Regulation of Glycogen Metabolism as a Potential Therapeutic Approach Against Glioblastoma

Abstract AIMS Glioblastoma (GB) is one of the most aggressive forms of cancer of the brain and spinal cord with a mean sur- vival of only 15 months following maximal treatment. This demonstrates a demand for discovery of effective compounds as novel therapeutics for GB. One of the hallmarks of cancer includes the ability of malignant cells to reprogramme cellular metabolism. This includes up-regulation of glycogenolysis, the process whereby stored glycogen is broken down into glucose. The rate-determining enzyme involved in this process is glycogen phos- phorylase (GP), of which there are three isoforms (brain, liver, muscle). Recent studies indicate GP as a promis- ing target of inhibition for the treatment of GB. We aim to identify effective GP inhibitor compounds, selective to the liver isoform, and investigate their anti-glioblastoma potential. METHODS Initial research utilises in silico screening of compounds to establish a narrow selection of compounds with the best chances of selectivity for liver GP via the quercetin binding site (QBS). These inhibitors will then be tested against GB cell lines, with normal human astrocytes as a control, in cell viability assays to assess their effectiveness in vitro. Results from cell viability assays will determine the best compounds for use in further experimental studies, including cell cycle analysis and wound healing assays to investigate their effect apoptotic potential and impact on migration. RESULTS The structure of human liver GP, determined through X-ray crystallography, was computationally optimised to effectively dock compounds of interest to the QBS. Compounds were assessed based on their respective docking score and binding interactions observed in silico to predict effective inhibitors. Results indicate that certain compounds display greater affinity liver GP. These were validated through in vitro experiments. CONCLUSION Targeting the QBS demonstrates promise as a therapeutic approach against GB by providing selectivity for the inhibition of liver GP