Targeting energy metabolism in brain cancer: review and hypothesis

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.

The control systems structures of energy metabolism

“…A better understanding of the systems aspects of energy regulation could thus have significant implications in the analysis of various diseases as well as in the design of therapies. For example, Seyfried & Mukherjee (2005) report that a correct understanding of energy regulation in cancer cells allowed the design of a nutritional regime to arrest the growth of an inoperable brain tumour. However, a precise regime, both in terms of quantity and timing, was necessary for the approach to be efficient (Seyfried & Mukherjee 2005).…”

“…For example, Seyfried & Mukherjee (2005) report that a correct understanding of energy regulation in cancer cells allowed the design of a nutritional regime to arrest the growth of an inoperable brain tumour. However, a precise regime, both in terms of quantity and timing, was necessary for the approach to be efficient (Seyfried & Mukherjee 2005). This in turn implies a need for an understanding of dynamic control mechanisms involved in cancer cells.…”

Interactions among mitochondrial proteins altered in glioblastoma

“…Mitochondria are essential cellular organelles involved in numerous complex physiological processes including energy generation, regulation of cellular proliferation and apoptosis [5]. GBM, like many malignant cancers, favour abnormal energy production via aerobic glycolysis, and show an inherent resistance to apoptosis [6–8]. To provide an insight into mitochondrial dysfunction in GBM, we have quantified the proteomic alterations in mitochondrial fractions from GBM using a label-free proteomics (LC–MS) approach.…”

Want to Cure Cancer? Then Revisit the Past; “Warburg Was Correct”, Cancer Is a Metabolic Disease

“…This means that cancer cells have increased glucose uptake with increased lactic acid production in the presence of oxygen. The majority of cancers overexpress the genes for glycolysis [7]- [18].…”

“…These six alterations were: 1) self-sufficiency in growth signals, 2) insensitivity to inhibitory growth signals, 3) evasion of apoptosis, 4) limitless replicative potential, 5) sustained vascularity (angiogenesis), and 6) tissue invasion and metastasis. Seyfried, others and I believe that in addition to these six recognized hallmarks of cancer, the "Warburg Effect" or aerobic fermentation is also a very robust metabolic hallmark of most tumors [7]- [12].…”