Pro-angiogenic and Angiostatic Compounds from Terrestrial and Marine Sources

The formation of new blood vessels out of pre-existing capillaries or angiogenesis is a sequence of events that is of key importance in a broad array of physiologic and pathologic processes. In several diseases, excessive angiogenesis is a part of the pathology such as cancer (both solid and hematologic tumors), cardiovascular disease (atherosclerosis), chronic inflammation (rheumatoid arthritis, Crohn’s disease), diabetes (proliferative diabetic retinopathy), neovascular wet age related macular degeneration, retinopathy of prematurity, psoriasis, and AIDS complications. These diseases may benefit from the therapeutic inhibition of angiogenesis. There has been a substantial progress made in research on natural products possessing several therapeutic actions as a result of which they have attracted attention of scientists, the world over and has profoundly influenced the course of discovery from traditional remedies. The present review entails such natural products from terrestrial and marine sources that have exhibited pro-angiogenic or antiangiogenic effects and offer subsequent potential for the development of novel pharmacological agents in the near future.

Pro-angiogenic compounds; Angiostatic compounds

From several decades, much of the attention has been given to the approach of isolating novel chemical structures and compounds from natural resources, with immense pharmacological potential in order to counteract the pathological conditions of human body. Marine natural products bioprospecting has yielded a considerable number of drug candidates till date with 4 clinically approved drugs and 13 natural products (or derivatives thereof) in different phases of the clinical pipeline and a large number of marine chemicals in the preclinical pipeline [1]. Organisms in the marine source are majorly unexplored domain and can therefore, greatly account for the identification of compounds with higher potency and novel biological activities. The serendipitous isolation of the first bioactive marine compounds dates back more than 50 years whereby antiviral compounds, spongothymidine and spongouridine were reported from the Caribbean sponge Cryptotheca crypta in the early 1950s and further studies on these compounds subsequently led to the development of antiviral compound, Ara-A and anticancer agent Ara-C [2]. From thereon, the search for pharmacologically active compounds from marine sources increased drastically and several novel therapeutic compounds were reported with time e.g. Blunt et al reviewed 243 articles for the year 2003 and signified over 656 new marine compounds from the available literature with biological activities being reported for about 354 of them [3].

The bioactivity-guided fractionation of crude extracts has provided lead molecules for the discovery of novel drugs from traditionally used plants that continue to play an essential role in the human health care system and World Health Organization has earlier estimated that approximately 80% of the world’s inhabitants rely mainly on traditional medicines for their primary health care needs [4]. There has been a substantial progress made in research on natural products possessing several therapeutic actions as a result of which they have attracted attention of biologists, chemists and pharmacologists, the world over and has profoundly influenced the course of discovery from traditional remedies.

The formation of new blood vessels out of pre-existing capillaries or angiogenesis is a sequence of events that is of key importance in a broad array of physiologic and pathologic processes [5]. In several diseases, excessive angiogenesis is a part of the pathology such as cancer (both solid and hematologic tumors), cardiovascular disease (atherosclerosis), chronic inflammation (rheumatoid arthritis, Crohn’s disease), diabetes (proliferative diabetic retinopathy), neovascular wet age related macular degeneration, retinopathy of prematurity, psoriasis, and AIDS complications [6]. These diseases may benefit from the therapeutic inhibition of angiogenesis. A growing tumor needs an extensive capillary network to provide nutrients and oxygen to the body tissues. In addition, the new intra-tumoral blood vessels provide a way for tumor cells to enter the circulation and to metastasize to distant organs. Thus, every organ system may involve diseases in which angiogenesis is an important component. Several compounds from terrestrial and marine sources are under clinical trials and have been shown to possess potent angiostatic effect in the pre-clinical phases e.g. squalamine. On the other hand pro-angiogenic compounds are those which stimulate the process of angiogenesis and may play a vital role in diseases where angiogenesis is found to be deficient such as in case of infertility, ulcers, heart diseases, scleroderma and stroke.

Several compounds isolated from terrestrial and marine sources have shown potent pro-angiogenic and antiangiogenic efficacy in the pre-clinical studies warranting their further development for use in humans and the present article entails such pro-angiogenic or angiostatic compounds.

