Metabolic management of brain cancer

Abstract

Malignant brain tumors are a significant health problem in children and adults. Conventional therapeutic approaches have been largely unsuccessful in providing long-term management. As primarily a metabolic disease, malignant brain cancer can be managed through changes in metabolic environment. In contrast to normal neurons and glia, which readily transition to ketone bodies (β-hydroxybutyrate) for energy under reduced glucose, malignant brain tumors are strongly dependent on glycolysis for energy. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome and normal mitochondria can effectively transition from one energy state to another. Mutations restrict genomic and metabolic flexibility thus making tumor cells more vulnerable to energy stress than normal cells. We propose an alternative approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and metabolically challenged tumor cells. This approach to brain cancer management is supported from recent studies in mice and humans treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are presented for the metabolic management of brain cancer.

The ketogenic diet for the treatment of malignant glioma

“…The combination of CR and the KD [calorie restricted KD (RKD)] has also been studied as a cancer therapy. The anti-proliferative and anti-angiogenic effects of CR and the RKD have been substantiated in a number of studies using experimental mouse and human brain tumor models ( 13,31,(47)(48)(49)(50). Angiogenesis is currently a therapeutic target for the treatment of gliomas, and bevacizumab, a monoclonal antibody targeting the proangiogenic factor VEGF, is the only US Food and Drug Administration-approved molecular drug for use in GBMs.…”

“…Unlike normal brain cells, many tumor cells cannot utilize ketones effectively due to their various genetic and mitochondrial defects, and must rely on glucose as their primary energy source ( 13,(30)(31)(32)(33)(34)(35). Ketone bodies may also be toxic to some human tumor cells (36)(37)(38).…”

Dietary Therapies for Epilepsy and Other Neurological Disorders: Highlights of the 3rd International Symposium

“…For example, cancer cells differ from normal cells in having high metabolic needs for the purpose of proliferation, using aerobic glycolysisthe Warburg effect-whereby glucose is metabolized into lactate for energy, regardless of oxygen availability. This concept has been previously invoked to link a beneficial effect of the ketogenic diet or calorie restriction to slow the growth of brain tumors (30). Given the great diversity of cell types and functions in the CNS and their varying energy requirements, this idea has fundamental implications as to how we attempt to unravel the energetic principles by which dietary therapies work.…”

Foods as a Novel Treatment for Glioblastoma

“…It has been found that there is a balance in cancer cell's growth between the availability of energy, sufficient macromolecular synthesis for increased growth, modulation of reactive oxygen species (ROS), nutritional needs of cancer cells, metabolomics, and proteomics of tumors. [13] A lot of studies have been done to fight with cancer cells on the basis of Warburg effect. Reducing the amount of glucose and providing lactate have been tried to challenge the cancer metabolism however new techniques such as the discoveries of oncogenes, tumor suppressor genes, growth factor pathways, molecular subtypes of cancers have overshadowed the Warburg effect recently.…”