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: The dose-response relationship between the probability of tumor control on the basis of pathologic tumor response (pTCP) and the residual metabolic rate of glucose (MRglc) in response to preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer was determined and the level of residual MRglc that corresponds to pTCP 50% and p TCP > or = 95%.
Abstract: Purpose: To determine the dose-response relationship between the probability of tumor control on the basis of pathologic tumor response (pTCP) and the residual metabolic rate of glucose (MRglc) in response to preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer and to define the level of residual MRglc that corresponds to pTCP 50% and pTCP ≥95%. Methods and Materials: Quantitative dynamic 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography was performed to measure regional MRglc at the primary lesion before and 2 weeks after preoperative chemoradiotherapy in an initial group of 13 patients with locally advanced NSCLC. A simplified kinetic method was developed subsequently from the initial dynamic study and used in the subsequent 16 patients. The preoperative radiotherapy programs consisted of ( 1 ) a split course of 42 Gy in 28 fractions within a period of 28 days using a twice-daily treatment schedule for Stage IIIA(N2) NSCLC ( n = 18) and ( 2 ) standard once-daily radiation schedule of 45–63 Gy in 25–35 fractions during a 5–7-week period ( n = 11). The preoperative chemotherapy regimens included two cycles of cisplatin, vinblastine, and 5-fluorouracil ( n = 24), cisplatin and etoposide ( n = 2), and cisplatin, Taxol, and 5-fluorouracil ( n = 3). Patients free of tumor progression after preoperative chemoradiotherapy underwent surgery. The degree of residual MRglc measured 2 weeks after preoperative chemoradiotherapy and 2 weeks before surgery was correlated with the pathologic tumor response. The relationship between MRglc and pTCP was modeled using logistic regression. Results: Of 32 patients entered into the study, 29 (16 men and 13 women; 30 lesions) were evaluated for the correlation between residual MRglc and pathologic tumor response. Three patients did not participate in the second study because of a steady decline in general condition. The median age was 60 years (range 42–78). One of the 29 patients had two separate lesions, and MRglc was measured in each separately. The tumor histologic types included squamous cell carcinoma ( n = 9), adenocarcinoma ( n = 13), large cell carcinoma ( n = 6), and poorly differentiated carcinoma ( n = 2). The extent of the primary and nodal disease was as follows: Stage IIB (T3N0M0), Pancoast tumor ( n = 2); Stage IIIA, T2-T3N2M0 ( n = 18); Stage IIIB: T1-T3N3M0 ( n = 5) and T4N0M0 ( n = 2); a second lesion, T1 ( n = 1); and localized stump recurrence ( n = 2). A pathologically complete response was obtained in 14 (47%) of the 30 lesions. The remaining 16 lesions had residual cancer. The mean baseline value of the maximal MRglc was 0.333 ± 0.087 μmol/min/g ( n = 16), and it was reduced to 0.0957 ± 0.059 μmol/min/g 2 weeks after chemoradiotherapy ( p = 0.011). The correlation between residual MRglc and pTCP was made using an increment value of 0.02 μmol/min/g between the maximal and minimal values of MRglc. A pathologically complete response was obtained in 6 of 6 patients with residual MRglc of ≤0.050 μmol/min/g, 3 of 4 with ≤0.070, 4 of 7 with ≤0.090, 0 of 4 with ≤0.110, 1 of 3 with ≤0.130, and 0 of 6 with ≥0.130 μmol/min/g. The fitted logistic model showed that residual MRglc corresponding to pTCP 50% and pTCP ≥95% was 0.076 and ≤0.040 μmol/min/g, respectively. Conclusion: The correlation between the gradient of residual MRglc after chemoradiotherapy and pTCP is an inverse dose-response relationship. Residual MRglc of 0.076 and ≤0.040 μmol/min/g, representing pTCP 50% and pTCP ≥95%, respectively, may be useful surrogate markers for the tumor response to radiotherapy or chemoradiotherapy in lung cancer.
122 citations
"Is there a role for carbohydrate re..." refers background in this paper
...In PET-studies, tumor areas with high FDG 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: It is suggested that casual hyperglycemia is a risk factor for gastric cancer and is a possible cofactor increasing the risk posed by Helicobacter pylori infection.