Squalamine is an aminosterol antibiotic synthesized from the tissues of the dogfish shark, Squalus acanthias [7]. It is a 7, 24-dihydroxylated, 24-sulfated cholestane steroid conjugated to a spermidine at C3 and has been reported to inhibit angiogenesis and solid tumor growth in vivo in the rabbit corneal micropocket assay [8,9]. It was later postulated that squalamine inhibited new blood vessel growth by selectively inhibiting the sodium-hydrogen antiporter sodium-proton exchangers (specifically the NHE3 isoform) causing inhibition of hydrogen ion efflux from endothelial cells with subsequent reduction of cellular proliferation [10]. Further studies reported its efficacy in the treatment of retinal neovascularization in a mouse model of oxygen induced retinopathy [11]. The phase I and pharmacokinetic studies of Squalamine in patients with advanced cancers demonstrated the efficacy and safety profile of the compound in humans [12]. The systemic administration of squalamine lactate significantly reduced choroidal neovascularization in a rat laser-induced choroidal neovascularization and is under investigation in phase II clinical trials for choroidal neovascularization due to age related macular degeneration [13,14]. Neovastat is another naturally occurring compound derived from the marine cartilage (dogfish) that possesses antiangiogenic potential mediated via the inhibition of matrix metalloproteinases (MMPs) specifically MMP-2, MMP-9 and MMP-12 [15,16]. Neovastat reached phase III clinical trials for the treatment of malignant diseases and was reported to inhibit vascular endothelial growth factor (VEGF) mediated angiogenesis as it significantly blocked VEGF-dependent microvessel sprouting from Matrigel-embedded rat aortic rings and also inhibited VEGF-induced endothelial cell tubulogenesis in vitro [17,18]. The presence of an endothelial-specific proapoptotic factor within neovastat was reported to contribute towards its antiangiogenic efficacy as it was able to interfere with several steps associated with angiogenesis through its ability to induce endothelial cell apoptosis [19].

A new antiangiogenic polysaccharide was reported from the marine algae Grateloupia longifolia that noticeably inhibited proliferation of human microvascular endothelial cells (HMEC-1) and human umbilical vein endothelial cells (HUVEC) in a dose dependent manner with IC50 values of 0.86 and 0.64 mg/ml, respectively. The observed inhibition was found to be VEGF-independent although tissue factor was down regulated at both mRNA and protein levels following the polysaccharide treatment of HMEC-1 thereby postulating the same to be the mechanism of the antiangiogenic effect. The polysaccharide also evinced significant antiangiogenic effect in the chick chorio-allantoic membrane assay also reduced the vessel density in Matrigel plugs implanted in mice [20]. A new purine analog, 1,3-dimethylisoguaninium was reported from the ethanolic extract of the Okinawan sponge Amphimedon paraviridis that exhibited angiostatic effect via specific inhibition of the basic fibroblast growth factor (bFGF)-induced proliferation of bovine aorta endothelial cells (BAECs) in a time dependent manner [21].

The bacteria’s associated with marine invertebrates are also rich sources of bioactive metabolites and this was revealed when the extract obtained from the bacterium (PB2) isolated from the primmorphs of the sponge Suberites domuncula was found to exhibit antiangiogenic activity in the chick chorio-allantoic membrane (CAM) assay with 50% activity at 5 µg/ml and 100% activity at 10 and 20 µg/ml concentrations [22]. A benzyl pyrrolidine derivative, streptopyrrolidine obtained from the fermentation broth of a marine bacterium, Streptomyces sp. KORDI-3973 isolated from the deep sea sediment exhibited significant anti-angiogenic activity without any cytotoxicity against human umbilical vein endothelial cells (HUVECs) at the concentration of 100 µg/ml [23]. The unique chemical structure of streptopyrrolidine was distinct from the known angiogenesis small molecule inhibitors and its antiangiogenic activity at non-toxic threshold dose marks towards its further developments.

A marine-derived antitumour compound aplidine (dehydrodidemnin B) isolated from the Mediterranean tunicate Aplidium albicans evinced noticeable inhibition of spontaneous angiogenesis, angiogenesis elicited by exogenous angiogenic growth factors (VEGF and FGF-2) and angiogenesis induced by VEGF overexpressing IA9 ovarian carcinoma cells, in the in ovo chick CAM assay [24]. Tong et al. isolated a novel sulfated saponin Philinopside A from the sea cucumber Pentacta quadrangulari that exhibited significant inhibition of the proliferation, migration and tube formation of human microvascular endothelial cells in a dose dependent manner with average IC50 values of 1.4 ± 0.17, 0.89 ± 0.23 and 0.98 ± 0.19 µM signifying its dual anti-angiogenic and anti-tumor effects in a series of in vitro and in vivo models [25]. A brominated compound (+)-Aeroplysinin-1 isolated and purified from marine sponge Apliisina aerophoba exhibited significant antiangiogenic activity as the compound evinced dose-dependent inhibitory effect in the in ovo CAM assay, showing potent apoptosis-inducing activity in the developing endothelium and the inhibitory effect of the compound was further confirmed in the in vivo Matrigel plug assay [26]. Castro et al. isolated puupehenone and 11 related compounds from marine sponges and evaluated their anti-angiogenic efficacy using Matrigel and chick chorio-allantoic membrane assay [27]. Three of these compounds isozonarol, 8-epipuupehedione and 8 epi-9,11-dihydropuupehedione completely inhibited angiogenesis in the chick CAM assay at doses equal or lower than 30nmol/egg thereby signifying their potential of further evaluations. Two novel sulfated sterols lembehsterols A and B, isolated from the marine sponge Petrosia strongylata exhibited inhibitory activity against thymidine phosphorylase, an enzyme related to angiogenesis in solid tumors [28]. Wrasidlo et al. reported the antiangiogenic potential of a lipopeptide, somocystinamide A derived from Lyngbya majuscule [29]. Systemic treatment of zebrafish or local treatment of the chick chorio-allantoic membrane with the compound exhibited dose dependent inhibition of angiogenesis suggesting the future development of the agent as an anti-angiogenic drug. Fucoidans are a group of marine sulfated polysaccharides in the cell-wall matrix of brown algae with main skeleton consisting of α1,3-linked-L-fucose-4-sulfate moiety. Cumashi et al. reported the antiangiogenic activity of nine different fucoidans from brown seaweeds. Laminaria saccharina, Laminaria digitata, Fucus evanescens, Fucus serratus and Fucus distichus potently inhibited human umbilical vein endothelial cell (HUVEC) tubulogenesis in vitro and this significantly correlated with the decreased levels of Plasminogen-activator inhibitor-1 in HUVEC supernatants, thereby suggesting the possible mechanism of fucoidan-induced inhibition of tubulogenesis [30].

