| Luteolin (1) |
Fruits and vegetables (Miean and Mohamed, 2001) |
HUVECs, 5 µM, inhibited VEGF-induced VEGFR2 autophosphorylation and activation of PI3K/Akt but not ERK1/2 (Bagli et al., 2004) HRECs, 1 µM, decreased VEGF-induced migration and tube formation (Park et al., 2012) |
Suppressed VEGF-induced angiogenesis in rabbit corneal pocket assay (Bagli et al., 2004) Intravitreal injection, 0.1 µM on P14, suppressed retinal neovascularization in OIR mouse model (Park et al., 2012)
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| Apigenin (2) |
Fruits and vegetables (Horinaka et al., 2006) |
HUVECs and choroidal endothelial cells (CECs), 3 & 10 µg/mL: inhibited proliferation, migration and tube formation (Zou and Chiou, 2006) |
Daily i.p. injection for 4 weeks, 15 and 30 mg/kg, reduced CNV after laser photocoagulation in rats (Zou and Chiou, 2006) |
| Genistein (3) |
Soybeans (Fotsis et al., 1993) |
BAECs, 20 µM, inhibited migration and proliferation due to non-specific inhibition of tyrosine kinases (Koroma and de Juan, 1994) |
Gavage administration, 32 mg/kg, had partial inhibitory effects on laser-induced CNV mouse model compared to specific inhibitors of VEGF/PEDF receptor kinases (Kwak et al., 2000) i.p. injection, 50-200 mg/kg/day from P14 to P20, inhibited hypoxia-induced expression of VEGF and HIF-1α in OIR mouse model (Wang et al., 2005) Long-term oral dosing, 150 and 300 mg/kg, decreased vascular leakage in STZ rat model of DR (Nakajima et al., 2001)
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| Hesperetin (4) |
Citrus fruits (Kawaii et al., 1999) |
HRECs, 16 µM, inhibited proliferation (Basavarajappa et al., 2013) |
Long-term oral dosing, 100 mg/kg, in STZ rats:
Significantly improved retinal antioxidant defense system Decreased retinal levels of VEGF, IL-1β and TNFα (Kumar et al., 2013)
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| Cremastranone (5) |
Cremastra appendiculata (Shim et al., 2004) |
HUVECs, 5 µM:
Inhibited FGF-induced migration and tube formation Suppressed proliferation without affecting cell viability by causing G2/M phase cell cycle arrest (Kim et al., 2007) HRECs, GI50 217 nM, inhibited proliferation, migration, and tube formation (Lee et al., 2014)
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Inhibited capillary formation in chick chorioallantoic membrane (CAM) assay in a dose-dependent manner (Shim et al., 2004) Intravitreal, 1 µM on P14, reduced neovascularization in OIR model without cytotoxic effects (Kim et al., 2007) Intravitreal, 1 µM, reduced vascular leakage in laser-induced CNV mouse model (Kim et al., 2008a)
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| SH-11052 |
Synthetic isomer of cremastranone |
HUVECs, GI50 18 µM, inhibited proliferation (Basavarajappa et al., 2014)
HRECs, GI50 43 µM,
Inhibition of proliferation, migration, tube formation and cell cycle progression without inducing apoptosis Decreased TNFα induced NF-κB activation and the expression of downstream genes (Basavarajappa et al., 2014)
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| SH-11037 |
Synthetic derivative of cremastranone |
HRECs, GI50 150 nM, very potent in inhibiting proliferation with 10-fold selectivity over HUVECs (Basavarajappa et al., 2014) |
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| Quercetin (6) |
Abundant in human food – e.g. apples and onions (Formica and Regelson, 1995) |
Inhibited proliferation, migration and tube formation of the Rhesus choroidretina endothelial cell line (RF/6A) (Chen et al., 2008) BAECs, GI50 20 µM, inhibition of proliferation by a dual mechanism; suppression of endothelial nitric oxide synthase (eNOS) and early M phase cell cycle arrest (Jackson and Venema, 2006) Inhibited oxidation-induced damage in HUVECs (Zhuang et al., 2011)
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1% quercetin eye drops, 3 drops/day, inhibited laser-induced CNV formation in rats (Zhuang et al., 2011)
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| Isoliquiritigenin (7) |
Licorice root (Vaya et al., 1997) |
HUVECs:
Suppressed cell growth in both VEGF-dependent and independent fashion at a subtoxic concentration of 10 µM (Cao et al., 2010) Inhibited migration and tube formation in a dose- and time-dependent manner (Kang et al., 2010) Downregulated VEGF and upregulated PEDF expression levels (Jhanji et al., 2011)
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Significantly reduced vasculature formation in a CAM assay (Jhanji et al., 2011) Intravitreal injection, 10–200 µM, dosedependent decrease in vascular leakage and neovascular area in the laser-induced CNV mouse model (Jhanji et al., 2011) Intravitreal, 10 but not 100 µM on P12, significant reduction in retinal neovascularization in the OIR model (Jhanji et al., 2011)
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| Deguelin (8) |
