Metabolic control of brain cancer: role of glucose and ketone bodies

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Metabolic control theory applies principles of bioenergetics for the control or management of complex diseases. Since metabolism is a universal process underlying all phenotypes, modification of metabolism can modify phenotype. The theory is based on findings that compensatory genetic and biochemical pathways regulate the bioenergetic potential of cells. Glucose is the primary fuel for brain cells under normal physiological conditions, but both neurons and glia can transition to ketone bodies for energy when glucose levels become limiting. This is a conserved physiological adaptation that evolved to enhance survival during periods of prolonged food restriction. The transition from glucose to ketone bodies (β-hydroxybutyrate, β-OHB) as a major fuel source involves an increase in TCA cycle activity, a down regulation of glycolytic flux, and a general increase in the delta G’ of ATP hydrolysis. Ketone body metabolism can also reduce tissue inflammation that contributes to brain tumor angiogenesis. While normal brain cells possess metabolic flexibility in their use of energy metabolites, gliomas lack flexibility and are largely dependent on glycolytic energy. Nuclear mutations and mitochondrial defects are thought to underlie the metabolic inflexibility of glioma cells. Therapies that exploit the genetic and metabolic weaknesses of brain tumor cells should therefore be effective in controlling brain cancer. Our recent in vivo studies show that reduced caloric intake, which reduces glucose and elevates ketones, has powerful proapoptotic and antiangiogenic effects in experimental brain cancer. An in vitro system is presented to evaluate the role of glucose and β-OHB in brain tumor control using malignant mouse astrocytoma (CT-2A) cells and normal syngeneic mouse astrocytes grown in the presence or absence of glucose, glutamine, and β-OHB. The results show that caspase 3-mediated apoptosis is greater in the CT-2A astrocytoma cells than in the normal astrocytes under reduced glucose/glutamine conditions and that β-OHB can rescue normal astrocytes, but not the CT-2A astrocytoma cells. These findings support the hypothesis that brain tumors are potentially manageable through metabolic intervention. Supported by NCI grant (CA102135).