Recently, a screening program carried out by Gupta et al. evaluated the antiangiogenic efficacy of twenty two marine invertebrates extracts of phylum mollusca using in ovo and in vivo models of angiogenesis such as CAM assay, corneal neovascularization assay in rats and oxygen induced retinopathy in rat pups and it was found that among all the extracts, the methanolic extract of Telescopium telescopium evinced most noticeable antiangiogenic activity in all the tested models that was mediated via the inhibition of vascular endothelial growth factor [31].

The antiangiogenic efficacy of two newer sapogenins viz. 20(S)-protopanaxadiol and 20(S)-protopanaxatriol that were obtained by alkaline hydrolysis of an extract of American ginseng Panax quinquefolium L. were evaluated in human umbilical vein endothelial cells (HUVEC) whereby both the compounds evinced dose dependent antiproliferatory activity envisioning their potential for development as novel antiangiogenic drug candidates [32]. The antiangiogenic potential of two naturally occurring sesterterpenes, leucosesterterpenone and leucosterlactone isolated from the Himalayan plant Leucosceptrum canum Sm was evaluated using the in vitro and in vivo angiogenic assays and cultures of large (bovine aortic endothelial cells) and small endothelial cells (human dermal microvascular endothelial cells) whereby these derived compounds showed noticeable antiangiogenic activity exhibited via the specific inhibition of the fibroblast growth factor-2 induced angiogenesis [33]. Taraboletti et al. reported a seco taxane derivative IDN 5390 to inhibit in vivo fibroblast growth factor-2 induced angiogenesis in Matrigel implants and exhibited efficacy in the in vitro tubulin polymerization assay as it caused a concentration dependent increase in the fraction of polymerized tubulin and a parallel decrease in soluble tubulin [34]. The methanolic and chloroform extracts of Sphenocentrum jollyanum Pierre (menispermaceae) exhibited significant anti-angiogenic efficacy in a dose dependent manner in the chick chorio-allantoic membrane assay bringing to the fore, the need for further studies towards confirming the antiangiogenic potentials of the plant as well as identifying and characterizing the active principles for drug development [35].

The ethanolic extract of the whole plant of Andrographis paniculata (Acanthaceae) and its major component andrographolide (extracted from dried plant powder) were reported to exert significant antiangiogenic effects in both in vitro and in vivo models of angiogenesis whereby they inhibited the tumor specific angiogenesis by regulating the production of various pro- and anti-angiogenic factors such as pro-inflammatory cytokine, nitric oxide, VEGF, IL-2 and TIMP-1 [36]. Kwak et al. investigated the anti-angiogenic activities of the herbal extracts of Cnidium officinale Makino and Tabanus bovinus using cultured glomerular capillary endothelial cells, CAM and rat cornea [37]. The herbal extracts conspicuously inhibited the neovascularization and the blood vessels patterns in CAMs treated with extracts ran parallel to each other without much branching and the oral administration of herbal extracts (20 mg/kg per day) for 4 weeks significantly inhibited the rat corneal neovascularization induced by suture and the length of the blood vessels was conspicuously lower than that in control animals. Yoon et al. investigated the antiangiogenic efficacy of Soamsan, a traditional Korean herbal remedy, using CAM and rat corneal neovascularization assays and reported the blood vessels in CAM treated with Soamsan were with less branching and the length of blood vessels in Soamsan-treated rat cornea were conspicuously low as compared to control thereby implicating the antitumor efficacy of the herbal remedy via the suppression of angiogenesis and growth factor transcription [38]. Huh et al. isolated 1,2,3,4,6-penta-O-galloyl-beta-D-glucose from the gallnut of Rhus chinensis Mill and reported the compound to possess anticancer activity via the inhibition of angiogenesis through COX-2 and MAPK-dependent pathways [39]. The compound effectively disrupted the basic fibroblast growth factor induced neovascularization in the chick CAM assay and in matrigel plugs in the mice suggesting the scope of development of a novel non-toxic chemopreventive agent. Torilin, a sesquiterpene compound isolated and purified from the fruits of Torilis japonica (Umbelliferae) was reported to decrease both neovascularization of chick embryos in the chorio-allantoic membrane assay and basic fibroblast growth factor-induced vessel formation in the mouse Matrigel plug assay [40]. Wu et al. reported the ethyl acetate fraction from fresh whole plants of Bidens pilosa Linn. var. radiata (Compositae) from Taiwan to exhibit significant anti-cell proliferation and anti-tube formation activities against human umbilical vein endothelium cells (HUVEC) [41]. Two polyacetylenes, 1,2-dihydroxytrideca-5,7,9,11-tetrayne and 1,3-dihydroxy-6(E)-tetradecene-8,10,12-triyne were isolated from the ethyl acetate fraction of Bidens pilosa using bioassay-guided fractionation, that manifested highly specific and significant activities against HUVEC proliferation with IC50 values of 2.5 and 0.375 µg/ml, respectively, however the first compound exhibited more potent effect on preventing tube formation of HUVEC than the latter at a dose of 2.5 µg/ml.

