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.

Natural Compounds in Glioblastoma Therapy: Preclinical Insights, Mechanistic Pathways, and Outlook

“…These compounds have well-characterized antitumor effects through the upregulation of apoptosis and disruption of migration, invasion, and metastasis [15,16]. Moreover, flavonoids modulate tumor cell glucose metabolism and downregulate the Warburg effect [17][18][19]. Flavonoids with anti-GBM potential include diosmin, a flavone glycoside from germander; epigallocatechin-3-gallate (EGCG), a catechin found mainly in green tea; matteucinol, a dihydroxyflavonone from naudin; naringin, a flavonone glycoside found in grapefruit and other citrus fruits; quercetin, a flavonol found in oak, onions, and kale; resveratrol, a stilbenoid found in grapes and red wine; rutin, a flavonol glycoside found in rue and citrus fruits; silymarin, an extract from milk thistle of which silibinin (a flavonolignan) is the major constituent; tectorigenin, a methylated isoflavone found in the leopard lily; chrysin, a dihydroxyflavone found in honey and propolis; galangin, a trihydroxylflavone that occurs in galangal; and xanthohumol, a chalcone (prenylated chalconoid) found in hops.…”

Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

“…Naturally occurring phytochemicals have numerous beneficial effects on human health [ 127 , 128 , 129 ]. They exhibit anticancer efficacy through the regulation of molecular cascades associated with cancer initiation, promotion and progression, including those for angiogenesis [ 130 , 131 , 132 , 133 ], hypoxia [ 134 ], metabolism [ 44 ], metastasis [ 135 ], apoptosis [ 136 , 137 ] and epigenetic machinery [ 138 , 139 , 140 ]. Zhang et al [ 141 ] evaluated the combined anticancer effects of melatonin and epigallocatechin-3 gallate (EGCG) in the HCC HepG2 cell line.…”

Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles

“…lavonoids are phenolic compounds widely found in vegetables, fruits, beverages, nuts, olive oil, red wine, and medicinal plants [3,7,46,47,71,72]. Chemically, flavonoids have fifteen-carbon skeletons consisting of two benzene rings connected through a pyrane ring.…”