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Classification | Polyphenols | Natural sources | Cell types/animal models | Effects | Involved mechanisms | Ref. |
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Induce apoptosis and inhibit proliferation |
Flavone | Vitexin | Vitex agnus-castus | SK-Hep1 and Hepa1-6 cells | Induce apoptosis | Activation of the JNK signaling pathway | [153] |
Luteolin | Celery, green pepper, parsley, thyme, dandelion, and others | HepG2 cells | Induce apoptosis | ROS-mediated pathway, regulating intrinsic and extrinsic caspases as well as executioner caspases | [154] |
Chrysin | Honey, propolis, the passion flowers, and Passiflora caerulea | HepG2 cells and QGY7701 cells | Reduce proliferation and cell motility as well as induce apoptosis | Downregulation of Skp2 and LRP6 expression; activation of the p53/Bcl-2/caspase-9 pathway | [155] |
Isoorientin | Passion flower, Vitex negundo, Terminalia myriocarpa | HepG2 cells | Induce apoptosis | Mitochondrial-mediated pathway: the regulation of cell cycle-related genes; elevate ROS formation, followed by attenuation of mitochondria membrane potential; increase in caspase-3 and caspase-9 proteolytic activities | [130] |
Luteolin-7-O-glucoside | Dandelion coffee and in Cynara scolymus | HepG2 cells | Induce apoptosis and inhibit proliferation | G2/M phase cell cycle arrest by JNK activation and caspase-independent apoptotic signaling pathways | [156] |
Oroxylin A | Scutellaria baicalensis and the Oroxylum indicum tree | HepG2 cells | Induce apoptosis | Suppressing of PI3K-FTEN-Akt-mTOR signaling pathway; activation of the PERK-eIF2α-ATF4-CHOP branch of the UPR pathway | [136, 137] |
Wogonin | Scutellaria baicalensis | HepG2, SMMC-7721, and Hep3B cells | Induce apoptosis and necrosis | Activation of the UPR pathway and consequent inactivation of AKT signaling | [157] |
Baicalein | Roots of Scutellaria baicalensis and Scutellaria lateriflora | HepG2 cells; HCC a in mice | Induce apoptosis and inhibit tumor growth | Inhibiting the PKB/mTOR pathway; blocking MEK-ERK signaling | [134, 135] |
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Flavanone | Eriodictyol | Eriodictyon californicum | HepG2 cells | Induce apoptosis | Upregulation of Bax and PARP and downregulation of Bcl-2 protein | [158] |
Hesperidin | Citrus fruits | HepG2 cells; xenograft tumors | Induce apoptosis | Regulating mitochondrial pathway and death receptor pathway; triggering the activation of the mitochondrial pathway by increasing the levels of intracellular ROS, ATP, and Ca2+. | [159]; [160] |
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Isoflavones | Puerarin | Root of Pueraria | SMMC-7721 HCC cells | Induce apoptosis | Regulating MAPK pathways | [161] |
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Flavonols | Galangin | Alpinia officinarum and Helichrysum aureonitens | HepG2, Hep3B, and PLC/PRF/5 cells | Induce apoptosis | Via mitochondrial pathway, translocating the proapoptotic protein Bax to the mitochondria to release apoptosis-inducing factor and cytochrome c into the cytosol; regulating MAPK signaling pathways | [162, 163] |
Kaempferol | Delphinium, grapefruit | HepG2 and Huh7 cells | Autophagy-mediated cell death | ER stress-CHOP-autophagy signaling pathway | [99] |
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Flavanols | EGCG | Tea | SMMC7721, SK-hep1, HLE, HepG2, HuH-7, and PLC/PPF/5 cells; a xenograft model | Induce apoptosis and antiproliferation | Inhibit receptor tyrosine kinase; downregulating PI3K/AKT activity; downregulating Bcl-2 alpha and Bcl-xl by inactivation of NF-κB | [138, 139] |
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Flavanonols | Dihydromyricetin | Ampelopsis species japonica; Hovenia dulcis | HepG2 cells | Inhibit proliferation and induce apoptosis | Via a p53-dependent manner; reducing TGF-β via p53-dependent signal pathway | [164] |
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Other flavonoids | Daphnegiravone D | Daphne giraldii | Hep3B and HepG2; nude mouse xenograft model | Inhibit proliferation | Regulating p38 and JNK MAPK pathways | [165] |
