Dietary Polyphenol Combinations Have a Multifaceted Inhibitory Effect on Metabolic Rewiring and Signaling Pathways in Neuroblastoma

<b>Background/Objectives</b>: Numerous studies have demonstrated that dietary plant-derived polyphenols suppress signaling and metabolic pathways in various malignancies, including neuroblastoma. In the present study, we compared the inhibitory activities of selected polyphenols and their combinations on key metabolic and signaling pathways in two human neuroblastoma cell lines and two noncancerous cell lines-mesenchymal stem cells (MSCs). <b>Methods</b>: The influence of polyphenols on neuroblastoma cells and MSCs were studied via an MTT-assay, cell cycle analysis, and an apoptosis assay (flow cytometry). Chou-Talalay algorithms were used to quantify drug interactions. SeaHorse energy profiling was applied to study energy metabolism. The influence of the compounds on metabolic enzymes and signaling pathways was examined using immunoblotting. Total protein biosynthesis was assessed using o-propargyl-puromycin labeling (flow cytometry). <b>Results</b>: While most of the studied polyphenols displayed a more significant inhibitory effect on neuroblastoma cells than on mesenchymal stem cells (MSCs), we found that the combinations of curcumin and quercetin (CQ) and curcumin, quercetin, and resveratrol (CQR) were significantly superior to the individual compounds. These combinations displayed synergistic effects and inhibited the cell cycle while inducing apoptosis. The CQ and CQR combinations effectively suppressed metabolic reprogramming by downregulating key enzymes of glycolysis, respiration, one-carbon metabolism, glutaminolysis, and fatty acid biosynthesis, as well as N-Myc and c-Myc, which are master regulators of metabolic processes. Furthermore, CQ and CQR inhibited AKT/mTOR, MAPK/ERK, and WNT/β-catenin signaling pathways and total protein biosynthesis and sensitized malignant cells to doxorubicin. <b>Conclusions</b>: Polyphenol combinations exert multifaceted inhibitory effects on metabolic rewiring and signaling networks in neuroblastoma cells.