Background
Methods
Identification of studies
Selection criteria
Study characteristics and data extraction
Quality of evidence and risk of bias
Data synthesis and statistical analysis
Results
Search results
Study characteristics and quality assessment
Author, year, country | Species, strain, gender, age | Model cell line | Experiment | Control | Outcome | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Dosage | Frequency | Adnimistration | Duration | type | mean0 | Sd0 | n0 | mean1 | Sd1 | n1 | p value | ||||
Breast cancer | |||||||||||||||
Elisa Pierpaoli, 2015, Italy [10] | mice, FVB/N, F, 4w | SK-BR-3 | 2.5 mg/kg | biw | ip | 32.5w | DMSO | VD | 16.81 | 7.24 | 10 | 12.09 | 1.98 | 10 | 0.07 |
Yuwan Zhao, 2017, China [11] | mice, BALB/c, F, 6w | MDA-MB-231 | 100 mg/kg | tiw | po | 3w | DMSO | TV | 2.70 | 0.18 | 7 | 0.68 | 0.08 | 7 | < 0.01 |
BW | 24.40 | 0.69 | 7 | 22.48 | 0.81 | 7 | < 0.01 | ||||||||
Alaa Refaat, 2013, Japan [12] | mice, BALB/c, F, 6w | 4 T1 | 100 mg/kg | qd | po | 4.3w | CMC | TW | 0.21 | 0.01 | 6 | 0.15 | 0.01 | 6 | < 0.01 |
Sangmin Kim, 2018, Korea [13] | mice, Balb/c, F, 6-8w | MDA-MB-231 | 0.1% BBR in the drinking water | Daily free intake | po | 6.6w | – | TV | 0.42 | 0.18 | 5 | 0.21 | 0.08 | 5 | 0.05 |
Kalyani Chowdary Karnam, 2017, India [14] | rats, SD, F, 6.4–8.3w | Induced by DMBA | 50 mg/kg [pretreatment] | tiw | po | 4w | Corn oil | TV | 3.79 | 0.90 | 6 | 0.63 | 0.30 | 6 | < 0.01 |
TW | 9.64 | 0.90 | 6 | 3.80 | 0.99 | 6 | < 0.01 | ||||||||
50 mg/kg [posttreatment] | TV | 3.79 | 0.90 | 6 | 1.31 | 0.60 | 6 | < 0.01 | |||||||
TW | 9.64 | 0.90 | 6 | 5.71 | 1.32 | 6 | < 0.01 | ||||||||
Elisa Damiani, 2015, Italy [15] | miceFVB/NF4w | HER2/neu transgenic mice | 2.5 mg/kg | biw | ip | NR | Sterile saline | VD | 16.77 | 5.31 | 7 | 11.07 | 1.75 | 9 | 0.03 |
Ke Su, 2016, China [16] | mice, Balb/c, F, 6w | MDA-MB-231 | 10 mg/kg | q4d | ip | 3w | DMSO | TV | 0.59 | 0.27 | 6 | 0.27 | 0.12 | 6 | 0.02 |
TW | 0.50 | 0.11 | 6 | 0.29 | 0.06 | 6 | < 0.01 | ||||||||
BW | 22.59 | 7.31 | 6 | 19.10 | 3.71 | 6 | 0.32 | ||||||||
Liver cancer | |||||||||||||||
Guan-Yu Wang, 2009, China [17] | mice, Balb/c, M, 6w | HEPG2 | 40 mg/kg | qd | ip | 1.4w | Saline | TV | 3.31 | 0.38 | 5 | 2.21 | 0.22 | 6 | < 0.01 |
BW | 3.13 | 0.43 | 5 | 4.62 | 0.41 | 6 | < 0.01 | ||||||||
80 mg/kg | TV | 3.31 | 0.38 | 5 | 1.43 | 0.13 | 5 | < 0.01 | |||||||
BW | 3.13 | 0.43 | 5 | 3.74 | 0.36 | 5 | 0.04 | ||||||||
Jing Li, 2015, Canada [18] | mice, Balb/c, NR, 6-8w | H22 | 50 mg/kg | qd | po | 2w | Water | TV | 4.24 | 0.56 | 10 | 0.33 | 0.35 | 10 | < 0.01 |
