Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma

Table 1

EGCG in HCC with possible mechanisms discussed in this paper.

Subfamily	Flavonoids	Typical origin	In vitro/in vivo; Cell lines/modes; Effective dose	Effects and related mechanisms	Author (year); References
Flavonol	EGCG	Green tea; red grapes and red wines	In vitro/in vivo; HepG2/SD rats by thioacetamide; 20 mg/kg/N/A	↓ α-FP restoration of heparin sulfate proteoglycans receptors, ↓ vascular invasion via ↓ MMP-9, ↓ syndecan-1 ↓ FGF-2, and ↓ fibrosis	Darweish et al. (2014) [36]
			In-vitro; Acrylamide-induced HepG2 cells; 10 M	↓ CYP2E1, ↓ EGFR, ↓ cyclin D1 and ↓ NF-B ↓ growth by affecting the cell cycle, and ↑ apoptosis	Shan et al. (2014) [17]
			In vitro; HepG2, SMMC7721 and SK-hep1 cells; IC50 74.7, 59.6, and 61.3 g/mL	↑ apoptosis by ↓ PI3K/AKT activity, ↓ NF-B, and ↑ S phase arrest (in SMMC7721 cells)	Shen et al. (2014) [33]
			In vitro; HepG2 cells; 70 g/mL	↑ TRAIL-induced apoptosis via ↑ caspase-3 activity, ↑ DR4 ↑ DR5 expression, and ↓ Bcl-2 expression and ↓ c-FLIP expression level	Abou El Naga et al. (2013) [85]
			In vitro; BEL-7402 and QGY-7703; 40 M	↓ STAT3 signaling pathway. ↓ Bcl-xL, ↓ c-Myc, ↓ VEGF, and ↓ cyclin D1	Wang et al. (2013) [86]
			In vitro; HCCLM6 cells; dose-dependent (10–100 g/mL)	↑ apoptosis, ↓ metastasis via ↓ MMP-2, ↓ MMP-9; ↓ HSP1, and ↓ chaperonin	Zhang et al. (2013) [18]
			In vitro; HepG2 cells; 100 g/mL	↓ EP(1) receptor expression and ↓ PGE(2) production	Jin et al. (2012) [87]
			In vitro; HepG2 cells; 100 M	↑ apoptosis and ↓ Bcl-2 and ↑ miR-16	Tsang and Kwok (2010) [34]
			In vitro; HEP-3B; 10 M	↓ thrombin-induced HCC invasion and p42/p44-MAPKinase activation	Kaufmann et al. (2009) [15]
			In vitro; p53 positive Hep G2 and p53 negative Hep 3B cells; 80 M	↑ AMPK, ↓ mTOR, ↓ 4E-BP1, ↓ mRNA translation, ↓ FASN, and ↓ ACC	Huang et al. (2009) [88]
			In vitro/in vivo; HuH7 cells/nude mouse xenograft model; 25 g/mL, time dependent; 0–100 g/mL, dose dependent/0.01%–0.1%	↓ VEGF2, ↓ p-VEGFR-2; ↓ ERK and Akt, and ↓ Bcl-x(L)	Shirakami et al. (2009) [89]
			In vitro; BEL7404/ADM cells, BEL7402/5-FU cells; IC10 24.76 mg/L, 20.60 mg/L; IC50 3.85 mg/L, 2833.62 mol/L	↓ MDR in HCC, ↓ MDR1, ↓ LRP expression, and ↑ cyclin G1 expression	Tang et al. (2008) [90]
			In vitro; HepG2, SMMC-7721; 100–400 g/mL	↓ COX-2, ↓ Bcl-2 (over 200 μg/mL); ↑ caspase-9 and ↑ caspase-3 (100 and 200 μg/mL for 12 h)	Chen et al. (2008) [16]
			In vitro; HepG2; 20 g/mL	↓ IGF/IGF-1 receptor dependent signaling pathway by ↑ apoptosis, ↓ p-IGF-1R protein, ↓ p-ERK, ↓ p-Akt, ↓ p-Stat-3, and ↓ p-GSK-3 proteins; ↓ IGF-1, IGF-2, and ↑ IGFBP-3	Shimizu et al. (2008) [32]
			In vitro; SK-Hep-1 cells; 20 g/mL	↓ tumor invasion and migration via ↓ MMP-9 and MMP-2	Sang et al. (2007) [91]
			In vitro/in vivo; HLE cells/BALB/c nude mice; 0–100 g/mL/0.8, 2.5 and 7.5 mg/mL	↑ apoptosis in HLE cells via ↓ Bcl-2, ↓ Bcl-xl ↓ NF-B; ↑ TRAIL-induced apoptosis	Nishikawa et al. (2006) [75]
			In vitro; HepG2; 50 mol/L	↓ hypoxia induced HIF-1 protein; ↓ VEGF; ↓ PI3/Akt/mTOR pathways, and ↓ ERK 1/2 signaling pathways	Zhang et al. (2006) [92]

↑: Intensify; ↓: attenuate; N/A: none available; EGCG: (−)-epi-gallocatechin-3-gallate; SD rats: Sprague Dawley rats; DEN: diethylnitrosamine; MMP: matrix metalloproteinase; TIMP: metallopeptidase inhibitor 1; FGF: fibroblast growth factor; EGFR: epidermal growth factor receptor; CYP: cytochrome; PKCα: protein kinase C-alpha; EMT: epithelial-mesenchymal transition; IB-: I-kappa-; PI3: phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homolog; NFAT1: nuclear factor of activated T cells 1; DR: death receptor; TRAIL: tumor necrosis factor-related apoptosis inducing ligand; c-FLIP: cellular FLICE inhibitory protein; STAT3: signal transducer and activator of transcription 3; VEGF: vascular endothelial growth factor; EP(1): prostaglandin E receptor 1; MAPK: p38-beta mitogen-activated protein kinase; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; 4E-BP1: eukaryotic initiation factor 4E-binding protein-1; FASN: fatty acid synthase; ACC: acetyl-CoA carboxylase; ERK: extracellular signal regulated kinases; MDR: multidrug resistance; LRP: lung resistance protein; IGF: insulin-like growth factor; GSK-3: glycogen synthase kinase-3; HIF-1: hypoxia-inducible factors; IGFBP-3: insulin-like growth factor binding protein-3; ER: endoplasmic reticulum; UPR: unfolded protein response; JNK: c-Jun N-terminal kinases; MTP: mitochondrial transmembrane potential; CAM-DR: cell adhesion mediated drug resistance; MDR: multidrug resistance; MAC: mitochondrial apoptosis-induced channel; AIF: apoptosis-inducing factor; 5-FU: 5-fluororuracil; PARP: poly ADP-ribose polymerase; AP-1: activator protein 1; ATO: arsenic trioxide; FAK: focal adhesion kinase; CDK: cyclin-dependent kinases; GRP: glucose-regulated protein; CHOP: C/EBP-homologous protein; ROS: reactive oxygen species; DOX: doxorubicin; HSP: heat shock proteins; PKC-: protein kinase C-alpha; -FP: alpha-fetoprotein; CPK: checkpoint kinase 1; SOD: superoxide dismutase; HIF: hypoxia-inducible factor; GSH: glutathione; T-AOC: total antioxidant capability; AC-H: acetylation of histone H.