Cardenas et al. evaluated the anti-angiogenic potential of aloe-emodin, a hydroxyanthraquinone from Aloe vera and reported the compound to possess significant inhibitory effects in the in ovo chick CAM assay with two main possible targets of the anti-angiogenic action namely the urokinase secretion and tubule formation of endothelial cells [42]. A tanshinone derivative dihydrotanshinone I extracted from a traditional Chinese medicinal plant Salvia miltiorrhiza Bunge (Labiateae) was investigated for its antiangiogenic capacity in human umbilical vein endothelial cell migration, invasion and tube formation detected by wound healing, Transwell invasion and Matrigel tube formation assays, respectively. The compound inhibited angiogenesis through suppressing endothelial cell proliferation, migration, invasion and tube formation indicating its potential for further development as a novel anti-angiogenic agent [43]. Earlier another compound from the same plant, cryptotanshinone was reported to inhibit basic fibroblast growth factor-induced angiogenesis of bovine aortic endothelial cells at 10 µmol ranges in vitro without  cytotoxicity and demonstrated in the structure, the double bond at the C-15 position of the dihydrofuran ring to play a crucial role in the anti-angiogenic activity [44].

Genistein (4’5,7-trihydroxy isoflavone) occurring in the plant family Leguminosae, including soybean (Glycine max) was evaluated for its antitumor and antiangiogenic potential in mouse models of melanoma and breast cancers. In vivo, intraperitoneal administration of genistein at a dose of 10 mg/kg/day reduced tumor induced angiogenesis in syngenetic mice implanted with B16 or F311 cells and similar antiangiogenic effects were observed with the soybean-based diet [45]. Mathur et al. reported the anti-angiogenic efficacy of a traditionally used indigenous medicinal plant in the Indian system of medicine, Withania somnifera Dunal (Solanaceae) [46]. The hydroalcoholic extract of the roots was preliminarily investigated for the anti-angiogenic potential using the chick chorio-allantoic membrane assay wherein a significant inhibition (p<0.0001) of vascular endothelial growth factor induced neovascularization was recorded. The effect was further confirmed using in vivo mouse sponge implantation method. The antiangiogenic activity of resveratrol, a natural polyphenol compound found in various plants including grapes, was examined in several in vivo models of angiogenesis including the mouse corneal model, the chick chorio-allantoic membrane assay, a wound healing model and a tumor model wherein the compound significantly inhibited angiogenesis-dependent physiological and pathological processes including wound healing and tumor growth [47]. The antiangiogenic effect of resveratrol was attributed towards direct inhibition of capillary endothelial cell growth via suppression of the phosphorylation of the mitogen-activated kinase, a pathway common to fibroblast growth factor-2 and vascular endothelial growth factor-induced angiogenesis suggesting the beneficial effects of consumption of various plant products containing polyphenol based compounds and adequate amount of red wine in the prevention of cancer. Inokuchi et al. reported the in vitro antiangiogenic activity of vitamin E compounds with particular emphasis on tocotrienol which is a minor constituent of plants with high levels occurring in palm oil, cereal grains and rice bran [48]. Tocotrienol inhibited both the proliferation and tube formation of bovine aortic endothelial cells with δ-tocotrienol exhibiting the highest activity as it reduced the vascular endothelial growth factor-stimulated tube formation by human umbilical vein endothelial cells directing towards its potential use as a therapeutic dietary supplement for minimizing tumor angiogenesis.

