Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach
Abstract
:1. Introduction
2. The Implication of PI3K/Akt/mTOR Pathway in Cancer
3. Inhibition of PI3K/Akt/mTOR Signaling Pathway by Different Flavonoids
3.1. Quercetin
3.2. Myricetin
3.3. Kaempferol
3.4. Isorhamnetin
3.5. Green Tea Catechins, Epicatechin, and Epigallocatechin-3-Gallate
3.6. Fisetin
3.7. Lupiwighteone
3.8. Apigenin
3.9. Nobiletin
3.10. Galangin
3.11. Hesperidin
3.12. Anthocyanins
3.13. Delphinidin
3.14. Sulforaphane
4. Biodisponibility/Bioavailability of Flavonoids
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Akt | Protein kinase |
BAD | BCL2 associated agonist of cell death |
BCL2 | B-cell lymphoma 2 |
4EBP1 | Eukaryotic translation initiation factor 4E binding protein 1 |
EGCG | Epigallocatechin gallate |
EGFR | Epidermal growth factor receptor |
eIF4E | Eukaryotic translation initiation factor 4E |
ERK | Extracellular signal-regulated kinase |
GPCRs | G-protein-coupled receptors |
GSK-3β | Glycogen synthase kinase 3 beta |
GLUT4 | Glucose transporter type 4 |
HER2 | Human epidermal growth factor receptor 2 |
HIF-1α | Hypoxia-inducible factor 1-alpha |
IKK | Inhibitory-κB kinase |
MAPK | Mitogen-activated protein kinase |
MEK MITF | Mitogen-activated protein kinase kinase Microphthalmia-associated transcription factor |
NF-κB NO | Nuclear factor kappa-light-chain-enhancer of activated B cells Nitric oxide |
mTOR | mammalian target of rapamycin |
PI3K | Phosphoinositide 3-kinase |
PH | Pleckstrin homology |
PDK1 | Phosphoinositide-dependent kinase-1 |
p70S6K1 | p70 ribosomal S6 kinase 1 |
PIK3CA | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha |
PIP3 | Phosphatidylinositol-3,4,5-triphosphate |
PP2A | Protein phosphatase 2A |
PTEN | Phosphatase and tensin homolog deleted on chromosome 10 |
RHEB GDP | Ras homolog enriched in brain GDP |
RHEB GTP | Ras homolog enriched in brain GTP |
ROS | Reactive oxygen species |
RTK | Receptor tyrosine kinase |
S6k1 | Ribosomal protein S6 kinase beta-1 |
TSC | Tuberous sclerosis complex |
VEGF | Vascular endothelial growth factor |
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Class of Flavonoids | Inhibitors of PI3K/Akt/mTOR | Dietary Sources | References |
---|---|---|---|
Flavonols | Quercetin, myricetin, kaempferol, isorhamnetin, ampelopsin | Green tea, black tea, onion, apple with peel, oranges, blueberries, raw spinach, kale, broccoli, almonds, walnuts, dark chocolate, white wine, and red wine | [25,26,27,28,29] |
Flavanol | EGCG | Green tea, black tea, cranberries, strawberries, red wine, almonds, hazelnuts, and dark chocolate | [30] |
Flavanones | Hesperidin | citrus fruit, oranges, lemon, and grapefruit | [31] |
Flavones | Baicalein, acacetin, genkwanin, oroxylin A, pectolinarigenin, galangin | Orange, yellow fruits, spices, and vegetables | [32,33,34] |
Isoflavones | Genistein, lupiwighteone | Soy, tofu, legumes, Glycyrrhiza glabra, Lupinus, and Lotus pedunculatus | [35] |
Flavonolignan | Silibinin | Milk thistle (Silybum marianum) | [36] |
Anthocyanins | Delphinidin, cyanidin, pelargonidin | Red to purplish, blue-colored leafy vegetables, blueberries, other berries, currants, grapes, pomegranate, blue corn, grains, roots, tubers, and red wine | [37,38] |
Name of Inhibitor | Structure of Inhibitor | Inhibitory Activity | Cancer/Cell Type | Reference |
---|---|---|---|---|
