Anti-tumour and associated metabolic effects of repurposed afuresertib and taxifolin for glioblastoma treatment

Abstract

Isocitrate dehydrogenase wild-type glioblastoma (GBM) is a particularly devastating central nervous system tumour with limited treatments. Taking advantage of computational strategies, drug repurposing has been regarded as an alternative and effective tool in GBM drug development, especially models targeting altered metabolic pathways and genomic alterations. In previous work, afuresertib and taxifolin were selected as repurposed candidates after the application of Transcriptomics-informed Stoichiometric Modelling and Network analysis. Although these two candidates have been studied in other types of cancers, they have not been tested against GBM. This study explored the in vitro anti-tumour effect of afuresertib and taxifolin using the PrestoBlue metabolic viability assay and Transwell collagen barrier assay on patient-derived glioblastoma cell lines. Their associated metabolic impact was revealed by the application of an untargeted metabolomics method. The results showed that afuresertib exhibited stronger inhibition of GBM cell proliferation and invasion than taxifolin. Glycerophospholipid metabolism was more active in cells derived from the invasion margin than in cells from the tumour core, indicating the possibility of varying underlining genetic mutations between GIN and GCE cell lines. Afuresertib could affect amino acid metabolism and glycerophospholipid metabolism, exerting the function of anti-proliferation and anti-invasion. Taxifolin could damage nicotinate and nicotinamide metabolism, leading to the death of tumour cells.