Metabolic Targeting of Glioblastoma Cells

In the 1920s, Otto Warburg and his colleagues showed that normal liver tissue exhibited the “Pasteur effect,” which is inhibition of fermentation in the presence of oxygen, whereas tumour tissue continued to produce lactate even in the presence of oxygen (aerobic glycolysis). Warburg showed that tumour tissue consumed ten-fold more glucose than accounted for by respiration and twice as much lactate as produced by normal tissue. This phenomenon was described as the “Warburg effect”. Upregulated glycolysis has not only been shown to provide intermediates for biosynthesis, but studies have also demonstrated that it plays a vital role in transformation, cell cycle progression, proliferation, resistance to cell death, metastasis, angiogenesis and maintenance of stemness; the hallmarks of cancer. The study aimed to target metabolic dependence of cancer cells on glucose. We have shown that glucose deprivation led to significant cell death in glioma cell lines whereas it did not affect untransformed human fibroblasts. We have also demonstrated that glucose deprivation led to an atypical form of cell death in glioma cells which was not mediated by apoptosis, autophagy or necrosis. We have also shown that free radical scavenger N-acetylcysteine was able to suppress glucose withdrawal-induced cell death. Our data indicate that glucose deprivation led to energetic and oxidative stress. We have also shown that metformin potentiates glucose withdrawal-induced cell death in glioma cells which was again not mediated by apoptosis, autophagy or necrosis. We have demonstrated that metformin potentiates glucose deprivation-induced energetic stress whereas it suppresses glucose deprivation-induced unfolded protein response leading to significant cell death. Finally, we have shown that metformin and 2-deoxyglucose combination treatment led to significant cell death in glioma cells. As both metformin and 2-deoxyglucose are in human use, our study may pave the way for future preclinical work to see if combination treatment can suppress glioma cell growth in vivo.