Anticancer Activity of Natural Flavonoids: Inhibition of HIF-1α Signaling Pathway

Abstract

Rapid tumor growth is dependent on the capability of tumor blood vessels and glycolysis to provide oxygen and nutrients. Tumor hypoxia is a common characteristic of many solid tumors, and it essentially happens when the growth of the tumor exceeds the concomitant angiogenesis. Hypoxia-inducible factor 1 (HIF-1) as the critical transcription factor in hypoxia regulation is activated to adapt to this hypoxia situation. Flavonoids, widely distributed in plants, comprise many polyphenolic secondary metabolites, possessing broadspectrum pharmacological activities, including their potentiality as anticancer agents. Due to their low toxicity, intense efforts have been made for investigating natural flavonoids and their derivatives that can be used as HIF-1α inhibitors for cancer therapy during the past few decades. In this review, we sum up the findings concerning the inhibition of HIF-1α by natural flavonoids in the last few years and propose the idea of designing tumor vascular and glycolytic multi-target inhibitors with HIF-1α as one of the targets.

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

“…HIF-1 is a critical transcription factor targeting essential genes contributing to the Warburg phenotype. Therefore, it is necessary to comprehensively discuss the effects of secondary plant metabolites on HIF-1 activity [ 4 ]. In this regard, we summarize the current status of experimental studies that focus on the modulation of HIF-1 activity by flavonoids in cancer models.…”

“…The uncontrolled and rapid proliferation of tumor cells and insufficient formation of new blood vessels lead to inadequate oxygen supply to tumor tissues. Therefore, it is not unusual for developing malignant tissue to possess hypoxic and necrotic areas [ 4 ]. A cell’s adaptation to a lower level of oxygen in hypoxic regions is accompanied by the activation of several survival pathways [ 5 ].…”

“…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.…”

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

“…Elevated expression of HIF-1 promotes tumour-associated angiogenesis, proliferation and progression through the modulation of glycolytic cascades [156]. Current evidence suggests that flavonoids may play a considerable role in cancer treatment and have multiple potential targets in tumourigenesis, including HIF-1 [157]. Baicalein (BA; 5,6,7-trihydroxyflavone), a flavonoid isolated from Scutellaria baicalensis, exerts strong anticancer activity on various tumours [158][159][160].…”

Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism

“…According to the current research, several phytocompounds also have been shown to play a significant role in cancer therapy and have numerous potential targets in tumorigenesis, including HIF-1 ( Deng et al, 2019 ). Baicalein (PubChem CID: 5281605), (5,6,7- trihydroxyflavone), a flavonoid derived from Scutellaria baicalensis has been reported to have potent cytotoxic activity against a wide range of cancer ( Bie et al, 2017 ; Dou et al, 2018 ; Wang et al, 2019 ).…”