Mundulea sericea (Gerhauser et al., 1997) |
HUVECs, 0.1 µM, inhibited tube formation without affecting cell viability and dramatically reduced VEGF expression (Kim et al., 2008b) |
Blocked angiogenesis in the CAM assay (Kim et al., 2008b) Intravitreal, 0.1 µM, significantly reduced CNV and leakage in mice after laser photocoagulation (Kim et al., 2008b) Intravitreal, 0.1 µM on P14, reduced retinal neovasculariozation in the OIR mouse model (Kim et al., 2008c)
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| Curcumin (9) |
Indian spice turmeric (Kuttan et al., 1987) |
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Interfered with FGF-2 signaling in the corneal pocket assay (Mohan et al., 2000) Dietary, 0.5 g/kg, inhibited diabetes-induced retinal oxidative stress and production of pro-inflammatory mediators in the STZ rat model (Kowluru and Kanwar, 2007)
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| Resveratrol (10) |
Red wine and grape skin (Soleas et al., 1997) |
HUVECs, 1–2.5 µM, blocked VEGF-induced migration and tube formation (Lin et al., 2003) After hyperoxic injury of primary cultured retinal cells, resveratrol reduced eNOS expression by modulating NO-mediated mechanisms (Kim and Suh, 2010)
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Suppressed the formation of new vasculature in the CAM assay (Brakenhielm et al., 2001) Inhibited VEGF- and FGF-2-induced neovascularization in the mouse corneal pocket assay (Brakenhielm et al., 2001) Dietary, 5 mg/kg/day, inhibited NK-κB activation and apoptosis in retinas of STZ rats (Soufi et al., 2012) i.p. injection, 30 mg/kg daily from P14 to P20, reduced eNOS expression by modulating NO-mediated mechanisms in OIR rat model (Kim and Suh, 2010)
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| Honokiol (11) |
Magnolia species (Lee et al., 2011) |
Inhibited proliferation of HUVECs, but not primary fibroblasts, through suppressing VEGFR2 autophosphorylation (Bai et al., 2003) Suppressed reactive oxygen species production, NF-κB activation and expression of COX2 in high glucosestimulated HUVECs (Sheu et al., 2008)
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i.p. injection, 10–20 mg/kg daily from P12 to P17, inhibited pathological retinal angiogenesis and promoted physiological revascularization in the OIR model (Vavilala et al., 2013)
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| Combretastatin A4 (12) |
Combretum caffrum (Young and Chaplin, 2004) |
HUVECs, 80 ng/ml, inhibited proliferation, migration and tube formation, with induction of apoptosis after 48 hours (Ahmed et al., 2003) |
i.p. injections, 0.78–12 mg/kg daily from P13 to P17, dose-dependently inhibited retinal neovascularization in the OIR mouse model (Griggs et al., 2002) Intravenous injection failed to ameliorate retinal neovascularization induced by longterm galactose feeding in dogs (Kador et al., 2007) i.p. injection, 4 mg/kg, inhibited VEGF-induced retinal neovascularization in transgenic mice overexpressing VEGF in retina (rho/VEGF) (Nambu et al., 2003) i.p. injections daily for one week, 100 mg/kg, significantly reduced CNV after laser photocoagulation in mice (Nambu et al., 2003)
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| Decursin (13) |
Angelica gigas (Konoshima et al., 1968) |
HUVECs, 2–20 µM, significantly inhibited VEGF-mediated proliferation,migration and tube formation in a dosedependent manner (Jung et al., 2009) HRECs, 12.5–100 µM, inhibited proliferation, migration and tube formation by effectively down-regulating VEGFR2 expression and blocking its phosphorylation (Yang et al., 2013)
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Reduced neovascularization in the CAM assay and Matrigel plug assay in mice (Jung et al., 2009) Orally, supplemented in drinking water at 20 mg/kg/day, suppressed VEGFR2 expression levels in the STZ rat model (Yang et al., 2013) Intravitreal, 5 µM on P14, reduced retinal neovascularization in the OIR model (Kim et al., 2009)
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| Withaferin A (14) |
Withania somnifera (Mohan et al., 2004) |
HUVECs, GI50 12 nM: decreased proliferation and induced apoptosis by causing a dose-dependent decrease in cyclin D1 expression levels and inhibited NF-κB signaling at lower concentrations (Fugner, 1973; Mohan et al., 2004) CECs, inhibited TNFα-induced angiogenesis (Bargagna-Mohan et al., 2006)
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i.p. injection, anti-angiogenic activity in the FGF-2 Matrigel plug mouse model; at 500-fold lower doses that those reported for its anti-tumor activity in vivo (Mohan et al., 2004) i.p. injection, 2 mg/kg, inhibited corneal neovascularization and retinal gliosis elicited by alkali injury with corneal scraping in mouse eye (Paranthan et al., 2011)
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