Flavonoids against the Warburg phenotype—concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism

Abstract

The Warburg effect is characterised by increased glucose uptake and lactate secretion in cancer cells resulting from metabolic transformation in tumour tissue. The corresponding molecular pathways switch from oxidative phosphorylation to aerobic glycolysis, due to changes in glucose degradation mechanisms known as the 'Warburg reprogramming' of cancer cells. Key glycolytic enzymes, glucose transporters and transcription factors involved in the Warburg transformation are frequently dysregulated during carcinogenesis considered as promising diagnostic and prognostic markers as well as treatment targets. Flavonoids are molecules with pleiotropic activities. The metabolism-regulating anticancer effects of flavonoids are broadly demonstrated in preclinical studies. Flavonoids modulate key pathways involved in the Warburg phenotype including but not limited to PKM2, HK2, GLUT1 and HIF-1. The corresponding molecular mechanisms and clinical relevance of 'anti-Warburg' effects of flavonoids are discussed in this review article. The most prominent examples are provided for the potential application of targeted 'anti-Warburg' measures in cancer management. Individualised profiling and patient stratification are presented as powerful tools for implementing targeted 'anti-Warburg' measures in the context of predictive, preventive and personalised medicine.

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

“…The observation revealed that cancer cells receive enormous amounts of glucose compared to surrounding non-malignant tissue. The repression of cancer cell respiration and the enhancement of glucose fermentation into lactate were also identified [ 11 , 63 ]. Recent evidence has revealed the specific molecular mechanisms responsible for switching from OXPHOS to aerobic glycolysis.…”

“…Recent evidence has revealed the specific molecular mechanisms responsible for switching from OXPHOS to aerobic glycolysis. Alterations in molecular pathways, including PI3K/Akt/mTOR, specific genes such as cMYC and p53 , and changes in epigenetic machinery directly participate in the regulation of cancer metabolism [ 11 , 64 , 65 , 66 , 67 ]. HIF-1 plays an essential role in the regulation of changes leading to the Warburg phenotype; it acts as a central regulator of glucose metabolism and cell proliferation.…”

“…As principally described in the previous section, the metabolic reprogramming of cancer cells allows the switch from OXPHOS to less efficient aerobic glycolysis, regulated by various molecular events such as the HIF-1 regulatory pathway ( Figure 2 ) [ 11 , 68 ]. Dimerization of both HIF subunits (α and β) initiates the transcription of genes associated with increased glucose uptake and lactate production.…”

“…Flavonoids are secondary metabolites of plants with specific phenolic structures. These bioactive compounds are found in numerous fruits, vegetables, roots, bark, flowers of medicinal plants, and in beverages such as wine and tea [ 10 , 11 , 99 ]. Chemically, flavonoids are composed of a fifteen-carbon skeleton consisting of benzene rings (A and B) and a heterocyclic pyran ring (C) [ 100 , 101 ].…”

“…Flavonoids, a class of naturally occurring plant-derived compounds, exert numerous beneficial human health attributes [ 10 ]. Flavonoids modulate various signaling pathways associated with cancer initiation, promotion, and progression, both in vitro and in vivo [ 4 , 11 , 12 , 13 ]. The effects of flavonoids on the regulatory cascade connected to HIF-1 and glucose metabolism constitute a promising way to inhibit metabolic reprogramming via the regulation of HIF-1 activity, as well as critical components of glycolysis.…”