Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

Abstract

Tumor hypoxia is described as an oxygen deprivation in malignant tissue. The hypoxic condition is a consequence of an imbalance between rapidly proliferating cells and a vascularization that leads to lower oxygen levels in tumors. Hypoxia-inducible factor 1 (HIF-1) is an essential transcription factor contributing to the regulation of hypoxia-associated genes. Some of these genes modulate molecular cascades associated with the Warburg effect and its accompanying pathways and, therefore, represent promising targets for cancer treatment. Current progress in the development of therapeutic approaches brings several promising inhibitors of HIF-1. Flavonoids, widely occurring in various plants, exert a broad spectrum of beneficial effects on human health, and are potentially powerful therapeutic tools against cancer. Recent evidences identified numerous natural flavonoids and their derivatives as inhibitors of HIF-1, associated with the regulation of critical glycolytic components in cancer cells, including pyruvate kinase M2(PKM2), lactate dehydrogenase (LDHA), glucose transporters (GLUTs), hexokinase II (HKII), phosphofructokinase-1 (PFK-1), and pyruvate dehydrogenase kinase (PDK). Here, we discuss the results of most recent studies evaluating the impact of flavonoids on HIF-1 accompanied by the regulation of critical enzymes contributing to the Warburg phenotype. Besides, flavonoid effects on glucose metabolism via regulation of HIF-1 activity represent a promising avenue in cancer-related research. At the same time, only more-in depth investigations can further elucidate the mechanistic and clinical connections between HIF-1 and cancer metabolism.

Keywords: HIF-1; Warburg effect; cancer; flavonoids.

Figure 1

Domain structures of hypoxia-inducible factor 1 (HIF-1α) and HIF-1β.

Figure 2

HIF-1α-mediated crosstalk between hypoxia and glucose metabolism in a cancer cell. Abbreviations: HKII, hexokinase II; PGI, phosphoglucose isomerase; PFK1, phosphofructokinase; TPI, triosephosphate isomerase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PKM2, pyruvate kinase M2; LDH, lactate dehydrogenase; ENO1, enolase 1; OXPHOS, oxidative phosphorylation; HRE, hypoxia-response elements; HIF-1α/1β, hypoxia-inducible factor 1α/1β; GLUT1/3, glucose transporter 1/3.

Figure 3

Classification and chemical structures of the main subgroups of flavonoids with examples [99,114,115,116,117].

Figure 4

Flavonoids targeting HIF-1 and critical components of glycolysis. Abbreviations: EGCG, epigallocatechin-3-gallate; EGC, epigallocatechin; 4′-OM, 4′-O methylalpinumisoflavone; LUT-7G, Luteolin-7-O-β-D-glucoside; HK 2, hexokinase 2; PFK, phosphofructokinase; PKM 2, pyruvate kinase muscle isoform 2; LDHA, lactate dehydrogenase A; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; HRE, hypoxia-response elements; HIF-1α/1β, hypoxia-inducible factor 1α/1β; GLUT1/2, glucose transporter 1/2.