116 citations
"Is there a role for carbohydrate re..." refers background in this paper
...Hyperglycemia, on the other hand, is a predictor of poor survival in patients with various cancers [22,26,86-88] and has been positively correlated to an increased risk for developing cancer at several sites including the pancreas, esophagus, liver, colon, rectum, stomach and prostate in large cohort studies [25,89,90]....
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TL;DR: This report summarizes progress made during the past decade and provides information about both the ketogenic diet’s documented usefulness in childhood epilepsy and its potential uses in other conditions.
114 citations
TL;DR: It is found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein.
Abstract: Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets. Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression.
112 citations
"Is there a role for carbohydrate re..." refers background or result in this paper
...A recent study suggests, however, that tumor growth inhibition neither depends on fat quality nor ketone body levels [131]....
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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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...Similarly, a recent study reported that NOP mice, which normally have a 70 - 80% chance of developing breast cancer over their lifetime due to genetic mutations, stayed tumor-free at 1 year of age when their calories from CHO were limited to 15%, while almost half of those on a 55% CHO diet developed tumors [131]....
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TL;DR: Persistent outpatient hyperglycemia was associated with decreased survival in patients undergoing surgical resection for malignant astro- cytomas and was independent of the degree of disability, tumor grade, diabetes, prolonged dexamethasone use, or subsequent treatment modalities.
Abstract: Objective Patients with malignant brain astrocytomas are at high risk for developing hyperglycemia secondary to frequent corticosteroid administration. Several clinical studies have shown that hyperglycemia is associated with poor outcome in multiple disease states. Furthermore, hyperglycemia augments in vitro astrocytoma growth, whereas hypoglycemia attenuates in vitro astrocytoma cell growth. We hypothesized that persistent hyperglycemic states in the outpatient setting may serve as a prognostic marker of decreased survival in patients with malignant brain astrocytomas. Methods We retrospectively reviewed 367 cases of craniotomy for malignant brain astrocytomas (World Health Organization Grade III or IV). Persistent hyperglycemia was defined as serum glucose greater than 180 mg/dL occurring three or more times between 1 and 3 months postoperatively. Isolated hyperglycemia was defined as an isolated occurrence of serum glucose greater than 180 mg/dL. The independent association of outpatient glucose levels and recorded clinical and treatment variables with overall survival was assessed via multivariate proportional-hazards regression analysis. Results A total of 367 craniotomies (209 primary, 158 secondary) were performed for malignant brain astrocytomas (glioblastoma multiforme, 297; anaplastic astrocytomas, 70); 68 (19%) and 28 (8%) of the patients experienced isolated or persistent outpatient hyperglycemia, respectively. Patients experiencing persistent hyperglycemia were older (59 +/- 13 versus 51 +/- 14 yr), were diabetic more frequently (7 [25%] versus 10 [3%]), continued to receive corticosteroids more frequently (21 [75%] versus 35 [10%]); and received temozolomide less often (4 [14%] versus 116 [34%]). Adjusting for intergroup differences and variables associated with survival in this model, age (P = 0.001), Karnofsky Performance Scale score (P = 0.001), tumor grade (P = 0.001), primary versus secondary resection (P = 0.008), temozolomide (P = 0.007), subsequent resection (P = 0.07), and continued outpatient dexamethasone therapy, persistent outpatient hyperglycemia (relative risk, 1.79; 95% confidence interval, 1.05-3.05, P = 0.03) remained independently associated with decreased survival. Median survival for persistently hyperglycemic versus normal-glycemic cohorts was 5 and 11 months, respectively. Conclusion In our experience, persistent outpatient hyperglycemia was associated with decreased survival in patients undergoing surgical resection for malignant astro- cytomas and was independent of the degree of disability, tumor grade, diabetes, prolonged dexamethasone use, or subsequent treatment modalities. Increased glucose control is warranted in this patient population and may contribute to improved outcomes in the treatment of malignant brain astrocytomas.
112 citations
"Is there a role for carbohydrate re..." refers background in this paper
...Hyperglycemia, on the other hand, is a predictor of poor survival in patients with various cancers [22,26,86-88] and has been positively correlated to an increased risk for developing cancer at several sites including the pancreas, esophagus, liver, colon, rectum, stomach and prostate in large cohort studies [25,89,90]....
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