Ketotherapy as an epigenetic modifier in cancer

Bandera-Merchan, Borja; Boughanem, Hatim; Crujeiras, Ana B.; Macías-González, Manuel; Tinahones, Francisco J.

doi:10.1007/s11154-020-09567-4

Cited by 17 publications

(15 citation statements)

References 122 publications

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“…For patients diagnosed with endometrial or breast cancer, preclinical evidence suggests that a ketogenic diet (KD; a diet of high fats, moderate proteins, and very low carbohydrates) might improve the efficacy of PI3K inhibitors by inhibiting insulin signalling. 44 , 223 It has recently been shown in murine KPC tumour models that treatment with PI3K inhibitors causes a transient hyperglycaemia and hyperinsulinaemia. This resultant hyperinsulinaemia can partially reactivate PI3K signalling, and following PI3K inhibition, can reactivate PI3K signalling in both normal and tumour tissues.…”

Section: Non-pharmacological/lifestyle Interventionsmentioning

confidence: 99%

Targeting obesity-related dysfunction in hormonally driven cancers

2021

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Obesity is a risk factor for at least 13 different types of cancer, many of which are hormonally driven, and is associated with increased cancer incidence and morbidity. Adult obesity rates are steadily increasing and a subsequent increase in cancer burden is anticipated. Obesity-related dysfunction can contribute to cancer pathogenesis and treatment resistance through various mechanisms, including those mediated by insulin, leptin, adipokine, and aromatase signalling pathways, particularly in women. Furthermore, adiposity-related changes can influence tumour vascularity and inflammation in the tumour microenvironment, which can support tumour development and growth. Trials investigating non-pharmacological approaches to target the mechanisms driving obesity-mediated cancer pathogenesis are emerging and are necessary to better appreciate the interplay between malignancy, adiposity, diet and exercise. Diet, exercise and bariatric surgery are potential strategies to reverse the cancer-promoting effects of obesity; trials of these interventions should be conducted in a scientifically rigorous manner with dose escalation and appropriate selection of tumour phenotypes and have cancer-related clinical and mechanistic endpoints. We are only beginning to understand the mechanisms by which obesity effects cell signalling and systemic factors that contribute to oncogenesis. As the rates of obesity and cancer increase, we must promote the development of non-pharmacological lifestyle trials for the treatment and prevention of malignancy.

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Section: Non-pharmacological/lifestyle Interventionsmentioning

confidence: 99%

Targeting obesity-related dysfunction in hormonally driven cancers

2021

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“…Ketogenic diets (KDs) are low-carbohydrate, moderate protein, high-fat diets characterized by the intentional restriction of dietary carbohydrate intake or nutritional ketosis, which generates ketone bodies (KBs) and induces a metabolic shift [ 53 , 54 ]. Given that there is no exact definition for KD macronutrient composition, its variability could serve different clinical purposes [ 55 ]. Evidence suggests that KDs produce anticonvulsive, antioxidant and anti-inflammatory effects [ 56 ].…”

Section: Ketogenic Diet In Cancermentioning

confidence: 99%

“…For example, the IGF1/PI3K/Akt/mTOR system is often hyperactive in cancer cells due to chronic hyperglycemia and hyperinsulinemia, as well as the mutations in genes that code for pathway proteins [ 88 ]. In PC, PI3K/AKT/mTOR and Ras/Raf/Mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) pathways are upregulated and favor cancer cells proliferation and growth [ 55 , 89 ]. AMP-activated protein kinase (AMPK) regulates glycolisis and is involved in tumorigenesis and PC progression [ 90 ].…”

Section: Cellular Mechanisms Of Kds In Pdac and Cachexiamentioning

confidence: 99%

“…Importantly, KBs can be used by healthy cells as energy sources, but many tumors are largely unable to metabolize them [ 102 ]. Therefore, KD tumor-suppressive effects are mainly based on the Warburg effect [ 55 ]. Since cancer cells depend heavily on glycolysis, by reducing glucose, insulin, IGF-1 levels, plus lactate production, KDs potentially induce selective starvation in cancer cells [ 92 , 103 ].…”

Section: Cellular Mechanisms Of Kds In Pdac and Cachexiamentioning

confidence: 99%

“…Interestingly, stage specific DNA methylation, and histone modifications have been detected in early tumorigenesis, PDAC progression and metastasis [ 119 , 120 ]. KD could inhibit tumor growth and/or improve the effectiveness of cancer therapies through epigenetic modifications, such as DNA methylation, that affect the regulation of genes involved in tumor survival and proliferation [ 55 , 66 ].…”

Section: Cellular Mechanisms Of Kds In Pdac and Cachexiamentioning

confidence: 99%

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Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

Cortez

Mackenzie

2021

Nutrients

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and extremely therapy-resistant cancer. It is estimated that up to 80% of PDAC patients present with cachexia, a multifactorial disorder characterized by the involuntary and ongoing wasting of skeletal muscle that affects therapeutic response and survival. During the last decade, there has been an increased interest in exploring dietary interventions to complement the treatment of PDAC and associated cachexia. Ketogenic diets (KDs) have gained attention for their anti-tumor potential. Characterized by a very low carbohydrate, moderate protein, and high fat composition, this diet mimics the metabolic changes that occur in fasting. Numerous studies report that a KD reduces tumor growth and can act as an adjuvant therapy in various cancers, including pancreatic cancer. However, research on the effect and mechanisms of action of KDs on PDAC-associated cachexia is limited. In this narrative review, we summarize the evidence of the impact of KDs in PDAC treatment and cachexia mitigation. Furthermore, we discuss key cellular mechanisms that explain KDs’ potential anti-tumor and anti-cachexia effects, focusing primarily on reprogramming of cell metabolism, epigenome, and the gut microbiome. Finally, we provide a perspective on future research needed to advance KDs into clinical use.

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