Flavonoids Attentuate Cancer Metabolism by Modulating Redox State, lipid metabolism, and use of amino acids or ketone bodies

Abstract

Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. Cancer cells rewire metabolism to meet increased nutritional requirements necessary for enhanced cellular proliferation and growth. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation also involves an alteration in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, redox balance, and utilization of ketone bodies as an alternative fuel promoting carcinogenesis. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological phenotype. Recent evidence has identified numerous flavonoids and their derivates as modulators of critical components of cancer metabolism. Flavonoids affect lipid metabolism by regulating fatty acid synthase (FAS) or transcription activity of sterol regulatory element-binding protein 1/2 (SREBP1/2), redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, amino acid flux and synthesis by phosphoglycerate mutase 1 (PGAM1), or ketone bodies generation mediated by 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in stromal cells to supplement energetic demands of epithelial cancer cells. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies. Flavonoids, which affect metabolic pathways of cancer cells by targeting critical enzymes and transporters, represent a promising avenue to accelerate cancer-related research; however, more in-depth investigation is essential to implement innovative and progressive therapeutic approaches in cancer management.