Table 1.

Terpenoid and steroidal saponins with anti-angiogenesis activities.

Saponins	Anti-Angiogenesis Mechanisms	Administration Rout/Dosage	Natural Sources	References
Terpenoid saponin
AG36	↓ VEGF and FAK/PI3K/Akt gene expression	In vivo study; 75 and 1.5 mg/kg/day/i.p. in vitro study; 20 5, 10, and 20 μM	Ardisia gigantifolia (Primulaceae)	[188]
Arenaroside C, D, E, and G	NR	In vitro study; <5 μM	Polycarpaea arenaria (Caryophyllaceae)	[189]
Ginsenoside-Rb1	↑ PEDF and PPAR-γ gene expression	In vitro study; 100–500 nM	Panax spp. (Araliaceae)	[192,193]
Ginsenoside-Rb2	NR	In vivo study; 100 µg/mouse, i.v.	Panax spp. (Araliaceae)	[194]
Ginsenoside K	↓ SPHK1 activities	In vitro study; 10 µg/mL	Panax ginseng (Araliaceae)	[196]
Ginsenoside Rg3	↓ VEGF gene expression	In vivo study; 20 mg/kg	Panax spp. (Araliaceae)	[197]
senegin III	↑ PEDF, inhibition VEGF activities	In vitro study; 0.1, 1, and 10 μM	Polygala senega (Polygalaceae)	[198]
Theasaponin E1	↓ VEGF, Akt, and HIF-1α gene expression	In vitro study; 2 μM and 10 μg/mL	Camellia sinensis (Theaceae)	[201,202]
Oldhamianoside II	↓ VEGF and VEGFR2, COX-2, bFGF gene expression, ↓ pro-inflammatory cytokines activities including TNF-α and IL-6	In vivo study; 5, 10, and 20 mg/kg, i.p.	Gypsophila oldhamiana (Caryophyllaceae)	[170,200]
Platycodin D	↓ VEGFR2, PLCγ1, JAK2, FAK, Src, and Akt gene expression	In vitro study; 0.3, 1, 3, 10, and 30 μM	Platycodon grandiflorus (Campanulaceae)	[209,210]
Julibroside J8	NR	In vivo study; 0.5, 1.5, and 3 mg/kg, p.o. In vitro study; 0.5, 1, 2, and 4 μg/mL. Ex vivo study 30 and 50 μg/egg	Albizia julibrissin (Fabaceae)	[211]
Maesasaponins (I-VII.1)		25 and 50 μg/mL for in vivo (zebrafish model) and in vitro studies. Ex vivo study 1 µg/pellet.	Maesa lanceolata (Myrsinaceae)	[212]
Astragaloside IV	↓ VEGF and FGF2 gene expression	In vivo study; 20 mg/kg, p.o.	Astragalus membranaceus (Fabaceae)	[213]
Capilliposide B	↓ VEGF, Erk, VEGFR2, and Akt gene expression	In vitro study; 0.25, 0.5, 1 μM	Lysimachia capillipes (Primulaceae)	[214]
Chiisanoside	↓ VEGF gene expression	In vivo study; 60, 120, and 240 mg/kg, i.p.	Acanthopanax sessiliflorus (Araliaceae)	[203]
Pulsatilla saponin D	↓ VEGF and HIF-1α gene expression	In vitro study; 10 μM	Pulsatilla koreana (Ranunculaceae)	[204,205,206,207]
Gleditsiosides B	↓ VEGF and bFGF gene expression	In vitro study; 1 μM	Gleditsia sinensis (Fabaceae)	[217]
Raddeanin A	↓ PLCγ 1, JAK2, FAK, Src, and Akt and VEGFR2 activities and ↓ Wnt/β-catenin gene expression	In vivo study; 100 mg/kg/day, i.p. in vitro study; 100, 200 nM, 0.1, 0.3, 1, and 3 μM. Ex vivo study; 0.3, 1, 3, and 10 μM.	Anemone raddeana (Ranunculaceae)	[215,216]
Philinopside E *	↓ (KDR)/VEGFR2 gene expression	In vivo study; 2 mg/kg and 3 mg/kg, i.v. In vitro study; 1.25, 2.5, and 5 μM. Ex vivo; 2.5, 5, 10, and 10 nM/egg	pentacta quadrangularis (Cucumariidae)	[219,220]
Philinopside A *	↓ VEGF, bFGF and PDGF gene expression	In vivo study; 1, 2, and 4 mg/kg, i.v. In vitro study; 50 μM. Ex vivo study, 10 nM/egg	pentacta quadrangularis (Cucumariidae)	[221]
Frondoside A *	↓ bFGF activities	In vivo study; 1 and 0.01 mg/kg/day, i.p. Ex vivo study 100 and 500 nM/egg	Cucumaria frondose (Cucumariidae)	[222]
Steroidal saponin
Diosgenin	↓ VEGF and bFGF gene expression	In vitro study; 5, 15, and 25 µM.	Dioscorea spp. (Dioscoreaceae), Trigonella foenum-graecum (Fabaceae)	[177]
Deltonin	↓ VEGF, MAPK/AKT pathway activities	In vitro study; 1 and 4 μM	Dioscorea zingiberensis (Dioscoreaceae)	[178]
Terrestrosin D	Direct inhibition of vascular endothelial cell proliferation	In vivo study; 20 mg/kg, i.p.	Tribulus terrestris (Zygophyllaceae)	[180]
Paris saponin II	↓ NF-κB gene expression	In vivo study; 25 mg/kg, i.p. In vitro study 2.5 μM.	Paris polyphylla (Melanthiaceae)	[183,184]
Paris saponin I, II, Ⅵ and Ⅶ	↓ PI3K/AKT/mTOR/S6K1, SRC/eNOS, PLCγ/ERK and JAK2/STAT3 and R2 gene expression	In vitro study, 2 and 4 μM	Paris polyphylla (Melanthiaceae)	[181]
Polyphyllin D	Direct inhibition of vascular endothelial cell proliferation	In vivo study; 0.313 μM and 0.156 μM, zebrafish model. In vitro study, 200, 300, and 400 nM	Paris polyphylla (Melanthiaceae)	[182]
ACS	↓ MMP 2 and 9 gene expression	In vivo study; 5 μM, i.p. In vitro study 1.25, 2.5, and 5 μM	Ophiopogon japonicas (Asparagaceae)	[185]
DT-13	↓ ERK1/2, HIF-1α and Akt gene expression	In vitro study, 0.01, 0.1, and 1 μM. Ex vivo study; 100, 10, and 1 μmol/egg.	Ophiopogon japonicas (Asparagaceae)	[186]
Convallamaroside	NR	In vivo study; 5, 10, 20, 50, and 100 μg/mL, p.o. In vitro study; 10 and 50 μg/mL	Convallaria majalis (Asparagaceae)	[187]

