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: A meta-analysis of case-control and cohort studies did not support that total energy intake is related to endometrial cancer risk, in contrast to fat energy.
Abstract: Background: Previous epidemiologic studies on the association between energy intake and endometrial cancer risk have only generated contradictory results. The role of energy intake in endometrial carcinogenesis thus remains unclear. To quantitatively assess the potential association between energy intake and endometrial cancer, a meta-analysis of case-control and cohort studies was here conducted. Materials and Methods: Eligible studies were retrieved via both computerized searches and review of references. Fixed-or random-effect models were used to summarize the estimates of OR with 95%CIs. Stratified analyses on study design, region and macronutrients’ calorie were performed. Results: Sixteen studies met the inclusion criteria of the meta-analysis. No association between total energy intake and endometrial cancer was observed in either overall group (OR=1.11, 95%CI 0.92-1.30) or subgroups stratified by study design and region. In the specific macronutrients’ calorie analysis, higher fat energy intake was found to be associated with increased endometrial risk (OR=1.72, 95%CI 1.122.32) while energy from carbohydrate and protein was not related to endometrial cancer risk. Conclusions: Our analysis did not support that total energy intake is related to endometrial cancer risk, in contrast to fat energy.
3 citations
TL;DR: The Glucose Ketone Index (GKI) as mentioned in this paper is a simple tool that can help monitor the efficacy of metabolic therapy in preclinical animal models and in clinical trials for malignant brain cancer and possibly other cancers that express aerobic fermentation.
Abstract: BackgroundMetabolic therapy using ketogenic diets (KD) is emerging as an alternative or complementary approach to the current standard of care for brain cancer management. This therapeutic strategy targets the aerobic fermentation of glucose (Warburg effect), which is the common metabolic malady of most cancers including brain tumors. The KD targets tumor energy metabolism by lowering blood glucose and elevating blood ketones (β-hydroxybutyrate). Brain tumor cells, unlike normal brain cells, cannot use ketone bodies effectively for energy when glucose becomes limiting. Although plasma levels of glucose and ketone bodies have been used separately to predict the therapeutic success of metabolic therapy, daily glucose levels can fluctuate widely in brain cancer patients. This can create difficulty in linking changes in blood glucose and ketones to efficacy of metabolic therapy.MethodsA program was developed (Glucose Ketone Index Calculator, GKIC) that tracks the ratio of blood glucose to ketones as a single value. We have termed this ratio the Glucose Ketone Index (GKI).ResultsThe GKIC was used to compute the GKI for data published on blood glucose and ketone levels in humans and mice with brain tumors. The results showed a clear relationship between the GKI and therapeutic efficacy using ketogenic diets and calorie restriction.ConclusionsThe GKIC is a simple tool that can help monitor the efficacy of metabolic therapy in preclinical animal models and in clinical trials for malignant brain cancer and possibly other cancers that express aerobic fermentation.
3 citations
TL;DR: In this article, the association of low-carbohydrate diets with the risk of pancreatic cancer in a US population was examined, where a low carbohydrate-diet score was calculated to quantify adherence to this dietary pattern, with higher scores indicating greater adherence.
Abstract: Low-carbohydrate diets have become a popular approach for weight loss in recent years. However, whether low-carbohydrate diets are associated with the risk of pancreatic cancer remains to be elucidated. Hence, we examined the association of low-carbohydrate diets with the risk of pancreatic cancer in a US population. A population-based cohort of 95 962 individuals was identified. A low-carbohydrate-diet score was calculated to quantify adherence to this dietary pattern, with higher scores indicating greater adherence. Cox regression was used to calculate risk estimate for the association of the low-carbohydrate-diet score with the risk of pancreatic cancer. Subgroup analysis was used to identify the potential effect modifiers. After an average follow-up of 8.87 years (875856.9 person-years), we documented a total of 351 pancreatic cancer cases. In the fully adjusted model, the highest versus the lowest quartiles of the overall low-carbohydrate-diet score were found to be associated with a reduced risk of pancreatic cancer (hazard ratioquartile 4 versus 1: 0.61; 95% confidence interval: 0.45, 0.82; Ptrend < 0.001). Subgroup analysis found that the inverse association of low-carbohydrate diets with the risk of pancreatic cancer was more pronounced in individuals aged ≥65 years than in those aged <65 years (Pinteraction = 0.015). Similar results were obtained for animal and vegetable low-carbohydrate-diet scores. In conclusion, low-carbohydrate diets, regardless of the type of protein and fat, are associated with a lower risk of pancreatic cancer in the US population, suggesting that adherence to low-carbohydrate diets may be beneficial for pancreatic cancer prevention. Future studies should validate our findings in other populations.