Chi Man Tsang, 2015, China [19] | mice, NR, NR, NR | MHCC-97 L-luciferase | 10 mg/kg | qod | ip | 5w | Saline | TV | 1.00 | 0.05 | 7 | 0.21 | 0.03 | 7 | < 0.01 |
VD | 12.58 | 2.94 | 7 | 2.18 | 1.29 | 7 | < 0.01 | ||||||||
Colon cancer | |||||||||||||||
Norio Iizuka, 2002, Japan [20] | mice, Balb/c, M, 6w | Colon26/clone 20 | 0.1% BBR in the driNRing water | Daily free intake | po | 2w | – | TW | 0.22 | 0.15 | 9 | 0.25 | 0.12 | 9 | 0.65 |
BW | 18.20 | 1.50 | 9 | 18.40 | 1.80 | 9 | 0.80 | ||||||||
0.2% BBR in the driNRing water | TW | 0.22 | 0.15 | 9 | 0.25 | 0.15 | 9 | 0.68 | |||||||
BW | 18.20 | 1.50 | 9 | 22.20 | 1.50 | 9 | < 0.01 | ||||||||
0.4% BBR in the driNRing water | TW | 0.22 | 0.15 | 9 | 0.24 | 0.18 | 9 | 0.80 | |||||||
BW | 18.20 | 1.50 | 9 | 20.90 | 4.20 | 9 | 0.10 | ||||||||
H Ruan, 2017, China [21] | mice, Balb/c, NR, 6-7w | KM12C/shCtrl | 10 mg/kg | qd | ip | 2w | DMSO | TV | 1.26 | 0.97 | 6 | 0.79 | 0.53 | 6 | 0.32 |
KM12C/shRXRα | 1.54 | 0.92 | 6 | 1.40 | 0.46 | 6 | 0.76 | ||||||||
Yuchen Cai, 2013, Japan [22] | mice, Balb/c, NR, 5w | HT-29 | 10 mg/kg | qd | po | 2w | Sterile water | TV | 6.11 | 3.01 | 10 | 4.33 | 2.42 | 10 | 0.16 |
BW | 6.60 | 3.60 | 10 | 4.90 | 3.20 | 10 | 0.28 | ||||||||
30 mg/kg | TV | 6.11 | 3.01 | 10 | 4.09 | 1.76 | 10 | 0.08 | |||||||
BW | 6.60 | 3.60 | 10 | 3.90 | 2.70 | 10 | 0.07 | ||||||||
50 mg/kg | TV | 6.11 | 3.01 | 10 | 3.34 | 1.31 | 11 | 0.01 | |||||||
BW | 6.60 | 3.60 | 10 | 3.60 | 2.50 | 11 | 0.04 | ||||||||
nasopharyngeal carcinoma | |||||||||||||||
Chao Wang, 2017, China [23] | mice, NOD/SCID, F, 8w | HONE-1 | 10 mg/kg | tiw | ip | 3w | DMSO | TV | 0.58 | 0.06 | 5 | 0.10 | 0.03 | 5 | < 0.01 |
TW | 0.15 | 0.01 | 5 | 0.02 | 0.01 | 5 | < 0.01 | ||||||||
Chi Man Tsang, 2013, China [24] | mice, NR, M, 6-8w | C666–1 | 5 mg/kg | qod | ip | 6w | DMSO | TV | 0.15 | 0.05 | 5 | 0.04 | 0.03 | 5 | < 0.01 |
10 mg/kg | 0.15 | 0.05 | 5 | 0.02 | 0.02 | 4 | < 0.01 | ||||||||
Lung cancer | |||||||||||||||
Michael A. James, 2011, Missouri [25] | mice, Balb/c, M, 4-6w | A549 | 1800 ppm | Daily free intake | po | 4w | DMSO | TV | 0.06 | 0.02 | 3 | 0.02 | 0.02 | 4 | 0.05 |
5400 ppm | 0.06 | 0.02 | 3 | 0.01 | 0.01 | 2 | 0.04 | ||||||||
Santosh K. Katiyar, 2009, Alabama [26] | mice, Balb/c, F, 6-7w | A549 | 50 mg/kg | qd | po | 7w | PBS | TV | 1.40 | 0.07 | 10 | 0.99 | 0.04 | 10 | < 0.01 |
TW | 2.32 | 0.27 | 10 | 2.02 | 0.30 | 10 | 0.03 | ||||||||
100 mg/kg | TV | 1.40 | 0.07 | 10 | 0.60 | 0.03 | 10 | < 0.01 | |||||||
