|
| Ref. | Country | Article | Plant family/species | Used part of plant | Flavonoids type | Extraction and purification method | In vitro assay | Animal model/strain | Sex | Age/weight | Administration/
frequency | Induction of carcinoma concentration/
volume | Tumor measurement/
frequency | In vivo analysis |
|
| Wan et al., 2014 [15] | China | Preparation of morusin from Ramulus mori and its effects on mice with transplanted H22 hepatocarcinoma | Moraceae/Ramulus mori | Root bark | Isoprenylated flavone (morusin) | Ethanol extraction/Sephadex gel LH-20 and RF-HPLC | ? | Mice/SPF ICR | ♂ | 3–5 weeks/18–20 g | Intraperitoneal/
daily for 10 days | Transplanted H22 cells
1 × 107 cells/ml/0.1 ml | Weight of tumor/2 weeks | H&E, qRT-PCR (P53, survivin, cyclin D1, caspase-3, NF-Kβ) |
|
| Shu et al., 2014 [16] | China | Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling | Leguminosae/
Sophora flavescens | Root | Kushenol H, kurarinol, norkurarinol, kushenol N, kurarinone | Ethanol extraction, HPLC and Sephadex LH-20 column | HepG2, Huh-7, Bel-7402 cells humans, HL-7702, H22 cells mouse | Mice/Kunming | ♂ | ?/18–22 g | Intraperitoneal/
daily for 10 days | Transplant of H22 cells
1 × 106 cells/ml/? | Weight of tumor/experiment end | Serum (white blood, red blood cells, platelets, ALT, AST, BUN, uric acid, and CK), TUNEL, immunohistochemistry (STAT3) |
|
| Wang et al., 2014 [17] | China | Liquiritigenin induces tumor cell death through mitogen-activated protein kinase- (MPAKs-) mediated pathway in hepatocellular carcinoma cells | ?/Glycyrrhiza radix | ? | Liquiritigenin (LQ) | Purchased | PLC/PRF/5, HepG2 human cells | Mice/BALB/cA nude | ♂ | 5 weeks/? | Intraperitoneal/
daily for 18 days | Transplanted PLC/PRF/5
5 × 107 cells/ml/0.1 ml | Volume and diameters of tumor (mm3), body weight/every day | ? |
|
| Zhang et al., 2014 [18] | China | Dihydromyricetin promotes hepatocellular carcinoma regression via a p53 activation-dependent mechanism | ?/Hovenia dulcis | ? | Dihydromyricetin (DHM) | Purchased | HepG2, SMMC-7721, HL7702, L02 cells, primary cell: 4401, 4403, 1204 | Mice/BALB/cA nude | ♂ | 8–10 weeks/? | ?/daily for 21 days | Transplanted HepG2 cells
1 × 107 cells/ml/0.2 ml | ? | Immunohistochemistry (P53) |
|
| Darweish et al., 2014 [19] | Egypt | Chemopreventive and hepatoprotective effects of epigallocatechin gallate against hepatocellular carcinoma: role of heparan sulfate proteoglycans pathway | ?/Camellia sinensis | ? | Epigallocatechin gallate (EGCG) | ? | HepG2 cell | Rats/Sprague Dawley | ♂ | ?/180–200 g | ?/twice for week for 16 days | Thioacetamide (200 mg/Kg b.w.) | ? | H&E, immunohistochemistry (HSPGs), qRT-PCR (FGF-2), in serum (AST, albumin, and bilirubin), enzymatic determination (MDA, SOD, MPO, ELISA MMP-9, HSPGs, AFP, and syndecan-1) |
|
| Zheng et al., 2014 [20] | China/USA | Anticancer effects of Baicalein on hepatocellular carcinoma cells | ?/Scutellaria sp. | Radix | Baicalein | Purchased | MIHAs, H22, BEL-7404, HepG2 cells | Mice/ICR | ♂ | ?/18–22 g | Intraperitoneal/
daily for 12 days | Transplanted H22
2 × 105 cells/ml/0.2 ml | Weight of tumors/experiment end | Immunohistochemistry (AKT, p-AKT Ser473, β-catenin, cyclin D1) |
|
| Fan et al., 2014 [21] | China | Luteoloside suppresses proliferation and metastasis of hepatocellular carcinoma cells by Inhibition of NLRP3 inflammasome | ?/Gentiana macrophylla | ? | Luteoloside | Purchased | Hep3B, SNU-449, Huh-7, SMMC-7721, MHCCLM3, MHCC97-H cell | Mice/BALB/cA nude | ♂ | 6 weeks/? | Oral/daily for 4 weeks (subcutaneous) and 8 weeks (metastasis) groups | Transplanted SMMC-7721
