Abstract
Over the last decade, we have seen tremendous progress in research on 2-deoxy-D-glucose (2-DG) and its analogs. Clinical trials of 2-DG have demonstrated the challenges of using 2-DG as a monotherapy, due to its poor drug-like characteristics, leading researchers to focus on improving its bioavailability to tissue and organs. Novel 2-DG analogs such as WP1122 and others have revived the old concept of glycolysis inhibition as an effective anticancer strategy. Combined with other potent cytotoxic agents, inhibitors of glycolysis could synergistically eliminate cancer cells. We focused our efforts on the development of new combinations of anticancer agents coupled with 2-DG and its derivatives, targeting glioblastoma, which is in desperate need of novel approaches and therapeutic options and is particularly suited to glycolysis inhibition, due to its reliance on aerobic glycolysis. Herein, we present evidence that a combined treatment of 2-DG analogs and modulation of histone deacetylases (HDAC) activity via HDAC inhibitors (sodium butyrate and sodium valproate) exerts synergistic cytotoxic effects in glioblastoma U-87 and U-251 cells and represents a promising therapeutic strategy.
Highlights
Glioblastoma (GBM) is the most common and aggressive form of primary brain cancer.Despite optimized therapy, consisting of surgery, chemotherapy, and radiation, its expected median survival remains under two years [1]
2-deoxy-D-glucose (2-DG), sodium butyrate (NaBt), sodium valproate (NaVPA), bovine serum albumin (BSA), phenazine methosulfate (PMS), sulforhodamine B (SRB), trichloroacetic acid (TCA), acetic acid, dimethyl sulfoxide (DMSO), cycloheximide (CHX), chloroquine (CQ), dimethyloxalylglycine (DMOG), rhodamine (Rho), 5-bromodeoxyuridine (BrdU) Cell Proliferation Assay Kit, and Lactate Assay Kit were purchased from SigmaAldrich, Saint Louis, MO, USA. 3,6-di-O-acetyl-2-deoxy-D-glucose (WP1122) was produced at the MD Anderson Cancer Institute by Professor Waldemar Priebe’s team and was kindly provided for research by the Dermin company, who, based on an exclusive license, conduct developmental studies of the molecule
Glycolysis inhibitors have been intensively studied as a group of compounds for potential anticancer therapy [9]
Summary
Glioblastoma (GBM) is the most common and aggressive form of primary brain cancer. Despite optimized therapy, consisting of surgery, chemotherapy, and radiation, its expected median survival remains under two years [1]. Cancer cells, including GBM, rely on aerobic glycolysis (the Warburg effect), reducing the tricarboxylic acid (TCA) cycle [8]. This metabolic divergence between GBM and normal cells creates a targeting opportunity that can be explored to develop novel therapeutic strategies. Targeting GBM cells through different mechanisms lowers the chance of the development of a resistant phenotype Based on this hypothesis, we evaluated the cytotoxic effect of simultaneous inhibition of glycolysis and HDAC activity, two upregulated pathways driving GBM growth, using. We report the synergistic cytotoxicity of glycolysis and HDAC inhibitors combination, a promising prospect for future GBM therapy strategies
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