Liu et al. tested the aqueous extracts of leaves of Rubus suavissimus S. Lee (Rosaceae) for antiangiogenic activity in a human tissue-based fibrin-thrombin clot angiogenesis assay and subjected the crude extract for further activity guided fractionation [49]. The extract significantly inhibited initiation of the angiogenic response and subsequent neovessel growth at 0.1% w/v concentration and gallic acid, elucidated as one of the active angiogenesis inhibitors in one of the fractions exhibited inhibition at 1 mM concentration warranting further bioassay directed identification of other responsible compounds present in the extract. Noni, the juice of the fruit from Morinda citrifolia L. was tested in a three-dimensional fibrin clot matrix model using human placental vein and human breast tumor explants as sources for angiogenesis vessel development. Noni in concentrations of 5% (v/v) significantly inhibited the initiation of new vessel sprouts from placental vein explants and also reduced the growth rate and proliferation of newly developing capillary sprouts whereas 10% noni juice in media effectively inhibited capillary initiation in explants from human breast tumors [50]. Demirci et al. examined the essential oil from the aerial parts of Phlomis linearis Boiss. and Bal. (Lamiaceae) for possible anti-angiogenic effect on chick chorio-allantoic membrane and reported very weak effect at a concentration of 100 µg/pellet [51]. Nasunin, delphinidin-3-(Ñ�-coumaroylrutinoside)-5-glucoside, isolated from the eggplant peels exhibited significant antiangiogenic effect as it suppressed microvessel outgrowth in an ex vivo angiogenesis assay using a rat aortic ring as well suppressed HUVEC proliferation in a dose dependent manner at a concentration ranging from 50-200 µM implicating its usefulness for the prevention of angiogenesis-related diseases [52]. Yoysungnoen et al. reported the dose dependent anti-angiogenic effects of tetrahydrocurcumin on tumor angiogenesis compared with curcumin using both in vitro and in vivo models of human hepatocellular carcinoma cell line (HepG2) wherein the more beneficial effect of tetrahydrocurcumin treatment was observed over curcumin as it exerted its antiangiogenic effect without any cytotoxic activities to HepG2 cells even at higher doses [53]. Curcumin is a phenolic compound isolated from Curcuma longa that was earlier expressed significant antiangiogenic activity in the hepatocellular carcinoma cells implanted nude mice [54]. The aqueous extracts of black cumin seeds (Nigella sativa) and green tea leaves (Camellia sinensis) were reported to express marked anti-angiogenic effects on endothelial cells of rat’s aorta augmenting the efficacies of the extracts as potential remedies for angiogenesis related diseases [55]. Agarwal et al. evaluated the in vitro antiangiogenic efficacy of grape seed extract on HUVEC proliferation, survival, matrix metalloproteinases secretion and capillary tube formation [56]. Grapes (Vitis vinifera) and grape seeds are rich in polyphenols, commonly known as procyanidins and commercial preparations for dietary supplement of grape seed polyphenols are marketed as ‘grape seed extract’ with 95% standardized procyanidins [57]. Grape seed extract have been reported to significantly inhibit cell growth and viability of HUVEC, induce apoptotic cell death in HUVEC, decrease secreted levels of matrix metalloproteinase-2 (MMP-2) from HUVEC and also inhibite capillary tube formation on Matrigel by endothelial cells in a dose dependent manner suggesting the possible association of anti-angiogenic potential of grape seed extract with its antiproliferative, proapoptotic and matrix metalloproteinase inhibitory activities.

Kaur et al. reported a peptide tubulysin A, isolated from a strain of myxobateria Archangium geophyra to depolymerize microtubules and induce mitotic arrest [58]. The compound exhibited significant in vitro anti-angiogenic activity as judged by both cell migration and cord formation using HUVEC (human umbilical-vein endothelial cells). Fucoxanthin, a major carotenoid extracted and refined from edible brown algae (Undaria pinnatifida) and its deacetylated product, fucoxanthinol were examined for any antiangiogenic effects using human umbilical vein endothelial cells (HUVEC) proliferation and tube formation assays in addition to the ex vivo angiogenesis assay using a rat aortic ring [59]. Fucoxanthin significantly expressed HUVEC proliferation and tube formation at more than 10 µM concentration and both the compounds suppressed the microvessel outgrowth in the ex vivo angiogenesis assay in a dose-dependent manner.

A sulfated steroid sokotrasterol sulfate isolated from the sponge Topsentia ophirhaphidites was reported for its pro-angiogenic potential as it promoted endothelial sprouting in vitro, new blood vessels formation on the chick chorio-allantoic membrane and accelerated angiogenesis and reperfusion in a mouse hindlimb ischemia model [60]. A novel angiogenic factor β-sitosterol was derived from the Aloe vera gel that evinced angiogenic activity in the chick chorio-allantoic membrane assay as well as stimulated neovascularization in the presence of heparin in the mouse Matrigel plug assay and the motility of human umbilical vein endothelial cells in an in vitro wound migration assay implicating its potential pharmaceutical applications for the future management of chronic wounds [61]. Matou et al. reported the angiogenic property of an oversulphated exopolysaccharide derived from a polysaccharide secreted by the mesophilic bacterium Alteromonas infernos [62]. The oversulfated exopolysaccharide enhanced human umbilical vein endothelial cell proliferation, migration and differentiation induced by basic fibroblast growth factor or vascular endothelial growth factor and also increased the density of tubular structures on Matrigel in the presence of FGF-2 or VEGF thereby suggesting its potential to accelerate vascular wound healing or for promoting the growth of collateral blood vessels in ischemic tissues.

