Quercetin inhibits choroidal and retinal angiogenesis in vitro
ABSTRACT Quercetin is a natural substance found abundantly in grapes, red wine and other food products. In this study, we examined the effect of quercetin on choroidal and retinal angiogenesis in vitro using rhesus choroids-retina endothelial cell line (RF/6A).
RF/6A cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal bovine serum. Then cells were treated with different concentrations (from 0 to 100 microM) of quercetin. The cell proliferation was assessed using choromogenic methylthiazol tetrazolium bromide (MTT) dye after 24, 48 and 72 hours. Cell migration after 24-hour incubation with quercetin was investigated by wound assay. Following exposure to the various concentrations of quercetin for 24 hours, tube formation on matrigel by endothelial cells was also analyzed. Apoptosis was measured by flow cytometry using annexin V-FITC and propidium iodide staining.
Quercetin inhibits endothelial cell proliferation in a dose-dependent fashion; 10.1%, 42.6% and 65.2% inhibition on treating with 10, 50 and 100 microM Quercetin respectively. The migration and tube formation of RA/6A cells were also significantly inhibited by quercetin in a dose-dependent manner. Flow cytometric analysis showed that the percentages of apoptotic cells were slightly increased only in 100 microM quercetin-treated cells.
Our results show that quercetin inhibits choroidal and retinal angiogenesis in vitro. Further studies are ongoing to evaluate this drug as a potential candidate for the treatment of choroidal or retinal neovascularization.
Full-textDOI: · Available from: Xiao-Xin Li, Aug 15, 2015
- SourceAvailable from: Rania S Sulaiman
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- "HUVECs, 5 mM, inhibited VEGF-induced VEGFR2 autophosphorylation and activation of PI3K/Akt but not ERK1/2 (Bagli et al., 2004) HRECs, 1 mM, 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 mM on P14, suppressed retinal neovascularization in OIR mouse model (Park et al., 2012) Apigenin (2) Fruits and vegetables (Horinaka et al., 2006) HUVECs and CECs, 3 & 10 mg/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 mM, 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, 50e200 mg/kg/day from P14 to P20, inhibited hypoxia-induced expression of VEGF and HIF-1a 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) Hesperetin (4) Citrus fruits (Kawaii et al., 1999) HRECs, 16 mM, 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-1b and TNFa (Kumar et al., 2013) Cremastranone (5) Cremastra appendiculata (Shim et al., 2004) HUVECs, 5 mM: -Inhibited FGF-induced migration and tube formation -Suppressed proliferation without affecting cell viability by causing G 2 /M phase cell cycle arrest (Kim et al., 2007) HRECs, GI 50 217 nM, inhibited proliferation, migration, and tube formation (Lee et al., 2014) -Inhibited capillary formation in chick chorioallantoic membrane (CAM) assay in a dose-dependent manner (Shim et al., 2004) -Intravitreal, 1 mM on P14, reduced neovascularization in OIR model without cytotoxic effects (Kim et al., 2007) -Intravitreal, 1 mM, reduced vascular leakage in laser-induced CNV mouse model (Kim et al., 2008a) SH-11052 Synthetic isomer of cremastranone HUVECs, GI 50 18 mM, inhibited proliferation (Basavarajappa et al., 2014b) HRECs, GI 50 43 mM, -Inhibition of proliferation, migration, tube formation and cell cycle progression without inducing apoptosis -Decreased TNFa-induced NF-kB activation and the expression of downstream genes (Basavarajappa et al., 2014b) SH-11037 Synthetic derivative of cremastranone HRECs, GI 50 150 nM, very potent in inhibiting proliferation with 10-fold selectivity over HUVECs (Basavarajappa et al., 2014b) Quercetin (6) Abundant in human food e e.g. apples and onions (Formica and Regelson, 1995) -Inhibited proliferation, migration and tube formation of the Rhesus choroid-retina endothelial cell line (RF/6A) (Chen et al., 2008) -BAECs, GI 50 20 mM, 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) -1% quercetin eye drops, 3 drops/day, inhibited laser-induced CNV formation in rats (Zhuang et al., 2011) 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 mM (Cao et al., 2010) -Inhibited migration and tube formation in a concentration-and time-dependent manner (Kang et al., 2010) -Downregulated VEGF and upregulated PEDF expression levels (Jhanji et al., 2011) -Significantly reduced vasculature formation in a CAM assay (Jhanji et al., 2011) -Intravitreal injection, 10e200 mM, dose-dependent decrease in vascular leakage and neovascular area in the laser-induced CNV mouse model (Jhanji et al., 2011) -Intravitreal, 10 but not 100 mM on P12, significant reduction in retinal neovascularization in the OIR model (Jhanji et al., 2011) Deguelin (8) Mundulea sericea (Gerhauser et al., 1997) HUVECs, 0.1 mM, 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 mM, significantly reduced CNV and leakage in mice after laser photocoagulation (Kim et al., 2008b) "
ABSTRACT: Natural products are characterized by high chemical diversity and biochemical specificity; therefore, they are appealing as lead compounds for drug discovery. Given the importance of angiogenesis to many pathologies, numerous natural products have been explored as potential anti-angiogenic drugs. Ocular angiogenesis underlies blinding eye diseases such as retinopathy of prematurity (ROP) in children, proliferative diabetic retinopathy (DR) in adults of working age, and age-related macular degeneration (AMD) in the elderly. Despite the presence of effective therapy in many cases, these diseases are still a significant health burden. Anti-VEGF biologics are the standard of care, but may cause ocular or systemic side effects after intraocular administration and patients may be refractory. Many anti-angiogenic compounds inhibit tumor growth and metastasis alone or in combination therapy, but a more select subset of them has been tested in the context of ocular neovascular diseases. Here, we review the promise of natural products as anti-angiogenic agents, with a specific focus on retinal and choroidal neovascularization. The multifunctional curcumin and the chalcone isoliquiritigenin have demonstrated promising anti-angiogenic effects in mouse models of DR and choroidal neovascularization (CNV) respectively. The homoisoflavanone cremastranone and the flavonoid deguelin have been shown to inhibit ocular neovascularization in more than one disease model. The isoflavone genistein and the flavone apigenin on the other hand are showing potential in the prevention of retinal and choroidal angiogenesis with long-term administration. Many other products with anti-angiogenic potential in vitro such as the lactone withaferin A, the flavonol quercetin, and the stilbenoid combretastatin A4 are awaiting investigation in different ocular disease-relevant animal models. These natural products may serve as lead compounds for the design of more specific, efficacious, and affordable drugs with minimal side effects.Experimental Eye Research 10/2014; 129. DOI:10.1016/j.exer.2014.10.002
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