Glycolysis and Fatty Acid Oxidation Inhibition Improves Survival in Glioblastoma

Abstract

Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano). Gene expression data show that GBM subtypes have similar glucose and FAO pathways, and GBM tumors have significant upregulation of enzymes in both pathways, compared to normal brain tissue (p < 0.01). DCA and the DCA/Rano combination showed reduced colony-forming activity of GBM and increased oxidative stress, DNA damage, autophagy, and apoptosis in vitro. In the orthotopic Gl261 and CT2A syngeneic murine models of GBM, DCA, Rano, and DCA/Rano increased median survival and induced focal tumor necrosis and hemorrhage. In conclusion, dual targeting of glycolytic and FAO metabolic pathways provides a viable treatment that warrants further investigation concurrently or as an adjuvant to standard chemoradiation for GBM.

Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas

“…Indeed, HGGs, even within the same tumor, are inherently heterogeneous with histological and biological differences, varying degrees of immune infiltrates, and distinct molecular subtypes [ 26 , 27 , 28 ]. The heterogeneity in cancer cell metabolism and mitochondrial DNA content in HGG tumors and cell lines is not surprising [ 11 , 29 , 30 , 31 , 32 ]. While hierarchical clustering of gene expression data sets for metabolic pathways of 48 HGG primary cell lines showed no difference in glucose and fatty acid oxidation pathways among HGG subtypes [ 11 ], a larger cohort of 498 HGG IDH (isocitrate dehydrogenase) wildtype tumors suggests that mesenchymal tumors predominantly utilize glycolysis [ 29 ] and fatty acid oxidation (FAO) [ 31 ], while other subtypes are more variable [ 29 ].…”

“…The heterogeneity in cancer cell metabolism and mitochondrial DNA content in HGG tumors and cell lines is not surprising [ 11 , 29 , 30 , 31 , 32 ]. While hierarchical clustering of gene expression data sets for metabolic pathways of 48 HGG primary cell lines showed no difference in glucose and fatty acid oxidation pathways among HGG subtypes [ 11 ], a larger cohort of 498 HGG IDH (isocitrate dehydrogenase) wildtype tumors suggests that mesenchymal tumors predominantly utilize glycolysis [ 29 ] and fatty acid oxidation (FAO) [ 31 ], while other subtypes are more variable [ 29 ]. Mitochondrial and glycolytic ATP production was observed to be a 1:1 ratio of OXPHOS to glycolysis among some individual primary GSC lines, while others heavily favored glycolysis and lactate production and are therefore more responsive to glycolytic inhibition [ 29 ].…”

“…Despite the metabolic heterogeneity of HGGs, the cell survival/viability (in vitro) IC 50 of DCA is comparable among HGG stem cells (15–40 mM) [ 29 ], immortalized human (20–28 mM), and rodent glioma cell lines (27–28 mM) [ 11 , 71 ]. Although cell death HGG IC 50 values are at millimolar levels, concentrations of DCA as low as 0.1 and 1 mM still induce radiosensitization, decrease clonogenic survival, and increase sub-G1 specific apoptosis in human primary glioblastoma cells [ 72 ].…”

“…Although cell death HGG IC 50 values are at millimolar levels, concentrations of DCA as low as 0.1 and 1 mM still induce radiosensitization, decrease clonogenic survival, and increase sub-G1 specific apoptosis in human primary glioblastoma cells [ 72 ]. DCA appears to cause in vitro radiosensitization through the following mechanisms: reducing mitochondrial reserve capacity, increasing ROS-induced DNA damage, and inducing cell cycle arrest and autophagy, which ultimately leads to cell death [ 10 , 11 ]. Using the intracranial and in vivo human HGG U87-MG model, the combination of DCA and fractionated RT significantly reduced tumor Ki-67 proliferation and improved median survival by a modest 13%, when compared to RT alone [ 10 ].…”

“…Dichloroacetate (DCA) is an inhibitor of PDK with the capability of maintaining PDH in its unphosphorylated active form (Figures 1 and 2). It was originally used as an experimental drug to treat lactic acidosis induced by congenital mitochondrial disorders and has recently been repurposed as an anticancer drug [ 6 , 7 , 8 , 9 , 10 , 11 ]. As a water-soluble small molecule, it can be rapidly absorbed with almost 100% bioavailability, and it readily crosses the blood–brain barrier, making it an excellent candidate for managing patients with brain cancers.…”