In the search of newer pharmacologically active substances from natural sources, scientists have constantly been engaged into chemical studies on the bioactive compounds including structural elucidation, synthesis, and elucidation of pharmacophore by analysis of structure-activity relationship, action mechanisms and search for target proteins. Angiogenesis is the formation of new blood capillaries from pre-existing blood vessels and the switch to the angiogenic phenotype involves a local equilibrium between positive regulators of angiogenesis such as vascular endothelial growth factor, basic fibroblast growth factor etc. and negative regulators of angiogenesis such as angiostatin, endostatin etc. Under pathological conditional, this equilibrium may be disturbed leading to abnormal angiogenesis which is frequently the final pathway leading to the vast majority of diseases such as cancer and may even result in catastrophic loss of vision in some ocular diseases such as diabetic retinopathy, retinopathy of prematurity and wet age related macular degeneration. Therefore the substances that inhibit or promote angiogenesis have a considerable potential to become therapeutic agents. The concept of an anti-angiogenic approach as a promising strategy for the treatment of a variety of neovascular diseases in humans led to the discovery of many natural compounds with promising anti-angiogenic properties and of these only a few have been approved clinically. Therefore, there is a pressing need for the search of newer angiostatic agents for the treatment of neovascular diseases and also for pro-angiogenic agents for the treatment of diseases where angiogenesis is lying deficient.