Kurarinol | Roots of the medical plant Sophora flavescens | HepG2, Huh-7, and H22 cells; H22 tumor-bearing mice | Induce apoptosis | Suppressing STAT3 signaling | [166] |
Eriocitrin | Lemons | HCC cell lines | Induce apoptosis and arrest cell cycle | Arresting cell cycle in S phase through upregulation of p53, cyclin A, cyclin D3, and CDK6; trigger apoptosis by activating mitochondria-involved intrinsic signaling pathway | [167] |
Isoquercitrin | Mangifera indica (mango) and Rheum nobile (the Noble rhubarb) | Liver cancer cells; tumor-bearing nude mice | Induce apoptosis and inhibit tumor growth | Regulating MAPK and PKC signaling pathways | [168] |
Fisetin | Strawberries, apples, persimmons, onions, and cucumbers | Liver cancer cells | Induce apoptosis | Regulating CDK5 signaling, NRF2-mediated oxidative stress response, glucocorticoid signaling, and ERK/MAPK signaling | [141] |
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Nonflavonoids | Gigantol | Plants in the genus dendrobium | HepG2 cells | Inhibit proliferation | Regulating PI3K/Akt/NF-κB signaling pathway | [169] |
Licochalcone A | Root of Glycyrrhiza glabra and Glycyrrhiza inflata | HepG2 cells | Induce apoptosis | Induction of ER stress via phospholipase C γ1 (PLC γ1), Ca2+, and ROS-dependent pathway | [170] |
3-decylcatechol | Sap of the lacquer tree | Huh7 cells | Autophagy-mediated cell death | Activating ER stress to promote autophagy via p62 transcriptional activation involving IRE1α/JNK pathways | [171] |
Curcumin | Ginger family | SMMC-7721 cells | Inhibit proliferation | Regulating AMPK signaling pathway | [172] |
Sesamol | Sesame seeds and sesame oil | HepG2 cells; a xenograft nude mice model | Suppress colony formation, inhibit the proliferation and promote apoptosis | Impairing mitochondrial function and suppressing autophagy through impeding the PI3K class III/Belin-1 pathway | [173] |
E-[6-(5-hydroxypentyl)tricosyl]-4-hydroxy-3-methoxycinnamate | Fruits of Livistona chinensis | HepG2 cells | Autophagy-related apoptosis; suppress cell proliferation and colony formation | Via a mitochondria-dependent caspase pathway in HepG2; induce autophagy via inhibition of the Akt/mechanistic target of rapamycin/p70 ribosomal protein S6 kinase signaling pathway | [174] |
Chlorogenic acid | Leaves of Hibiscus sabdariffa, eggplants, peaches, and prunes | HepG2 cells; HepG2 xenograft animal model | Inhibit proliferation and the progression of HepG2 xenograft | Inactivation of ERK1/2 and suppressed the expression of MMP-2 and MMP-9 | [175] |
Gallic acid | Gallnuts, sumac, witch hazel, tea leaves, oak bark, and other plants | HepG2 and SMMC-7721 cells; DEN-induced HCC | Induce apoptosis and antiproliferation | Regulating mitochondrial-mediated pathways, induce caspase-3, caspase-9, and ROS activity, elevate Bcl-2-like protein 4, and reduce the mitochondrial membrane potential; decreasing the levels of argyophillic nucleolar organizing regions, and proliferating cell nuclear antigen | [176] |
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Antiangiogenesis |
Flavone | Eupafolin | Artemisia princeps Pampanini | Human umbilical vascular endothelial cells (HUVECs); HepG2 | Antiangiogenesis | Blocking VEGF-induced activation of VEGFR2 in Akt activity in HUVECs; inhibiting Akt activity and VEGF secretion in HepG2 | [142] |
Morusin | Root bark of Morus alba | HepG2 and Hep3B; HepG2 xenografts | Apoptosis induction and antiangiogenesis | Attenuation of the IL-6/STAT3 signaling pathway | [143] |
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Flavonol | Morin | Maclura pomifera, Maclura tinctoria, and from leaves of Psidium guajava | Rats with DEN-induced HCC | Antiangiogenesis | Upregulation of NF-κB-p65 and COX-2; reducing MMP-2 and MMP-9 | [144] |
