Review
Copyright ©The Author(s) 2020.
World J Gastroenterol. Jun 21, 2020; 26(23): 3170-3181
Published online Jun 21, 2020. doi: 10.3748/wjg.v26.i23.3170
Table 1 Chemopreventive activities of urolithin A against colorectal cancer
Cell lineMechanismRef.
SW620↓Proliferation, MMP-9 activityZhao et al[21]
↑Autophagy, LC3
G2/M arrest
↑Apoptosis, necrosis
HT-29↓ProliferationCho et al[22]
↑Apoptosis, necrosis
G2/M arrest
↑p21 expression
↓MMP, ↑caspase 8 and 9 activity
HT-29↓ProliferationKasimsetty et al[23]
↓G0/G1 ↑G2/M, G0
↓CYP1 activity
↑Apoptosis, caspase-3 like activity
HT-29↓ProliferationTortora et al[24]
Caco-2CYP1A1, UGT1A10González-Sarrías et al[25]
CYP1A1 activity
1Caco-2, HT-29, SW480↓ProliferationGonzález-Sarrías et al[26]
S arrest (SW480, Caco-2)
G2/M arrest
Gene expression in Caco-2:
ABCG2, TP53, c-MYC, CDKN1A, BIRC5
Gene expression in SW480:
↑c-MYC, CDKN1A, BIRC5, CASP3, EGFR
CTNNB1
Gene expression in HT-29:
CDKN1A
Caco-2, HT-29, SW480↓ProliferationGonzález-Sarrías et al[27]
G2/M (Caco-2, SW480, HT-29)
S (SW480, HT-29) arrest
HCT-116, Caco-2, HT-29↓Colony formationGiménez-Bastida et al[28]
G2/M arrest (Caco-2, HCT-116)
↑Senescence-associated β–galactosidase activity (HCT-116)
↑p53 and p21Cip1/Waf1 expression (HCT-116)
1CSCs (Caco-2 and primary human colon tumor cells)Caco-2:Núñez-Sánchez et al[29]
↓Colonosphere number
↓ALDHhigh cells
Primary human colon tumor cells:
↓Colonosphere number
↓Colonosphere size
↓ALDHhigh cells
HCT116↓Cell growthNorden et al[32]
p53, p21, TIGAR expression
↑p53, p21, TIGAR expression
Caco-2, HT-29, SW480↓ProliferationGonzález-Sarrías et al[33]
↑5-FU- and 5’-DFCR-induced cytotoxicity
G2/M arrest (Caco-2, SW480)
↑Caspase 9 activity (Caco-2)
Caco-2NS cell vitalityKojadinovic et al[36]
↓ROS
↓CAT activity
NS SOD and GPx activity
Caco-2↓ProliferationGonzález-Sarrías et al[37]
Kinase signaling pathway gene expression: ↓FGFR2, ↑DUSP6, c-MYC, Fos, CD44
Human tissue samples /pomegranate extract↓CD44, CTNNB1 CDKN1A, EGFR, TYMSNuñez-Sánchez et al[29,38]
Table 2 Anti-inflammatory activity of urolithin A relevant to the intestine
Cell line/modelMechanismRef.
CCD18-Co/cytokine-induced inflammation IL-1β or TNF-α↓IL-1β-induced PGE2 levelGiménez-Bastida et al[41]
↓IL-1β or TNF-α -stimulated migration
↓non-stimulated migration
↓IL-1β-stimulated adhesion
↑TNF-α -decreased cell viability
↓IL-1β or TNF-α -induced expression of members of the EGF, PGF, PDGF, VEGF, M-CSF, and IGF families
↓IL-1β -induced PAI-1 and TNF-α -induced IL-8 levels
Fischer rats/DSS-induced colitis↑HCT, RBCsLarrosa et al[42]
↓Loss of epithelium, total histological scores
↑Bifidobacteria
E. coli, enterobacteria, and total aerobic bacteria CAT activity
↓NO, iNOS
↓PGE2, COX-2, PTGES
Rb1, p53CD40, IL-1β and IL-4
C57BL/6 x FVB F1/BRB intervention↑Shannon diversity indexGu et al[44]
↑Bacteroidetes, Barnesiella
↓Firmicutes, Clostridium, Turicibacter, Lactobacillus
BMDMs/LPS↓IL-6, TNF-α levelSingh et al[45]
C57BL/6 mice↓LPS-induced serum level of IL-6, TNF-αSingh et al[45]
↑Colonic and hepatic Cyp1A1 activity in WT not in AhR−/− mice
↑Colonic Cldn4, Nrf2, and NQO1 in WT not in AhR−/− and Nrf2−/− mice
↑Colonic Cldn4, Nrf2, and NQO1 in WT not in AhR−/− and Nrf2−/− mice
HT-29, Caco-2Cldn4, Ocln, and ZO1Singh et al[45]
↑Cldn4, Ocln, and ZO1
↓LPS-induced leakage of FITC-dextran
Cyp1A1, Cyp1A1 protein expression, and activity
↑AhR-reporter, nuclear translocation of AhR
Cldn4 expression not affected in Ahr SiRNA and CYP1A1 SiRNA cells
↑Nrf2 levels, nuclear translocation of Nrf2
C57BL/6 mice/TNBS↓Weight loss, diseases activity index, intestinal permeabilitySingh et al[45]
↓Colonic MPO level
↓Serum IL-6, TNF-α, CXCL1, and IL-1β levels
↑Colon length, Cldn4
↓Tissue damage and inflammation scores
AhR-knockdown caco-2 cells/TCDD/IL-1β /TMFIL-6, CYP1A1, PTGS2 in siControlMuku et al[47]
NS IL-6, CYP1A1, PTGS2 in siAhR
Table 3 Chemopreventive activities of urolithin A against other cancers of the alimentary tract
Cell line/modelMechanismRef.
Liver
HepG2↓Cell survivalWang et al[50]
↓Wnt/β-catenin signalling; β-catenin
c-MYc, cyclin D1, phospo-c-Jun
IL-6, IL-1β, NF-κβ, Cox-2, iNOS
TP53, BAX, PUMA, NOXA, p53, phosphor-p53
Caspase-3, phospho-p38
↓H2O2-induced ROS, MDA level
↑SOD level, GPx activity in H2O2-induced oxidative stress
HepG2.2.15↓Cell proliferationQiu et al[51]
↓Bcl-2
↑Cleaved caspase-3, Bax
↓Lin28a, Zcchc11, Sp-1
↑Let-7a
↓HMGA2, K-ras
↓Invasive cell number
Cultured rat hepatocytes/t-BHT↓CytotoxicityOlennikov et al[55]
↓LDH, MDA level
Pancreas
The human PDAC cell lines (MiaPaCa2, PANC1, AsPC1, CFPAC1, Capan1, Capan2, SW1990, HPAC, BxPC3)↓Cell proliferation, migration, apoptosisTotiger et al[58]
↓pAKT (T308), p70S6K (T421/S424), PDK1, pGSK3β, p4E-BP1
PDAC xenografts in mice↓Tumor volumeTotiger et al[58]
↓pAKT (T308), p70S6K (T421/S424)
↓Ki67
↑Cleaved caspase-3
PKT mice↓Tumor weightTotiger et al[58]
↑Survival
↓pAKT (T308), p70S6K (T421/S424)
↓Ki67
↑Cleaved caspase-3
↓F4/80-, Fox-P3, CD3- positive cells
Esophagus
BE patients/LBR intervention↑GST-pi level in BE biopsiesKresty et al[59]