Abstract
Malignant brain tumors are a significant health problem in children and adults and are often unmanageable. As a metabolic disorder involving the dysregulation of glycolysis and respiration, malignant brain cancer is potentially manageable through changes in metabolic environment. A radically different approach to brain cancer management is proposed that combines metabolic control analysis with the evolutionarily conserved capacity of normal cells to survive extreme shifts in physiological environment. In contrast to malignant brain tumors that are largely dependent on glycolysis for energy, normal neurons and glia readily transition to ketone bodies (β-hydroxybutyrate) for energy in vivo when glucose levels are reduced. The bioenergetic transition from glucose to ketone bodies metabolically targets brain tumors through integrated anti-inflammatory, anti-angiogenic, and pro-apoptotic mechanisms. The approach focuses more on the genomic flexibility of normal cells than on the genomic defects of tumor cells and is supported from recent studies in orthotopic mouse brain tumor models and in human pediatric astrocytoma treated with dietary energy restriction and the ketogenic diet.
Highlights
The world-wide incidence of malignant brain tumors may be increasing in both children and the elderly [1,2,3,4]
Many tumors have reduced activity of succinyl-CoA-acetoacetate-CoA transferase (SCOT), the ratecontrolling step for utilizing β-OHB as a respiratory fuel [42,62,63]. Consistent with these observations, we recently found that β-OHB could rescue normal mouse astrocytes under low glucose conditions, but could not rescue mouse astrocytoma cells [20]
Structural defects of the inner mitochondrial membrane, that would reduce or dissipate the proton motive gradient, could prevent normal ATP production despite the appearance of oxidative metabolism, i.e., oxygen consumption and CO2 production [70,72,73]. Considered together, these findings indicate that brain tumors suffer from reduced respiratory capacity coupled to an increased glycolysis and lactic acid production
Summary
The world-wide incidence of malignant brain tumors may be increasing in both children and the elderly [1,2,3,4]. In the case of C6 glioma cells and most brain tumors for that mater, this energy is mostly derived from glycolysis [29,99] This would render brain tumor cells vulnerable to reductions in circulating glucose levels as these mutant cells would have difficulty oxidizing alternative fuels (ketone bodies) through respiration. Step three could involve the use of either conventional or novel targeted therapies While these therapeutic approaches might have little if any long-term benefit on malignant brain tumor management if used initially, they could be highly effective following the step one strategy after the tumor cells are weakened and metabolically isolated from the physiologically strengthened normal brain cells. KD, ketogenic diet; SCOT, succinyl-CoA-acetoacetate-CoA transferase; β-OHB, β-hydroxybutyrate; TCA, tricarboxylic acid
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