TW | 2.32 | 0.27 | 10 | 1.16 | 0.21 | 10 | < 0.01 | ||||||||
200 mg/kg | TV | 1.40 | 0.07 | 10 | 0.30 | 0.06 | 10 | < 0.01 | |||||||
TW | 2.32 | 0.27 | 10 | 0.62 | 0.09 | 10 | < 0.01 | ||||||||
H1299 | 50 mg/kg | TV | 1.59 | 0.10 | 10 | 1.36 | 0.05 | 10 | < 0.01 | ||||||
TW | 2.71 | 0.31 | 10 | 2.36 | 0.29 | 10 | 0.02 | ||||||||
100 mg/kg | TV | 1.59 | 0.10 | 10 | 1.05 | 0.05 | 10 | < 0.01 | |||||||
TW | 2.71 | 0.31 | 10 | 1.82 | 0.29 | 10 | < 0.01 | ||||||||
200 mg/kg | TV | 1.59 | 0.10 | 10 | 0.61 | 0.02 | 10 | < 0.01 | |||||||
TW | 2.71 | 0.31 | 10 | 1.15 | 0.10 | 10 | < 0.01 | ||||||||
Gastric cancer | |||||||||||||||
Junxiong Wang, 2016, China [27] | mice, Balb/c, F, 5w | BGC823 | 50 mg/kg | qd | po | 4w | NR | TV | 2.28 | 0.24 | 3 | 0.73 | 0.13 | 3 | < 0.01 |
TW | 1.37 | 0.37 | 3 | 0.32 | 0.08 | 3 | < 0.01 | ||||||||
BW | 2.51 | 0.69 | 3 | 0.10 | 0.46 | 3 | < 0.01 | ||||||||
Hongli Li, 2016, China [28] | mice, Balb/c, M, 4w | MGC803 | 15 mg/kg | qd | po | 3.3w | NR | TV | 0.85 | 0.29 | 6 | 0.44 | 0.09 | 6 | 0.02 |
TW | 0.68 | 0.18 | 6 | 0.42 | 0.07 | 6 | < 0.01 | ||||||||
Neuroepithelial tumor | |||||||||||||||
Juan Wang, 2015, China [29] | miceBalb/cNN | – | 100 mg/kg | qd | po | 3w | NR | TV | 0.04 | 0.02 | 8 | 0.02 | 0.00 | 8 | 0.05 |
Yuxue Sun, 2018, China [30] | miceBalb/cN6-8w | C6 | 10 mg/kg | qd | ip | 1w | DMSO | TV | 0.77 | 0.22 | 7 | 0.35 | 0.06 | 7 | < 0.01 |
Endometrial carcinoma | |||||||||||||||
Yu Wang, 2018, China [31] | mice, Balb/c, NR, 6w | HEC-1-A | 50 mg/kg | qd | po | 4w | DMSO | TV | 1.01 | 0.13 | 6 | 0.65 | 0.06 | 6 | < 0.01 |
100 mg/kg | 1.01 | 0.13 | 6 | 0.34 | 0.04 | 6 | < 0.01 | ||||||||
Esophageal cancer | |||||||||||||||
Kewei Ren, 2016, China [32] | mice, Balb/c, M, 6-8w | Eca9706 | 20 mg/kg | qd | po | 7w | DMSO | TV | 6.37 | 0.25 | 5 | 5.05 | 0.60 | 5 | < 0.01 |
TW | 2.66 | 0.29 | 5 | 1.82 | 0.21 | 5 | < 0.01 | ||||||||
Tongue squamous cell carcinima | |||||||||||||||
Yung-Tsuan Ho, 2009, China [33] | mice, Balb/c, F, 6w | SCC-4 | 10 mg/kg | q4d | ip | 4w | DMSO | TV | 0.18 | 0.06 | 6 | 0.03 | 0.02 | 6 | < 0.01 |
TW | 0.26 | 0.16 | 6 | 0.12 | 0.09 | 6 | 0.11 | ||||||||
Cholangiocarcinoma | |||||||||||||||
Nattapong Puthdee, 2013, Japan [34] | hamster, Syrian, M, 4-5w | Ham-1 | 10 mg/kg | qd | po | 3w | sterile water | TW | 0.70 | 0.18 | 5 | 0.67 | 0.11 | 5 | 0.79 |
Sarcoma | |||||||||||||||
Lei Zhang, 2012, China [35] | mice, Kunming, NR, 6w | S180 | 30 mg/kg | qd | ip | NR | NR | TW | 2.20 | 0.93 | 10 | 1.26 | 0.54 | 9 | 0.02 |
BW | 2.71 | 2.20 | 10 | −2.54 | 3.24 | 9 | < 0.01 |
