About this Research Topic
Addiction to glucose is a widespread characteristic of cancer cells, which rely on glycolytic metabolism as the main source of energy. Despite being energetically less effective than oxidative phosphorylation, this metabolic phenotype gives several advantages to cancer cells, including rapid energy production and growth of cancer cells, escape to the immune system and increased capacity to invade and induce metastases.
To compensate for this lower energy effectiveness, cancer cells consume large amounts of glucose, increasing the rates of glycolysis, which culminates in the production of lactic acid and other acids that are responsible for acidification of the tumor microenvironment. This metabolic phenotype has also been associated with resistance to cancer therapy, including the oncogene-targeted therapies.
Nutrition and the risk to develop certain types of cancer is a well-established association, however, the impact of diet on cancer cell biology and response to current therapy is a hot topic, which has been attracting the attention of researchers both in the fields of cancer research and nutrition. In this context, caloric restriction, carbohydrate restriction and ketogenic diet are the most explored approaches that have been demonstrating encouraging results in pre-clinical studies. Some clinical studies are already confirming the value of these interventions, and many clinical trials are now ongoing, aiming to exploit the combination of these diets, or drugs that mimic their effect, with conventional radio- and chemotherapy.
However, the use of caloric restriction strategies in cancer patients should be carefully assessed due to the risk of cachexia, which may force reduction of the doses of chemotherapy, compromising the effectiveness of the treatment. One viable alternative is the use of caloric restriction mimetic drugs that do not compromise the patient caloric intake. However, acting on specific pathways, these drugs may only partially simulate the whole beneficial effects of caloric restriction. These interventions take advantage of the differences in the metabolic needs of normal and cancer cells, being normal cells more capable to deal with nutrient restriction than cancer cells. Besides, targeting cancer metabolism would also enhance the cytotoxic effects of chemotherapy.
An alternative intervention that does not compromise caloric intake, is ketogenic diet, which is high in fat, low in carbohydrates and proteins. Fat metabolism induces the production of ketone bodies by the liver and this state of ketosis has been demonstrated to improve response to chemo- and radiotherapy, possibly also decreasing side effects to normal cells. Lipid metabolism forces cells to use mitochondria, which is more harmful to cancer cells that are addicted to glucose metabolism than normal cells. Dysfunctional mitochondrial oxidative phosphorylation in cancer cells will lead to production of reactive oxygen species, and consequent oxidative stress. This type of diet may also lead to acute and chronic side effects, which has to be taken into consideration.
Despite advances in cancer treatments, the cure for many malignant tumors is still far away and current patient treatments are very aggressive. Thus, these nutritional interventions could constitute a rational adjuvant therapy, which would enhance response to current treatments, with limited patient toxicity.
Keywords: Cancer metabolism, glycolysis, caloric restriction, ketogenic diet, carbohydrate restriction
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