2 × 106 cells 7/0.2 ml | Volume of tumor (cm3)/every 3 to 4 days | H&E |
|
| Feng et al., 2014 [22] | China | Effect of grape procyanidins on tumor angiogenesis in liver cancer xenograft models | ? | Seed | Proanthocyanidins (GPC) | ? | ? | Mice/ SPF Kunming | ? | 4–6 weeks/20 g | Intraperitoneal/
daily for 10 days | Transplanted H22 cells
1 × 106 cell/ml/0.2 ml | ? | Immunohistochemistry (VEGF and CD34), RT-PCR (VEGF and β-actin) |
|
| Zhang et al., 2013 [23] | China | Silybin-mediated inhibition of notch | ?/Silybum marianum | ? | Silybin (SIL) | ? | HepG2 cells | Mice/athymic nude | ♂ | 4–6 weeks/? | Intraperitoneal/5 times for week for 20 days | Transplanted HepG2
1 × 106 cells/ml/? | Size of tumor/every 3 days | Western blot (Notch1, Hes1, RBP-Jκ, survivin, cyclin D1, Bcl2, BAX, β-actin) |
|
| Yang et al., 2013 [24] | China | Antitumor effects of two extracts from Oxytropis falcata on hepatocellular carcinoma in vitro and in vivo | ?/Oxytropis falcata | Whole plant | Flavonoids (FOF) 2′,4′-dihydroxychalcone | Ethanol extraction/? | SMMC-7721 cells | Mice/ICR | ♂ | 5-6 weeks/18–22 g | Intragastric/? | Transplanted H22 cells
5 × 106 cell/ml/0.2 ml | Tumor growth inhibitory ratio/experiment end | ? |
|
| Yu et al., 2013 [25] | China | A study on the antitumor effect of total flavonoids from Pteris multifida poir in H22 tumor-bearing mice | ?/Pteris multifida | Whole plant | Total flavonoids | Ethanol extraction/? | ? | Mice/Kunming | 1/2 ♂ and 1/2 ♀ | ?/18–22 g | Intraperitoneal/
daily for 10 days | Transplanted H22 cell
5 × 107 cells/ml/0.3 ml | Tumor inhibition rate and organ index (spleen and thymus)/experiment end | ELISA (TNF-α and IL-2), enzymatic determination (T-AOC, MDA) |
|
| Xiang et al., 2013 [26] | China | Chemical composition of total flavonoids from Salvia chinensia Benth and their proapoptotic effect on hepatocellular carcinoma cells: potential roles of suppressing cellular NF-kB signaling | ?/Salvia chinensia | Whole plant | Total flavonoids | Alcoholic extraction 95%/HPLC and chromatography in silica gel column | HepG2, Huh-7 HCC cells | Mice/Kunming | ♂ | ?/18–22 g | Intraperitoneal/
daily for 10 days | Transplanted H22 cells
1 × 106 cells/ml/? | Weight of tumor, organ index/experiment end | Automatic counting (red blood cells, hemoglobin, white blood cells, platelets), serum (AST, ALT, BUN, CK, uric acid), ELISA (caspase-3, caspase-8, caspase-9) |
|
| Hashimoto et al., 2014 [27] | Japan | Methylated-(3′′)-epigallocatechin gallate analog suppresses tumor growth in Huh7 hepatoma cells via inhibition of angiogenesis | ?/Camellia sinensis | Green leaves | Polyphenolic, catechin, methylated-(3)-epigallocatechin gallate (MethylEGCG) | Purchased/HPLC purification | HUVECs, Huh7 cells | Mice/BALB/cA nude | ♂ | 6 weeks/20 g | Intraperitoneal/
daily for 21 days | Transplanted Huh7 cells
5 × 106 cell/ml/? | Size, volume of tumor/every week | Immunohistochemistry (CD31) |
|
| Saleem et al., 2013 [28] | India and Saudi Arabia | Anticancer potential of rhamnocitrin 40-b-D-galactopyranoside against N-diethylnitrosamine-induced hepatocellular carcinoma in rats | ?/Astragalus hamosus | Leaves | Flavonol glycoside (rhamnocitrin 40-b-D-galactopyranoside RGP) | MeOH/H2O extraction/column Sephadex LH-20 | ? | Rats/Wistar | ? | ?/150–220 g | Intraperitoneal/