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Flavonoid | Hydroxysafflor yellow A | Carthamus tinctorius L. | H22 tumor-bearing mice | Antiangiogenesis | Blocking ERK1/2 phosphorylation and then restraining the activation of NF-κB, suppressing mRNA expression levels of cell proliferation-related genes cyclin D1, cMyc, and c-Fos | [177] |
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Nonflavonoids | Resveratrol | Grapes, berries, red wine | HCC xenograft animal model | Antiangiogenesis | Inhibiting VEGF expression through a NF-κB-mediated mechanism | [145] |
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Inhibit the invasion and metastasis |
Flavanones | Hesperidin | Citrus fruits | HepG2 cells | Inhibit invasion and metastasis | Reducing MMP-9 expression through the inhibition of activated NF-κB and AP-1 activity by I κB, JNK, and p38 signaling pathways | [178, 179] |
Naringenin | Citrus fruits | HepG2, Huh-7, and HA22T cells | Inhibit the invasion and metastasis | Suppressing MMP-9 transcription by inhibiting NF-κB and AP-1 activity | [180] |
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Flavone | Luteoloside | Gentiana macrophylla | HCC cells; mouse lung metastasis model | Suppress proliferation and metastasis | Inhibition of NLRP3 inflammasome | [181] |
Wogonin | Scutellaria baicalensis | HepG2 and Bel7402 HCC cells | Inhibit proliferation and invasion | Regulating NF-κB/Bcl-2, EGFR, and EGFR downstream ERK/AKT signaling | [182] |
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Flavonol | Galangin | Alpinia officinarum and Helichrysum aureonitens | HepG2 cells | Inhibit metastasis | Protein kinase C (PKC)/ERK signaling pathway | [183] |
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Flavanols | EGCG | Tea | MHCC-97H and HepG2 cells | Inhibit metastasis | Reduce osteopontin by decreasing the half-life of osteopontin mRNA | [184] |
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Isoflavonoids | Genistein | Soy | HepG2, SMMC-7721, and Bel-7402 cells | Inhibit metastasis | Reversing the epithelial-mesenchymal transition, partly mediated by nuclear factor of activated T cell 1 | [185] |
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Nonflavonoids | Resveratrol | Grapes, berries, red wine | HepG2 cells; xenograft model | Inhibit invasion and metastasis | Reducing MMP-9 via downregulation of NF-κB signaling pathway; regulating HGF-c-Met signaling pathway | [186, 187] |
Theaflavins | Black tea | HepG2 and orthotopic model | Induce apoptosis; inhibit the growth and metastasis | Induce apoptosis by activating the caspase pathway; suppress the growth and metastasis through the blockage of STAT3 pathway | [188] |
(−)-Oleocanthal | Extravirgin olive oil | HCC cells; orthotopic HCC model | Inhibit growth and metastasis | Inhibiting STAT3 activation by decreasing JAK1 and JAK2 and enhancing SHP-1 | [189] |
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Anticarcinogenesis |
Flavonols | Quercetin | Berries, apples, broccoli, beans, and tea | HepG2 cells | Anticarcinogenesis | Upregulation of p53 and BAX via downregulation of ROS, PKC, PI3K, and COX-2 | [190] |
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Flavanols | EGCG | Tea | | Anticarcinogenesis | Regulation of self-renewal Wnt/beta-catenin, Hh/Gli1 pathways and their associated genes cyclin D1, cMyc, and EGFR along with downregulation of E-cadherin | [146] |
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Flavonoid | Myricetin | Vegetables, fruits, nuts, berries, tea, and red wine | Animal with DEN-induced HCC | Inhibit the development of HCC | Inhibiting PAK1 via coordinate abrogation of MAPK/ERK and PI3K/AKT and their downstream signaling Wnt/β-catenin pathway | [191] |
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Nonflavonoids | Ellagic acid | Pomegranate, grapes, berries, walnuts, chocolate, wine, and green tea | Rats with N-nitrosodiethylamine-induced HCC | Anticarcinogenesis | Removing free radicals, preventing DNA fragmentation | [192] |
Curcumin | Ginger family | | Anticarcinogenesis | Suppressing the protein expression of glypican-3, VEGF, and prothrombin | [86] |
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