Tumor volume
Tumor weight
Tumor vessel density
Body weight
Publication bias and sensitivity analysis
Molecular pathways and proteins
Molecular Pathway | Proteins | Functional clustering |
---|---|---|
Breast cancer | ||
↑ caspase-9/cytochrome c-mediated apoptosis [11]; TRAIL(TNF-related apoptosis-inducing ligand)-mediated apoptosis [12] ↓ cell proliferation [14] | Proliferation(including apoptosis) | |
↑ intracellular reactive oxygen species (ROS) levels [14] | ↑ MDA [14] ↓ SOD, CAT, GSH, Vit-C [14] | Intracellular oxidative stress |
↓ inflammation [14] | ↓ IL-1β, IL-6, TNF-α, NF-kB [14] | Inflammation |
↓TGF-β1, MMP-2, MMP-9 [13] No effect: VASP [16] | Migration | |
Liver cancer | ||
↑ Fas-mediated apoptosis [17] | ↑Fas, P53, caspase-3, caspase-8, caspase-9 [17] No effect: caspase-3, caspase-9 [18] | Proliferation(including apoptosis) |
↓ Id-1-induced angiogenesis [19] | ↓ Id-1, VEGF, HIF-1α [19] | Angiogenesis |
↓ Id-1-induced migration [19] | ↓Id-1 [19] | Migration |
Colon cancer | ||
↑ c-Cbl, p21WAF1/CIP1 [21] | Proliferation(including cell cycle arrest) | |
Nasopharyngeal carcinoma | ||
↑ Cleaved PARP [24] | Proliferation | |
Lung cancer | ||
↓cell proliferation via MAPK pathways [25] | Proliferation(including apoptosis and cell cycle arrest) | |
Gastric cancer | ||
↑ apoptosis and cell cycle arrest via inhibiting EGFR signaling [27] ↓ cell proliferation via MAPK pathways [28] | Proliferation(including apoptosis and cell cycle arrest) | |
Neuroepithelial cancer | ||
↑ ERK1/2-mediated impairment of mitochondrial aerobic respiration and autophagy [30] ↓cancer growth by suppressing Hedgehog signaling pathway [29] | ↑ C-parp-1, LC3II [30] | Proliferation(including autophagy) |
Endometrial carcinoma | ||
↓ cell growth via miR-101/COX-2 [31] | ↓ COX-2, PGE2 [31] | Proliferation |
↓ cell metastasis via miR-101/COX-2 [31] | ↓ COX-2, PGE2 [31] | Migration |
Esophageal cancer | ||
↑ cell growth inhibition, apoptosis and cell cycle arrest at G2/M phase [32] | ↑ P21, P27, P53, cleaved-PARP, caspase-3, Bax [32] ↓ PI3K, Rac, p-JAK2, p-STAT3, Wnt3a, β-catenin, Bcl-2, Mcl-1, XIAP, Ki-67, cyclin B, cyclin D, cyclin E, CDK1, CDK2, CDK4, CDK6 [32] | Proliferation(including apoptosis and cell cycle arrest) |
Cholangiocarcinoma | ||
↑ G1 cell cycle arrest [34] ↓ cell proliferation [34] | ↓ PCNA, cyclin D1, cyclin E [34] | Proliferation(including cell cycle arrest) |
Functional clustering | Molecular Pathway | Proteins |
---|---|---|