daily for 20 weeks | Single intraperitoneal dose of N-nitrosodiethylamine (NDEA) (200 mg/kg b.w.) | ? | Serum (ALT, AST, ALP, total bilirubin, protein content, LPO), enzymatic determination (SOD, CAT, GPx, GST), H&E |
|
| Monga et al., 2013 [29] | India | Growth inhibition and apoptosis induction by (+)-Cyanidan-3-ol in hepatocellular carcinoma | Fabaceae/Acacia catechu | Heart wood | Cyanidan-3-ol (CD-3) | Ethanol extraction/HPLC | HepG2 cells | Mice/BALB/cA | ♂ | 6-7 weeks/26-27 g | Oral/daily for 20 weeks | Single intraperitoneal dose of NDEA (200 mg/kg b.w.) and carbon tetrachloride (CCl4, 3 ml/kg b.w.) thrice a week for six weeks | Relative liver weight/experiment end | Serum (AST, ALT, ALP, γ-GT, TSA, LASA), enzymatic determination (MDA, SOD, CAT, GPx, GR, GST, T-SH, GSH, PrPr-SHs), H&E, immunohistochemistry (p53, p65, c-jun) |
|
| Zhao et al., 2013 [30] | China | Enhanced 5-fluorouracil cytotoxicity in high COX-2 expressing hepatocellular carcinoma cells by Wogonin via the PI3K/AKT pathway | ?/Scutellaria radix | ? | Wogonin 5,7-dihydroxy-8-methoxyflavone (WOG) | ? | HepG2, SMMC-7721 cells | Mice/BALB/cA nude | ♀ | 35–40 days/18–22 g | Intravenous/once every two days for 10 times | Transplanted SMMC-7721 cells
1 × 106 cells/mouse/? | Tumor inhibitory ratio, weight, size, volume of tumor/experiment end | ? |
|
| Wei et al., 2012 [31] | China | Antitumor and antiangiogenic effects of Macrothelypteris viridifrons and its constituents by HPLC-DAD/MS analysis | ?/Macrothelypteris viridifrons | Air dried roots | 2-(1,4-Dihydroxy-cyclohexyl)-5,7-dihydroxy-chromone-4′-O-glucoside; protoapigenin-4′-O-glucoside; 2-(1,2-dihydroxy-4-oxo-cyclohex-5-enyl)-5,7-dihydroxy-chromone; 5,7,2′,5′-tetrahydroxy-flavanone-2′-O-glucoside; protoapigenin; 2-(1,4-dihydroxy-cyclohexyl)-5,7-dihydroxy-chromone; 5,7,2′,5′-tetrahydroxy-flavanone-2′-O-6′′-O-acetylglucoside; 5,6-dihydro-6-methoxyprotoapigenone; quercetin-3-O-rutinose; protoapigenone; apigenin-4-O-glucoside; kaempferol-3-O-rutinose; kaempferol-3,7-di-O-rhamnoside; kaempferol-3-O-rhamnoside; apigenin-4-O-rhamnoside | ?/HPLC-DAD/MS Amethyst C18-P column | HUVECs, H-22 cells | Mice/Kunming | ♂ | ?/18–22 g | Intraperitoneal/
daily for 10 days | Transplanted H22 cells
2 × 106 cells/ml/0.2 ml | Weight of tumor, tumor inhibitory ratio/experiment end | Serum (red blood cell, white blood cell, platelet and hemoglobin), BUN, CRE, AST and ALT, TSA, LASA, enzymatic determination (MDA, SOD, CAT, GPx, GR, GST, T-SH, GSH, PrPr-SHs), H&E, immunohistochemistry (CD34, VEGF) |
|
| Wu et al., 2011 [32] | Taiwan | Suppression of hepatitis B virus × protein-mediated tumorigenic effects by ursolic acid | Rubiaceae/Morinda citrifolia | Leaves | Ursolic acid and silymarin | ? | Huh7, HepG2, Hep3B cells | Mice/nude | ? | 3 weeks/? | Intraperitoneal/?/8 weeks | Transplanted 6 2.2.15 cells
1 × 106 cell/ml/0.1 ml | Diameters of tumor/experiment end | Serum (ALT, AST, BUN, CRE) |
|
| Wang et al., 2011 [33] | Taiwan | Solanum nigrum L. polyphenolic extract inhibits hepatocarcinoma cell growth by inducing G2/M phase arrest and apoptosis | ?/Solanum nigrum | Whole plant | Total flavonoids | Water extract (SNWE)/? | HepG2 cells | Mice/Athymic nude | ? | ? | Intraperitoneal/?/35 days | Transplanted HepG2 cells
5 × 106 cell/ml/0.4 ml | Volume of tumor/every week, final volume, wet weight of tumor/experiment end | ? |
