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 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.
Abstract: Metabolic 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. A 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). The 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. The 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.
72 citations
Cites background from "Is there a role for carbohydrate re..."
...Therapies that can lower glucose and elevate ketone bodies will place more energy stress on the tumor cells than on the normal brain cells [12,24]....
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...Besides ketogenic diets, other dietary therapies, such as calorie restriction, low carbohydrate diets, and therapeutic fasting, can also lower blood glucose and elevate β-OHB levels and can have anti-tumor effects [24,33-38]....
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TL;DR: Current understanding of β-BH and its molecular targets is reviewed, finding indications that ketogenic diets or ketone administration, which increase β-HB may prevent ageing-associated progression of illnesses like cardiovascular and neurodegenerative diseases and cancer.
Abstract: Aging is a universal process that renders individuals vulnerable to many diseases. Although this process is irreversible, dietary modulation and caloric restriction are often considered to have antiaging effects. Dietary modulation can increase and maintain circulating ketone bodies, especially β-hydroxybutyrate (β-HB), which is one of the most abundant ketone bodies in human circulation. Increased β-HB has been reported to prevent or improve the symptoms of various age-associated diseases. Indeed, numerous studies have reported that a ketogenic diet or ketone ester administration alleviates symptoms of neurodegenerative diseases, cardiovascular diseases, and cancers. Considering the potential of β-HB and the intriguing data emerging from in vivo and in vitro experiments as well as clinical trials, this therapeutic area is worthy of attention. In this review, we highlight studies that focus on the identified targets of β-HB and the cellular signals regulated by β-HB with respect to alleviation of age-associated ailments. Boosting levels of a byproduct of fatty acid breakdown may help alleviate the symptoms of age-associated health conditions. When the body is low on glucose, it breaks down fatty acids for energy, generating byproduct metabolites called ketones. The ketone β-hydroxybutyrate (β-HB) regulates cellular signaling and gene and protein expression. There are indications that ketogenic diets or ketone administration, which increase β-BH may prevent ageing-associated progression of illnesses like cardiovascular and neurodegenerative diseases and cancer. Young-min Han and co-workers at Georgia State University in Atlanta, USA, reviewed current understanding of β-BH and its molecular targets. β-BH is a potent metabolite small enough to filter through cell membranes and circulate throughout the body, including the brain, influencing signaling pathways. Further investigations into associated molecular mechanisms will verify the metabolite’s potential as a therapeutic agent.
62 citations
TL;DR: Empirical and pathophysiological aspects of diabetes, which may influence cancer initiation and progression, are highlighted.
58 citations
TL;DR: Overall, the knowledge concerning the impact of increased body weight and DNA damage is poor and further research is warranted to shed light on this important issue.
Abstract: Health authorities are alarmed worldwide about the increase of obesity and overweight in the last decades which lead to adverse health effects including inflammation, cancer, accelerated aging and infertility. We evaluated the state of knowledge concerning the impact of elevated body mass on genomic instability. Results of investigations with humans (39 studies) in which DNA damage was monitored in lymphocytes and sperm cells, are conflicting and probably as a consequence of heterogeneous study designs and confounding factors (e.g. uncontrolled intake of vitamins and minerals and consumption of different food types). Results of animal studies with defined diets (23 studies) are more consistent and show that excess body fat causes DNA damage in multiple organs including brain, liver, colon and testes. Different molecular mechanisms may cause genetic instability in overweight/obese individuals. ROS formation and lipid peroxidation were found in several investigations and may be caused by increased insulin, fatty acid and glucose levels or indirectly via inflammation. Also reduced DNA repair and formation of advanced glycation end products may play a role but more data are required to draw firm conclusions. Reduction of telomere lengths and hormonal imbalances are characteristic for overweight/obesity but the former effects are delayed and moderate and hormonal effects were not investigated in regard to genomic instability in obese individuals. Increased BMI values affect also the activities of drug metabolizing enzymes which activate/detoxify genotoxic carcinogens, but no studies concerning the impact of these alterations of DNA damage in obese individuals are available. Overall, the knowledge concerning the impact of increased body weight and DNA damage is poor and further research is warranted to shed light on this important issue.
57 citations
TL;DR: The emerging relationship between a KD and adenosine is described as a way to reset brain metabolism and neuronal activity and disrupt a cycle of dysfunction.
Abstract: A link between metabolism and brain function is clear. Since ancient times, epileptic seizures were noted as treatable with fasting, and historical observations of the therapeutic benefits of fasting on epilepsy were confirmed nearly 100 years ago. Shortly thereafter a high-fat, low-carbohydrate ketogenic diet debuted as a therapy to reduce seizures. This strict regimen could mimic the metabolic effects of fasting while allowing adequate caloric intake for ongoing energy demands. Today, ketogenic diet therapy, which forces predominantly ketone-based rather than glucose-based metabolism, is now well-established as highly successful in reducing seizures. More recently, cellular metabolic dysfunction in the nervous system has been recognized as existing side-by-side with nervous system disorders - although often with much less obvious cause-and-effect as the relationship between fasting and seizures. Rekindled interest in metabolic and dietary therapies for brain disorders complements new insight into their mechanisms and broader implications. Here we describe the emerging relationship between a ketogenic diet and adenosine as a way to reset brain metabolism and neuronal activity and disrupt a cycle of dysfunction. We also provide an overview of the effects of a ketogenic diet on cognition and recent data on the effects of a ketogenic diet on pain, and explore the relative time course quantified among hallmark metabolic changes, altered neuron function and altered animal behavior assessed after diet administration. We predict continued applications of metabolic therapies in treating dysfunction including and beyond the nervous system.
55 citations
Cites background from "Is there a role for carbohydrate re..."
...Indeed, the KD is beginning to be used as an anti-tumorigenic treatment (Klement and Kammerer, 2011; Seyfried et al., 2012) and so could provide dual benefits....
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References
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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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