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.

Keywords: Aerobic glycolysis; Age; Aggressive metastatic disease; Anticancer effect; Biomarker patterns; Cancer; Carcinogenesis; Cell metabolism; Chemoresistance; Co-morbidities; Disease manifestation; FDG-PET; Flavonoids; Glucose intake; Glucose metabolism; Glycolysis; Glycolytic inhibitors; HIF-1; Individual outcome; Individualised patient profiles; Ischemic lesions; Liquid biopsy; Liver malignancy; Magnetic resonance spectroscopy; Malignancy; Metabolic reprogramming; Microcirculation; Modifiable risk factors; Multi-omics; Oxidative phosphorylation; PET-CT; Palliative medicine; Patient stratification; Pleiotropic activity; Polyphenols; Positron emission tomography; Predictive preventive personalised medicine (PPPM / 3PM); Pregnancy; Prognosis; Prognostic markers; Proliferation; Prostate cancer; Radioresistance; Risk assessment; Systemic hypoxia; Treatment algorithms; Triple-negative breast cancer; Tumour imaging; Warburg phenotype.

Fig. 1

Metabolism of glucose. The investment phase begins with the first enzyme, hexokinase (HK), which adds a phosphate group to glucose leading to the generation of glucose-6-phosphate (G6P). In the next step, phosphoglucose isomerase (PGI) modifies G6P into fructose-6-phosphate (F6P). The enzyme phosphofructokinase (PFK1) transforms F6P into fructose-1,6-bisphosphate (FBP). FBP is further lysed into dihydroxyacetone (DHAP) and glyceraldehyde 3-phosphate (G3P) by fructose-bisphosphate aldolase (aldolase). The enzyme triosephosphate isomerase (TPI) converts DHAP into G3P. The payoff phase begins with the metabolisation of G3P into 1,3-bisphosphoglycerate (1,3BGP) by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Next, phosphoglycerate kinase (PGK) converts 1,3BGP into 3-phosphoglycerate (3PG). Phosphoglycerate mutase (PGM) generates 2-phosphoglycerate (2PG) from the 3PG, and 2PG then converts enolase into phosphoenolpyruvate (PEP). Pyruvate kinase (PK) catalyses the final step, in which PEP is transformed into pyruvate [19, 20]. Subsequently, pyruvate undergoes oxidative phosphorylation in mitochondria resulting in the generation of 36 molecules of ATP from the tricarboxylic acid cycle (TCA). ATP, adenosine triphosphate; ADP, adenosine diphosphate; NAD⁺, nicotinamide adenine dinucleotide (oxidised form); NADH, nicotinamide adenine dinucleotide (reduced form)

Fig. 2

Molecular mechanisms contributing to the Warburg effect in cancer cells. 6GP, glucose-6-phosphate; 6FP, fructose-6-phosphate; FBP, fructose-1,6-bisphosphate; DHAP, dihydroxyacetone; G3P, glyceraldehyde 3-phosphate; 1,3BGP, 1,3-bisphosphoglycerate; 3PG, 3-phosphoglycerate; 2PG, 2-phosphoglycerate; PEP, phosphoenolpyruvate; HK2, hexokinase 2; PGI, phosphoglucose isomerase; PFK1, phosphofructokinase; TPI, triosephosphate isomerase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PKM2, pyruvate kinase 2; LDH, lactate dehydrogenase; TCA, tricarboxylic acid cycle

Fig. 3

Structures of the main subgroups of flavonoids

Fig. 4

The role of flavonoids in the regulation of glucose metabolism in cancer. AP, apigenin; PB2, proanthocyanidin B2; EGCG, epigallocatechin-3-gallate; TAX, taxifolin; NEO, neoeriocitrin; FIS, fisetin; CG, catechin gallate; EP, epicatechin; QUE, quercetin; SHI, shikonin; XA, xantohumol; ASG, astralangin; MO, morin; LU-7OβD, luteolin-7-O-β-D-glucoside; PH, phloretin; HES, hesperitin; KAE, kaempferol; SI, silibinin; BA, baicalein; MF, methylalpinumisoflavon; OX-A, oroxylin A; RES, resveratrol; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle; ATP, adenosine triphosphate