|
| Cai et al., 2011 [34] | China | Apigenin inhibits hepatoma cell growth through alteration of gene expression patterns | ? | ? | Apigenin | ? | Huh7 cells | Mice/BALB/c nude | ♀ | 5 weeks/16–18 g | Intraperitoneal/?/30 days | Transplanted Huh7 cells
2 × 106 cell/ml/? | Number of tumors, diameters, wet weight of tumor/experiment end | H&E |
|
| Huang et al., 2010 [35] | China | Carbonyl reductase 1 as a novel target of (−)-epigallocatechin gallate against hepatocellular carcinoma | ?/Camellia sinensis | ? | Epigallocatechin gallate (EGCG) | ? | Hep G2, Hep 3B, SMMC-7721 cells | Mice/? | ? | ? | Injected/?/15 days | Transplanted SMMC-7721 cells and Hep3B/?/? | Tumor growth, body weight/? | Serum (ALT, AST, LDH, CK-MBB, LDH, MDA, cTnT) |
|
| Liang et al., 2010 [36] | China and USA | Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer | ?/Camellia sinensis | ? | Catechin and epigallocatechin-3-gallate | ? | BEL-7404, BEL-7404/DOX cells | Mice/ BALB/cA nude | ♂ and ?? | 4-5 weeks/13–17 g | Intraperitoneal/?/33 days | Transplanted BEL-7404/DOX HCC cells
5 × 107 cell/ml/0.2 ml | Dimensions of tumor, volume of tumor/every 2 days, tumor growth, body weight/experiment end | Fluorospectrophotometry (DOX), immunohistochemistry, RT-PCR (MDR1) |
|
| Zhou et al., 2010 [37] | China | Inhibition of hepatoma 22 tumor by liquiritigenin | ?/Glycyrrhiza glabra | ? | Liquiritigenin (LQ) | Purchased | ? | Mice/ICR | ♂ | ?/20–22 g | Intragastric/?/15 days | Transplanted H22 cells
10 × 106 cell/ml/0.2 ml | Size, volume of tumor, body weight/every 3 days, Inhibition ratio of tumor growth, weight of tumor, organ index/experiment end | H&E, electron microscopy (tumor ultrastructure), enzymatic determination (MDA) |
|
| Yang et al., 2009 [38] | China | Antiproliferative efficacy of icariin on HepG2 hepatoma and its possible mechanism of action | ?/Herba epimedii | ? | Icariin (5-hydroxy 4-methoxy 8-isopentenyl 3-O-α-rhamnosyl 7-O-β-glucosyl flavone) | Purchased | HepG2 cells | Mice/NMRI nude | ♂ | ? | Oral/28 weeks | Transplanted HepG2 cells
1 × 107 cell/ml/? | Volume of tumor, tumor growth inhibition/twice per week | Immunohistochemistry (CD4, CD8, CD19) |
|
| Zhao et al., 2010 [39] | China | Synergistic effect of 5-fluorouracil and the flavonoid Oroxylin A on HepG2 human hepatocellular carcinoma and on H22 transplanted mice | ?/Scutellariae Radix | ? | Oroxylin A | ? | HepG2 cells | Mice/Kunming | ♂ | ?/18–22 g | Oral/?/7 days | Transplanted H22 cells
5 × 106 cells/ml/0.9 ml | Volume of tumor/experiment end | ? |
|
| Cui et al., 2009 [40] | USA | Effects and mechanisms of Silibinin on human hepatocellular carcinoma xenografts in nude mice | ?/Silybum marianum | ? | Silibinin | ? | HuH7 cells | Mice/nude | ? | ? | Oral/?/5 weeks | Transplanted HuH7 cells
5 × 106 cell/ml/0.25 ml | Volumes of tumor/every week, weight of tumor/experiment end | Immunoprecipitation (AFP, PTEN, binding interaction between p21, p27 with CDK4, binding of DP1 with E2F1), Western blotting (Ki-67, p21, p27, E2F1, CDK4, p-Rb, caspase-3, caspase-9, PTEN, AC-H3, AC-H4, p-AKT, p-survivin and p-ERK, Plk1, Chk1, SOD1), ELISA (NF-kB) |
|
| Umarani et al., 2008 [41] | India | Protective effect of Kalpaamruthaa in combating the oxidative stress posed by aflatoxin B1-induced hepatocellular carcinoma with special reference to flavonoid structure-activity relationship | Anacardiaceae/