Proliferation(apoptosis) | Breast cancer: ↑ caspase-9/cytochrome c-mediated apoptosis [11]; TRAIL(TNF-related apoptosis-inducing ligand)-mediated apoptosis [12] Lung cancer: ↑ P53-Induced growth inhibition and apoptosis [26] Gastric cancer: ↑ apoptosis via inhibiting EGFR signaling [27] Esophageal cancer: ↑ cell growth inhibition and apoptosis [32] | ↑ caspase-3 [11, 12, 17, 26, 32]; P53 [12, 17, 25, 26, 32]; Bax [11, 26, 32]; caspase-9 [11, 17]; PARP [12, 32]; ClvC-3, Ligase4 [11]; Fas [17]; caspase-8 [17]; Bak [26]; P21, P27 [32] ↓ Bcl-2 [11, 26, 32]; Mcl-1 [12, 32]; Bcl-xl [26, 28]; pERK [27, 28]; pSTAT3 [28, 32]; P65 [12]; PGE2, cPLA2, COX-2 [18]; pAKT, pNFκB, NFκB [28]; PI3K, Rac, p-JAK2, Wnt3a, β-catenin, XIAP, Ki-67 [32] No effect: caspase-3, caspase-9 [18] |
Proliferation(autophagy) | Neuroepithelial cancer: ↑ ERK1/2-mediated impairment of mitochondrial aerobic respiration and autophagy [30] | ↑ C-parp-1, LC3II [30] ↓ Ki-67, p-ERK1/2 [30] |
Proliferation(cell cycle arrest) | Colon cancer: ↓ cell proliferation by inducing the G2/M phase arrest and down-regulated the expression of the related cyclins [22] Lung cancer: ↑ G1 cell cycle arrest [25] Gastric cancer: ↑ cell cycle arrest via inhibiting EGFR signaling [27] Esophageal cancer: ↑ cell cycle arrest at G2/M phase [32] Cholangiocarcinoma: ↑ G1 cell cycle arrest [34] | |
Proliferation(others) | Breast cancer: ↓ cell proliferation [14] Liver cancer: ↓ Id-1-induced cell proliferation [19] Colon cancer: ↓ β-catenin - induced proliferation by binding RXR [21] Nasopharyngeal carcinoma: ↓ cell proliferation via an Epstein-Barr virus nuclear antigen 1(EBNA1)-dependent mechanism [23]; ↓ cell proliferation by inhibiting STAT3 activation [24] Lung cancer: ↓cell proliferation via MAPK pathways [25] Gastric cancer: ↓ cell proliferation via MAPK pathways [28] Neuroepithelial cancer: ↓cancer growth by suppressing Hedgehog signaling pathway [29] Endometrial carcinoma: ↓ cell growth via miR-101/COX-2 [31] Cholangiocarcinoma: ↓ cell proliferation [34] | |
Intracellular oxidative stress | Breast cancer: ↑ intracellular reactive oxygen species (ROS) levels [14] | ↑ MDA [14] ↓ SOD, CAT, GSH, Vit-C [14] |
Inflammation | Breast cancer: ↓ inflammation [14] | ↓ IL-1β, IL-6, TNF-α, NF-kB [14] |
Angiogenesis | Liver cancer: ↓ Id-1-induced angiogenesis [19] | ↓ Id-1, VEGF, HIF-1α [19] |
Migration | Breast cancer: ↓ TGF-β1-induced cell migration [13]; vasodilator-stimulated phosphoprotein (VASP)-induced cell migration [16] Liver cancer: ↓ Id-1-induced migration [19] Endometrial carcinoma: ↓ cell metastasis via miR-101/COX-2 [31] | No effect: VASP [16] |