References

1. Mayer AM, Glaser KB, Cuevas C, Jacobs RS, Kem W, et al. (2010) The odyssey of marine pharmaceuticals: a current pipeline perspective.Trends PharmacolSci 31: 255-265.
2. Cragg GM, Newman DJ (2005) Biodiversity: a continuing source of novel drug leads. Pure ApplChem 77: 1-24.
3. Blunt JW, Copp BR, Munro HG, Northcote PT, Prinsep MR (2005) Marine natural products. Nat Prod Rep 22: 15-61.
4. Farnsworth NR, Akerele O, Bingel AS, Soejarto DD, Guo Z (1985) Medicinal plants in therapy.Bull World Health Organ 63: 965-981.
5. Polverini PJ (1995) The pathophysiology of angiogenesis.Crit Rev Oral Biol Med 6: 230-247.
6. Folkman J (1995) Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis.N Engl J Med 333: 1757-1763.
7. Moore KS, Wehrli S, Roder H, Rogers M, Forrest JN Jr, et al. (1993) Squalamine: an aminosterol antibiotic from the shark.ProcNatlAcadSci U S A 90: 1354-1358.
8. Wehrli SL, Moore KS, Roder H, Durell S, Zasloff M (1993) Structure of the novel steroidal antibiotic squalamine determined by two-dimensional NMR spectroscopy.Steroids 58: 370-378.
9. Sills AK Jr, Williams JI, Tyler BM, Epstein DS, Sipos EP, Davis JD, McLane MP, Pitchford S, Cheshire K, Gannon FH, Kinney WA, Chao TL, Donowitz M, Laterra J, Zasloff M, Brem H (1998) Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature. Cancer Res 58: 2784-2792.
10. Akhter S, Nath SK, Tse CM, Williams J, Zasloff M, et al. (1999) Squalamine, a novel cationic steroid, specifically inhibits the brush-border Na+/H+ exchanger isoform NHE3.Am J Physiol 276: C136-144.
11. Higgins RD, Sanders RJ, Yan Y, Zasloff M, Williams JI (2000) Squalamine improves retinal neovascularization.Invest Ophthalmol Vis Sci 41: 1507-1512.
12. Bhargava P, Marshall JL, Dahut W, Rizvi N, Trocky N, et al. (2001) A phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers.Clin Cancer Res 7: 3912-3919.
13. Ciulla TA, Criswell MH, Danis RP, Williams JI, Mclane MP, Holroyd KJ (2003) Squalamine lactate reduces choroidal neovascularization in a laser-injury model in the rat. Retina 23: 808-814.
14. Dorrell M, Uusitalo-Jarvinen H, Aguilar E, Friedlander M (2007) Ocular neovascularization: basic mechanisms and therapeutic advances.SurvOphthalmol 52 Suppl 1: S3-19.
15. Gingras D, Batist G, Béliveau R (2001) AE-941 (Neovastat): a novel multifunctional antiangiogenic compound.Expert Rev Anticancer Ther 1: 341-347.
16. Gingras D, Renaud A, Mousseau N, Beaulieu E, Kachra Z, et al. (2001) Matrix proteinase inhibition by AE-941, a multifunctional antiangiogenic compound.Anticancer Res 21: 145-155.
17. Falardeau P, Champagne P, Poyet P, Hariton C, Dupont E (2001) Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials.SeminOncol 28: 620-625.
18. Béliveau R, Gingras D, Kruger EA, Lamy S, Sirois P, et al. (2002) The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects.Clin Cancer Res 8: 1242-1250.
19. Boivin D, Gendron S, Beaulieu E, Gingras D, Béliveau R (2002) The antiangiogenic agent Neovastat (AE-941) induces endothelial cell apoptosis.Mol Cancer Ther 1: 795-802.
20. Zhang C, Yang F, Zhang XW, Wang SC, Li MH, Lin LP, Ding J (2006) Grateloupialongifolia polysaccharide inhibits angiogenesis by downregulating tissue factor expression in HMEC-1 endothelial cells. British J Pharmacol 148: 741-751.
21. Jeong SJ, Inagaki M, Higuchi R, Miyamoto T, Ono M, et al. (2003) 1,3-dimethylisoguaninium, an antiangiogenic purine analog from the sponge Amphimedonparaviridis.Chem Pharm Bull (Tokyo) 51: 731-733.
22. Thakur AN, Thakur NL, Indap MM, Pandit RA, Datar VV, et al. (2005) Antiangiogenic, antimicrobial, and cytotoxic potential of sponge-associated bacteria.Mar Biotechnol (NY) 7: 245-252.
23. Shin HJ, Kim TS, Lee HS, Park JY, Choi IK, et al. (2008) Streptopyrrolidine, an angiogenesis inhibitor from a marine-derived Streptomyces sp. KORDI-3973.Phytochemistry 69: 2363-2366.
24. Taraboletti G, Poli M, Dossi R, Manenti L, Borsotti P, et al. (2004) Antiangiogenic activity of aplidine, a new agent of marine origin.Br J Cancer 90: 2418-2424.
25. Tong Y, Zhang X, Tian F, Yi Y, Xu Q, et al. (2005) Philinopside A, a novel marine-derived compound possessing dual anti-angiogenic and anti-tumor effects.Int J Cancer 114: 843-853.
26. Rodriguez-Nieto S, Gonzalez-Iriarte M, Carmona R, Munoz-Chapuli R, Medina MA, Quesada AR (2001) Antiangiogenic activity of aeroplysinin-1, a brominated compound isolated from a marine sponge. The FASEB Journal, 2001.
27. Castro ME, González-Iriarte M, Barrero AF, Salvador-Tormo N, Muñoz-Chápuli R, et al. (2004) Study of puupehenone and related compounds as inhibitors of angiogenesis.Int J Cancer 110: 31-38.
28. Aoki S, Naka Y, Itoh T, Furukawa T, Rachmat R, et al. (2002) Lembehsterols A and B, novel sulfated sterols inhibiting thymidine phosphorylase, from the marine sponge Petrosiastrongylata.Chem Pharm Bull (Tokyo) 50: 827-830.
29. Wrasidlo W, Mielgo A, Torres VA, Barbero S, Stoletov K, et al. (2008) The marine lipopeptidesomocystinamide A triggers apoptosis via caspase 8.ProcNatlAcadSci U S A 105: 2313-2318.
30. Cumashi A, Ushakova NA, Preobrazhenskaya ME, D'Incecco A, Piccoli A, et al. (2007) A comparative study of the anti-inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds.Glycobiology 17: 541-552.
31. Gupta P, Arumugam M, Azad RV, Saxena R, Ghose S, Biswas NR, Velpandian T (2014) Screening of antiangiogenic potential of twenty two marine invertebrate extracts of phylum mollusca from south east coast of India. Asian Pac J Trop Biomed 4(suppl 1): S129-S138.
32. Usami Y, Liu YN, Lin AS, Shibano M, Akiyama T, et al. (2008) Antitumor agents. 261. 20(S)-protopanaxadiol and 20(s)-protopanaxatriol as antiangiogenic agents and total assignment of (1)H NMR spectra.J Nat Prod 71: 478-481.
