Table 3.

The effects and underlying mechanisms of polyphenols against liver cancer.

Classification	Polyphenols	Natural sources	Cell types/animal models	Effects	Involved mechanisms	Ref.
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]
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]
Isoflavones	Puerarin	Root of Pueraria	SMMC-7721 HCC cells	Induce apoptosis	Regulating MAPK pathways	[161]
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]
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]
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]
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]
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]
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]
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]
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]
Nonflavonoids	Resveratrol	Grapes, berries, red wine	HCC xenograft animal model	Antiangiogenesis	Inhibiting VEGF expression through a NF-κB-mediated mechanism	[145]
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]
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]
Flavonol	Galangin	Alpinia officinarum and Helichrysum aureonitens	HepG2 cells	Inhibit metastasis	Protein kinase C (PKC)/ERK signaling pathway	[183]
Flavanols	EGCG	Tea	MHCC-97H and HepG2 cells	Inhibit metastasis	Reduce osteopontin by decreasing the half-life of osteopontin mRNA	[184]
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]
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]
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]
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]
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]
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]