Anti angiogenic activity of natural products

Anti-angiogenic activity of natural products in ocular neovascularization A number of molecules, obtained from the natural source, have been evaluated for ocular neovascularization [14], [15]. As these compounds exhibit antioxidant effects, these were also tried for their therapeutic efficacy in inflammation and cancer [17], [22]. A number of polyphenolic compounds were found to exhibit their potentiality in ocular neovascularization [23]. These compounds mainly contain flavonoid and related structures. Withaferin A (cpd 1) (Fig. 2), a steroidal lactone, showed potent efficacy against human umbilical vein endothelial ana 2 (HUVECs) [24]. In human retinal microvascular endothelial cells (HRECs), homoisoflavonone type of compound cremastranone (cpd 2), flavone type compound luteolin (cpd 3) and flavanone type compound hesperitin (cpd 4) exhibited their efficacy [17]. A number of natural compounds exhibited potency in ocular retinopathy such as non-flavonoid polyphenol compound resveratrol (cpd 5), isoflavone compound genistein (cpd 6), coumarin derivative decursin (cpd 7) and β-diketo polyphenolic compound curcumin (cpd 8). Moreover, luteolin (cpd 3) and retinoid type of compound such as deguelin (cpd 9) displayed higher potency in the reduction of retinal neovascularization [25], [26] while administered intravitreally. Again, resveratrol (cpd 5), genistein (cpd 6), honokiol (cpd 10) and stilbenoid type of compound combretastatin A4 (cpd 11) showed potency while administered intraperitoneally [17], [27], [28]. Along with laser photocoagulation, natural compounds such as flavonol compound quercetin (cpd 12), cremastranone (cpd 2), genistein (cpd 6), deguelin (cpd 9), flavone compound apiginin (cpd 13), as well as chalcone compound isoliquiritigenin (cpd 14) were found to reduce the HUVECs through downregulation of matrix metalloproteinases [29], [30]. Luteolin (cpd 3) was found to block the downstream signaling pathways related to VEGF induction [31] as seen in HUVECs whereas curcumin (cpd 8) inhibited the PKC upregulation controlled by VEGF as seen in HRECs [32]. Resveratrol (cpd 5) and quercetin (cpd 12) reduced vascular permeability by blocking the release of nitric oxide from endothelial cells [17], [27], [33]. Deguelin (cpd 9) also showed efficacy by lowering the expression of hypoxia-inducible factor-1α (HIF-1α) whereas genistein (cpd 6) itself inhibited HIF-1α [34], [35]. Moreover, withaferin A (cpd 1) blocked the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation stimulated by angiogenic stimulator tumor necrosis factor alpha (TNF-α) [17].
Homoisoflavonone in retinal neovascularization Homoisoflavanone, 5,7-dihydroxy-3-(3-hydroxy-4-methoxybenzyl)-6-methoxychroman-4-one (cpd 2) was isolated from the bulb of Cremastra appendiculata (D. Don) Makino (Orchidaceae) [36]. Shim et al. [36] investigated the effect of cpd 2 on the basic fibroblast growth factor (bFGF)-induced invasion of HUVECs. Cpd 2 potentially inhibited bFGF-induced angiogenesis in vitro. This compound also exhibited in vivo angiogenic potency in the chorioallantoic membrane (CAM) of chick embryo without showing any toxicity. Furthermore, Kim and co-workers [37] showed that this compound also inhibited in vitro tube formation and cell migration of HUVECs. However, cpd 2 did not show retinal toxicity at 1–10μM dose without HUVECs cell viability. In addition, choroidal neovascularization (CNV) was reduced by treatment with cpd 2 in laser-photocoagulation-induced CNV mouse model. In another study, Kim et al. [38] reported that the anti-proliferative effect of cpd 2 by decreasing the expression of cdc2. This molecule arrested G2/M phase cell cycle in a dose-dependent manner. They also showed that cpd 2 reduced retinal neovascularization in a mouse model of ROP. Therefore, the application of homoisoflavanone is useful in the treatment of various vasoproliferative retinopathies such as age-related retinal degeneration and diabetic retinopathy.