33. Hussain S, Slevin M, Matou S, Ahmed N, Choudhary MI, et al. (2008) Anti-angiogenic activity of sesterterpenes; natural product inhibitors of FGF-2-induced angiogenesis.Angiogenesis 11: 245-256.
34. Taraboletti G, Micheletti G, Rieppi M, Poli M, Turatto M, et al. (2002) Antiangiogenic and antitumor activity of IDN 5390, a new taxane derivative.Clin Cancer Res 8: 1182-1188.
35. Nia R, Paper DH, Essien EE, Iyadi KC, Bassey AIL, Antai AB, Franz G (2004) Evaluation of the antioxidant and antiangiogenic effects of Sphenocentrumjollyanum Pierre. African J Biomed Res 7: 129-132.
36. Sheeja K, Guruvayoorappan C, Kuttan G (2007) Antiangiogenic activity of Andrographispaniculata extract and andrographolide.IntImmunopharmacol 7: 211-221.
37. Kwak DH, Kim JK, Kim JY, Jeong HY, Keum KS, et al. (2002) Anti-angiogenic activities of Cnidiumofficinale Makino and Tabanusbovinus.J Ethnopharmacol 81: 373-379.
38. Yoon SC, Kim JK, Kwak DH, Ko JJ, Lee S, et al. (2004) Antitumor activity of Soamsan, a traditional Korean medicine, via suppressing angiogenesis and growth factor transcription.J Ethnopharmacol 93: 403-408.
39. Huh JE, Lee EO, Kim MS, Kang KS, Kim CH, Cha BC, Surh YJ, Kim SH (2005) Penta-O-galloyl-beta-D-glucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis: roles of cyclooxygenase-2 and mitogen-activated protein kinase pathways. Carcinogenesis 8: 1436-1445.
40. Kim MS, Lee YM, Moon EJ, Kim SE, Lee JJ, et al. (2000) Anti-angiogenic activity of torilin, a sesquiterpene compound isolated from Torilis japonica.Int J Cancer 87: 269-275.
41. Wu LW, Chiang YM, Chuang HC, Wang SY, Yang GW, et al. (2004) Polyacetylenes function as anti-angiogenic agents.Pharm Res 21: 2112-2119.
42. Cárdenas C, Quesada AR, Medina MA (2006) Evaluation of the anti-angiogenic effect of aloe-emodin.Cell Mol Life Sci 63: 3083-3089.
43. Bian W, Chen F, Bai L, Zhang P, Qin W (2008) Dihydrotanshinone I inhibits angiogenesis both in vitro and in vivo.ActaBiochimBiophys Sin (Shanghai) 40: 1-6.
44. Hur JM, Shim JS, Jung HJ, Kwon HJ (2005) Cryptotanshinone but not tanshinone IIA inhibits angiogenesisin vitro.ExpMol Med 37: 133-137.
45. Farina HG, Pomies M, Alonso DF, Gomez DE (2006) Antitumor and antiangiogenic activity of soy isoflavonegenistein in mouse models of melanoma and breast cancer.Oncol Rep 16: 885-891.
46. Mathur R, Gupta SK, Singh N, Mathur S, Kochupillai V, et al. (2006) Evaluation of the effect of Withaniasomnifera root extracts on cell cycle and angiogenesis.J Ethnopharmacol 105: 336-341.
47. Bråkenhielm E, Cao R, Cao Y (2001) Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes.FASEB J 15: 1798-1800.
48. Inokuchi H, Hirokane H, Tsuzuki T, Nakagawa K, Igarashi M, et al. (2003) Anti-angiogenic activity of tocotrienol.BiosciBiotechnolBiochem 67: 1623-1627.
49. Liu Z, Schwimer J, Liu D, Lewis J, Greenway FL, et al. (2006) Gallic acid is partially responsible for the antiangiogenic activities of Rubus leaf extract.Phytother Res 20: 806-813.
50. Hornick CA, Myers A, Sadowska-Krowicka H, Anthony CT, Woltering EA (2003) Inhibition of angiogenic initiation and disruption of newly established human vascular networks by juice from Morindacitrifolia (noni).Angiogenesis 6: 143-149.
51. Demirci B, Dadandi MY, Paper DH, Franz G, Baser KHC (2003) Chemical composition of the essential oil of PhlomislinearisBoiss. & Bal., and biological effects on the CAM-assay: a safety evaluation. Z Naturforsch 58c: 826-829.
52. Matsubara K, Kaneyuki T, Miyake T, Mori M (2005) Antiangiogenic activity of nasunin, an antioxidant anthocyanin, in eggplant peels.J Agric Food Chem 53: 6272-6275.
53. Yoysungnoen P, Wirachwong P, Bhattarakosol P, Niimi H, Patumraj S (2005) Antiangiogenic effects of curcumin in hepatocellular carcinoma cells implanted nude mice. ClinHemorheolMicrocirc 33: 127-135.
54. Yoysungnoen P, Wirachwong P, Changtam C, Suksamrarn A, Patumraj S (2008) Anti-cancer and anti-angiogenic effects of curcumin and tetrahydrocurcumin on implanted hepatocellular carcinoma in nude mice.World J Gastroenterol 14: 2003-2009.
55. Zaher KS, Ahmed WM, Zerizer SN (2008) Observations on the biological effects of black cumin seed (Nigella sativa) and green tea (Camellia sinensis). Global Veterinaria 2: 198-204.
56. Agarwal C, Singh RP, Dhanalakshmi S, Agarwal R (2004) Anti-angiogenic efficacy of grape seed extract in endothelial cells.Oncol Rep 11: 681-685.
57. 56.Escribano-Bailon MT, Gutierrez-Fernandez Y, Rivas-Gonzalo JC, Santos-Buelga C (1992) Characterization of procyanidins of Vitisvinifera variety Tinta del Paris grape seeds. J Agric Food Chem 40: 1794-1799.
58. Kaur G, Hollingshead M, Holbeck S, Schauer-Vukasinović V, Camalier RF, et al. (2006) Biological evaluation of tubulysin A: a potential anticancer and antiangiogenic natural product.Biochem J 396: 235-242.
59. Sugawara T, Matsubara K, Akagi R, Mori M, Hirata T (2006) Antiangiogenic activity of brown algae fucoxanthin and its deacetylated product, fucoxanthinol.J Agric Food Chem 54: 9805-9810.
60. Murphy S, Larrivée B, Pollet I, Craig KS, Williams DE, et al. (2006) Identification of sokotrasterol sulfate as a novel proangiogenic steroid.Circ Res 99: 257-265.
61. Moon EJ, Lee YM, Lee OH, Lee MJ, Lee SK, et al. (1999) A novel angiogenic factor derived from Aloe vera gel: beta-sitosterol, a plant sterol.Angiogenesis 3: 117-123.
62. Matou S, Colliec-Jouault S, Galy-Fauroux I, Ratiskol J, Sinquin C, et al. (2005) Effect of an oversulfatedexopolysaccharide on angiogenesis induced by fibroblast growth factor-2 or vascular endothelial growth factor in vitro.BiochemPharmacol 69: 751-759.