Quercetin | Triggers apoptosis by stimulating autophagy, inhibits the Akt/mTOR pathway | HCC | [26,27] | |
Myricetin | Suppresses angiogenesis by inducing apoptosis, inhibits the PI3K/Akt/mTOR pathway | Endothelial cells | [28] | |
Kaempferol | Induces apoptosis, cell cycle arrest at G2/M, inhibits cell migration, PI3k/Akt/mTOR downregulation | Melanoma and liver cancer | [29,85] | |
Isorhamnetin | Cell cycle arrest at G2/M phase, inhibits cell proliferation by suppressing PI3K/Akt/mTOR pathway | Colorectal and breast cancer | [33,86] | |
Ampelopsin | Induces apoptotic and autophagy through the Akt-mTOR pathway via ER stress | MDA-MB-231 and MCF-7 breast cancer | [87] | |
EGCG | Suppresses the proliferation and induces apoptosis, downregulates the expression of pAkt and p-mTOR, inhibits the PI3K/Akt/mTOR | Gastric carcinoma | [30,88] | |
Genistein | Suppresses Akt and the NF-κB pathway through different cascades | HCC | [89,90] | |
Lupiwighteone | Induces the antiangiogenic activities, triggers the caspase-dependent and independent apoptosis through PI3K/Akt/mTOR pathway inhibition | Prostate and breast cancer | [91,92] | |
Baicalein | Deactivate PI3K/Akt pathway | HCC | [32] | |
Acacetin | Induces cell cycle arrest at G2/M phase, induces apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway | Breast cancer | [33] | |
Genkwanin | Significantly inhibits cell proliferation, induces cell cycle arrest at G2/M phase, induces apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway | Colorectal and breast cancer | [33,34] | |
Oroxylin A | Inhibits the proliferation by inducing autophagy and suppresses the Akt and ERK activation and the phosphorylation of mTOR and STAT3 | Glioma cells | [93,94] | |
Pectolinarigenin | Induces cell cycle arrest at G2/M phase, induces autophagic and apoptotic cell death through downregulation of PI3K/Akt/mTOR pathway | Gastric cancer | [95] | |
Galangin | Inhibits the cell proliferation, migration and invasion, induces apoptosis, suppresses PI3K/Akt/mTOR signaling | A498 cells | [96] | |
Hesperidin | Induces apoptosis and autophagy by inhibiting Aurora-A mediated PI3K/Akt/mTOR and GSK-3β pathways | Colon cancer | [31,97] | |
Silibinin | Anti-proliferative, inhibits HIF-1α and the mTOR/p70S6K/4E-BP1 signaling pathway | Hepatoma cells | [36,98] | |
Delphinidin | Inhibits cell proliferation by inactivating the PI3K/Akt, and ERK1/2 mitogen-activated protein pathway | Ovarian cancer | [99] | |
Cyanidin | Inhibits cell migration and reverses drug resistance by suppressing the PI3K/Akt pathway | HCC | [100] | |
Pelargonidin | Triggers autophagy and ROS-induced decline in MMP, cell cycle arrest at the G2/M phase through inhibiting PI3K and p-Akt signaling | Human osteosarcoma | [38] |
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Zughaibi, T.A.; Suhail, M.; Tarique, M.; Tabrez, S. Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach. Int. J. Mol. Sci. 2021, 22, 12455. https://doi.org/10.3390/ijms222212455
Zughaibi TA, Suhail M, Tarique M, Tabrez S. Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach. International Journal of Molecular Sciences. 2021; 22(22):12455. https://doi.org/10.3390/ijms222212455
Chicago/Turabian StyleZughaibi, Torki A., Mohd Suhail, Mohammad Tarique, and Shams Tabrez. 2021. "Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach" International Journal of Molecular Sciences 22, no. 22: 12455. https://doi.org/10.3390/ijms222212455