Semecarpus anacardium | Fruit | Flavonoids | Dried and powdered fruit/? | ? | Rats/? | ♂ | 8–10 weeks/120–150 g | Oral/?/28 days | Intraperitoneal dose of AFB1 (2 mg/kg b.w.) | ? | Serum (protein, LPO, lipid peroxides, G6PD, vitamin E, vitamin C, uric acid), enzymatic determination (SOD, CAT, GPx, GR) |
|
| Miura et al., 2007 [42] | Japan | Effect of apple polyphenol extract on hepatoma proliferation and invasion in culture and on tumor growth, metastasis, abnormal lipoprotein profiles in hepatoma-bearing rats | ?/Malusdomestica | Unripe apples | Apple polyphenol extract (APE) | Purchased | AH109A cells | Rats/Donryu | ♂ | 5 weeks/? | Oral/?/21 days | Transplanted AH109A cells
1 × 107 cells/ml/0.5 ml | Size of tumor/every day | Serum (T-Ch, HDL-Ch), LPO, fecal steroid, AI |
|
| Selvendiran et al., 2006 [43] | Japan | Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids | ? | Seeds | Luteolin | ?/HPLC | HepG2, HLF, HAK-1B, IMR-32 cells | Mice/BALB/cA nude | ♂ | 5 weeks/? | Oral/?/6 weeks | Transplanted HAK-1B cells
1 × 107 cell/ml/? | Size, volume (mm3) of tumor/weekly | Immunoblotting (Tyr705-P-STAT3) |
|
| Nishikawa et al., 2006 [44] | Japan | A green tea polyphenol, epigallocatechin-3-gallate, induces apoptosis of human hepatocellular carcinoma, possibly through inhibition of Bcl-2 family proteins | ?/Camellia sinensis | ? | Epigallocatechin-3-gallate | ? | HLE, HepG2, HuH-7, PLC/PRF/5 cells | Mice/BALB/cA nude | ♂ | 28 weeks/? | Oral/?/25 days | Transplanted HLE cells
1 × 106 cell/ml/? | Volume of tumor/daily | TUNEL, immunohistochemistry (Bcl-2a, Bcl-xl) |
|
| Premalatha and Sachdanandam, 1999 [45] | India | Semecarpus anacardium L. nut extract administration induces the in vivo antioxidant defense system in aflatoxin B1 mediated hepatocellular carcinoma | ?/Semecarpus anacardium L | Nuts | Total flavonoids | Purchased | ? | Rat/Wistar | ♂ | ?/100 g | Oral/?/14 days | Single intraperitoneal dose of AFB1 (2 mg/kg b.w.) | Weight of liver and kidney/experiment end | Total protein, enzymatic determination (GSH, uric acid, vitamin E, vitamin C, CYP, T-SH, NPSH) |
|
| Nishida et al., 1994 [46] | Japan | Inhibitory effects of (−)-epigallocatechin gallate on spontaneous hepatoma in C3H/HeNCrj mice and human hepatoma-derived PLC/PRF/5 cells | ?/Camellia sinensis | ? | Epigallocatechin gallate (EGCG) | ? | PLC/PRF5 cells | Mice/C3H/HenCrj | ♂ | 8 weeks/? | Oral/?/65 weeks | Spontaneous hepatocarcinogenesis | # of tumor, diameter of liver/experiment end | H&E, albumin, bilirubin, GPT, γ-GT, total cholesterol |
|
| Zhang et al., 2002 [47] | Japan | Effects of dietary powdered green tea and theanine on tumor growth and endogenous hyperlipidemia in hepatoma-bearing rats | ?/Camellia sinensis | ? | ? | ? | ? | Rat/Donryu | ♂ | 4 weeks/? | Oral/?/14 days | Transplanted AH109A cells
5 × 105 cell/ml/0.5 ml | Size, volume, diameter of tumor, radius tumor/every day, weight of tumor/experiment end | Precipitation method (HDL, LDL, VLDL), enzymatic determination (T-Ch and HDL-ChM, TBARS), fecal extraction (neutral sterol, bile acid) |
|
| Klaunig, 1992 [48] | USA | Chemopreventive effects of green tea components on hepatic carcinogenesis | ?/Camellia sinensis | ? | Epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate | Methanol extraction/steel column with silicic acid | Primary cells mouse hepatocytes | Rat/B6C3F1 | ♂ | ? | Oral/?/28 weeks | Single intraperitoneal dose NDEA (90 mg/kg b.w.) | ? | H&E |
|