bFGF: Basic fibroblast growth factor, COX-2: Cyclooxygenase-2, ERK: Extracellular signal-regulated kinase, FAK: Focal adhesion kinase, FGF2: Fibroblast growth factor 2, HIF-1α: Hypoxia-inducible factor 1-alpha, i.p.: Intraperitoneal, i.v.: intravenous, IL-6: Interleukin-6, JAK2: Janus kinase 2, MAPK: Mitogen-activated protein kinase, MMP: Matrix metalloproteinases, mTOR/S6K1: Mammalian target of rapamycin/ribosomal protein S6 kinase beta-1, NF-κB: Nuclear factor κ light chain enhancer of activated B cells, NR: Not report, p.o.: Oral administration (per os), PEDF: Pigment epithelium-derived factor, PI3K/Akt: Phosphoinositide 3-kinases/Protein kinase B, PLCγ: Phospholipase Cγ, PPAR-γ: Peroxisome proliferator-activated receptor gamma, SPHK1: Sphingosine kinase 1, SRC/eNOS: SRC kinase/endothelial nitric oxide synthase, STAT3: Signal transducer and activator of transcription 3, TNF-α: Tumor necrosis factor alpha, VEGF: Vascular endothelial growth factor, VEGFR2: VEGF receptor2, ↓: Reduce, ↑: Increase, *: Saponins isolated from marine organisms.