3 citations
01 Jan 2014
3 citations
Cites background from "Is there a role for carbohydrate re..."
...As described, the activity of the HIF-1 transcription factor plays an important role in every aspect of cancer progression, from tumorigenesis to metastasis [14, 15]....
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...Ketone supplementation can be used, however, to elevate blood ketone levels to a therapeutic range of 2-7mM [6], which is reported to be beneficial in a vast array of disease states, including epilepsy, Alzheimer’s disease, and other neurological disorders [7, 13-19]....
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...It is not surprising, perhaps, that cancer continues to be very rare among hunter-gatherer societies which derive the majority of their calories from animal fat and protein, with only a small contribution from complex carbohydrates such as berries and roots [15, 16]....
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...CR has been shown to slow disease progression in a variety of cancer models [14-18]....
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TL;DR: There are no standard evidence-based recommendations for diet therapies before or during cancer treatment, and few studies provide definitive data that certain diets can mediate tumor progression or therapeutic effectiveness in human cancer.
Abstract: The median overall survival of patients with metastatic breast cancer is only 2–3 years, and for patients with untreated liver metastasis, it is as short as 4–8 months. Improving the survival of women with breast cancer requires more effective anti-cancer strategies, especially for metastatic disease. Nutrients can influence tumor microenvironments, and cancer metabolism can be manipulated via a dietary modification to enhance anti-cancer strategies. Yet, there are no standard evidence-based recommendations for diet therapies before or during cancer treatment, and few studies provide definitive data that certain diets can mediate tumor progression or therapeutic effectiveness in human cancer. This review focuses on metastatic breast cancer, in particular liver metastatic forms, and recent studies on the impact of diets on disease progression and treatment.
3 citations
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TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
51,099 citations
"Is there a role for carbohydrate re..." refers background in this paper
..., a pathological capability common to most, if not all, cancer cells [39]....
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TL;DR: The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
9,282 citations
"Is there a role for carbohydrate re..." refers background in this paper
...Inflammation is a wellestablished driver of early tumorigenesis and accompanies most, if not all cancers [148]....
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TL;DR: In this article, the authors propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions, which leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity.
Abstract: If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.
4,361 citations
2,524 citations
TL;DR: Dietary restriction and reduced activity of nutrient-sensing pathways may slow aging by similar mechanisms, which have been conserved during evolution, and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects.
Abstract: When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors. In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. Dietary restriction also increases life span and protects against diabetes, cancer, and cardiovascular disease in rhesus monkeys, and in humans it causes changes that protect against these age-related pathologies. Tumors and diabetes are also uncommon in humans with mutations in the growth hormone receptor, and natural genetic variants in nutrient-sensing pathways are associated with increased human life span. Dietary restriction and reduced activity of nutrient-sensing pathways may thus slow aging by similar mechanisms, which have been conserved during evolution. We discuss these findings and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects.
2,522 citations
"Is there a role for carbohydrate re..." refers background in this paper
...As indicated in Figure 2, restriction of dietary CHOs would counteract this signalling cascade by normalizing glucose and insulin levels in subjects with metabolic syndrome, in this way acting similar to calorie restriction/fasting [61,62]....
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