underlies many so-called diseases of civilization, including coronary heart disease, obesity, hypertension, type 2 diabetes, epithelial cell cancers, autoimmune disease, and osteoporosis, which are rare or virtually absent in hunter–gatherers and other non-westernized populations. It is therefore proposed that the adoption of diet and lifestyle that mimic the beneficial characteristics of the preagricultural environment is an effective strategy to reduce the risk of chronic degenerative diseases.
269 citations
"Is there a role for carbohydrate re..." refers background in this paper
...This is even more the case for the changes that occurred over the past 100 years, in particular the switch from labor in the field to a sedentary lifestyle and an increase in the consumption of easily digestible CHOs with high glycemic indices (GIs), leading to diseases of civilization that are strongly associated with the so-called Western way of life [6]....
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TL;DR: The results indicate that KetoCal® has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts and should be considered as an alternative therapeutic option for malignant brain cancer.
Abstract: Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells. In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal®, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG). Adult mice were implanted orthotopically with the malignant brain tumors and KetoCal® was administered to the mice in either unrestricted amounts or in restricted amounts to reduce total caloric intake according to the manufacturers recommendation for children with refractory epilepsy. The effects KetoCal® on tumor growth, vascularity, and mouse survival were compared with that of an unrestricted high carbohydrate standard diet. KetoCal® administered in restricted amounts significantly decreased the intracerebral growth of the CT-2A and U87-MG tumors by about 65% and 35%, respectively, and significantly enhanced health and survival relative to that of the control groups receiving the standard low fat/high carbohydrate diet. The restricted KetoCal® diet reduced plasma glucose levels while elevating plasma ketone body (β-hydroxybutyrate) levels. Tumor microvessel density was less in the calorically restricted KetoCal® groups than in the calorically unrestricted control groups. Moreover, gene expression for the mitochondrial enzymes, β-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-ketoacid CoA transferase, was lower in the tumors than in the contralateral normal brain suggesting that these brain tumors have reduced ability to metabolize ketone bodies for energy. The results indicate that KetoCal® has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts. The therapeutic effect of KetoCal® for brain cancer management was due largely to the reduction of total caloric content, which reduces circulating glucose required for rapid tumor growth. A dependency on glucose for energy together with defects in ketone body metabolism largely account for why the brain tumors grow minimally on either a ketogenic-restricted diet or on a standard-restricted diet. Genes for ketone body metabolism should be useful for screening brain tumors that could be targeted with calorically restricted high fat/low carbohydrate ketogenic diets. This preclinical study indicates that restricted KetoCal® is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer.
269 citations
"Is there a role for carbohydrate re..." refers background or methods or result 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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...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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...C57BL/6 mice 11 CT-2A mouse astrocytoma ad libitum 3/17/ 80 soy oil (KetoCal) 3 > 8 - no significant differences in either tumor weight, survival or vascularity [114]...
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..., however, diet was presented as a liquid vegetable oil and energy intake was not monitored, allowing for the possibility that the animals underate voluntarily, in this way consuming a “caloric restricted KD” used in several experimental settings from the Seyfried lab [84,114,132], which was shown therein to be superior to the unrestricted KD in tumor growth control....
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