Table 4.
Effects of flavonoids on glucose transporters and enzymes of glucose metabolism.
| Enzyme | Flavonoid | Study Details | Mechanism of Action | Effects | Reference |
|---|---|---|---|---|---|
| Glucose transporters | |||||
| GLUT2 | Phloretin | Breast cancer cells (MDA-MB-231) | Inhibition of GLUT2 → accumulation of MDA-MB231 cells in the G0/G1 phase | suppression of migration and proliferation | [161] |
| GLUT1 | Wogonin | Colon cancer (HCT-116), ovarian cancer (A2780), and liver cancer (HepG2) cells, A2780 xenografts |
Suppression of glucose metabolism followed by upregulated p53 mRNA and protein level (wt-p53 cancer cells) and regulation of p53 downstream glycolytic factors | Upregulated p53 and p53-inducible glycolysis in cancer cells and decreased GLUT1 in cells expressing wild type, but not mutated p53. Inhibition of glycolysis was accompanied by the downregulation of GLUT1 in xenografts |
[162] |
| Red wine and green tea flavonoids | The evaluation of structure–function relationships in flavonoid–GLUT1 interactions | Stimulation of GLUT1-mediated sugar uptake at low concentrations → transport inhibition as the concentration raises (suggesting that at least two flavonoid-binding sites modulate GLUT1 function) | Act as: cis-allosteric activators of sugar uptake at low concentrations; and competitive inhibitors of GLUT1-mediated sugar uptake at higher concentrations | [163] | |
| Nanoliposomal encapsulation of celecoxib and genistein | Prostate cancer cells (PC-3, LNCaP) | Key processes behind the inhibition of prostate cancer cells: enhanced reactive oxygen species, decreased cellular GSH concentration, inhibited COX-2 synthesis and Glut-1 receptors | Suppressed GLUT1 receptors → prevention of prostate cancer cell proliferation | [164] | |
| Combinatorial liposomal formulation of plumbagin and genistein | Genistein (Glut-1 transporter protein inhibitor) induces high reactive oxygen species generation associated with AMPK signaling pathway. Low uptake of glucose → decreased metabolism of prostate cancer cells and simultaneous generation of reactive oxygen species and low GSH concentration → cell death |
Decreased population of GLUT1 transporters | [165] | ||
| Enzymes of glucose metabolism | |||||
| HKII | LUT-7G | Keratinocytes | LUT-7G suggested to represent a strong HKII inhibitor via the binding in the active sites | HKII suppression → repression of the glycolytic pathway | [166] |
| Quercetin | Hepatocellular carcinoma cells (SMMC-7721 and Bel-7402) and murine xenograft model | Quercetin suppresses glycolysis through Akt-mTOR pathway-mediated HKII regulation | Inhibition of glycolysis and proliferation of glycolysis-addicted HCC cells (by reduced HKII) and decrease of HKII expression in vivo | [167] | |
| Licochalcone A | Gastric cancer cells (MKN45 and SGC7901) | Licochalcone A inhibits glycolysis mainly through the blockade of Akt signaling pathway |
Suppression of HKII-mediated tumor glycolysis | [168] | |
| Gen-27 | Breast cancer cells (1H-I, MDA-MB-231, MCF-7 and MDA-MB-468) | The potential of Gen-27 to inhibit glycolysis and displaced HKII from mitochondrial membrane to the cytosol → blockage of its preferential access to ATP for glucose phosphorylation or preventing mechanism of cancer growth and immortality | Inhibition of glycolysis and induction of apoptosis (through HKII suppression accompanied by weakened interactions of HKII and VDAC) | [169] | |
| GL-V9 | Breast cancer cells (MDA-MB-231, MCF-7) | GL-V9 disrupts GSK-3β-modulated mitochondrial binding of HKII | Downregulation of HKII and disruption of mitochondrial binding of HKII resulting in apoptosis | [170] | |
| PKM1, PKM2 | Oroxylin A | Liver cancer model | Oroxylin A enhanced the protein expression of HNF-4α and its binding to the promoter region of HNF-1α and promoted direct interaction between PKM1 and HNF-4α in the nucleus | Increased PKM1/PKM2 ratio → HNF-4α activation → induction of hepatoma differentiation and suppression of cancer progression | [173] |
| Apigenin | Colon cancer cells (HCT116) | The potential of apigenin to ensure a low PKM2/PKM1 ratio through blockage of the β-catenin/c-Myc/PTBP1 signal pathway |
Apigenin → allosteric PKM2 inhibitor (can ensure a low PKM2/PKM1 ratio and restrain the proliferation of colon cancer cells through a blockade of PKM2-dependent glycolysis) | [174] | |
| LDHA | Wogonin | Human gastric cancer cells (SGC-7901) and human lung adenocarcinoma cells (A549) | Effects of wogonin on energy metabolism: affecting ATP generation and the activities of energy associated with metabolism | Reduced LDHA activity | [176] |
| EGCG | Evaluation of effects of EGCG on doxorubicin-induced cardiotoxicity in Sarcoma 180 tumor bearing mice | EGCG-exerted heart benefits related to reduced LDH release | Attenuation of LDHA release. | [177] | |
| Tangeretin-assisted platinum nanoparticles | Osteosarcoma cells (U2OS) | Tangeretin-assisted platinum nanoparticles promote LDHA leakage | Increase of LDHA leakage and cell death | [178] | |
| PFK | Quercetin | Breast cancer cells (MDA-MB-231) | The ability of quercetin to impair PFKP-LDHA signaling → inhibiting migration of cancer cells mediated by aerobic glycolysis | Impairment of the PFKP-LDHA signaling axis → inhibition of cell migration induced by aerobic glycolysis | [180] |
| EGCG | Hepatocellular carcinoma cells (HCC-LM3 and HepG2) | EGCG inhibits glycolysis (especially PFK activity) in aerobic glycolytic HCC cell lines | Inhibition of PFK expression and activity | [179] | |
| Pancreatic cancer cells (Panc-1 and MIA PaCa-2) | EGCG inhibits glycolysis through repressing rate-limiting enzymes (PFK and PKM2) | Suppression of PFKP and PKM2 levels | [181] | ||
| PDK | Quercetin | Hepatocellular carcinoma cells (HepG2) and liver cancer (A549) cells | Quercetin binds with PDK3 and significantly inhibits its kinase activity | Interaction with residues of the active site cavity of PDK3 (conformational fitting). PDK3 inhibitory potential in cancer cells |
[182] |
Abbreviations: COX-2, cyclooxygenase; EGCG, epigallocatechin-3-gallate; GLUT, glucose transporters; GLUT1, glucose transporter type 1; GLUT2, glucose transporter type 2; GSH, glutathione; HEKII, hexokinase II; HK, hexokinases; HNF-4α, hepatocyte nuclear factor 4 alpha; LDHA, lactate dehydrogenase; LUT-7G, luteolin-7-O-β-D-glucoside; PDK, pyruvate dehydrogenase kinase; PDK3, pyruvate dehydrogenase kinase 3; PFK, phosphofructokinase; PFK-1, phosphofructokinase-1; PFKP, phosphofructokinase platelet-type; PK, pyruvate kinase; PKM1, pyruvate kinase isoenzyme M1; PKM2, pyruvate kinase isoenzyme M2; PTBP1, polypyrimidine tract binding protein; VDAC, voltage-dependent anion channel.