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Dietary factor combinations and anti-angiogenesis.

ABSTRACT: Angiogenesis, the formation of new blood vessels from a primary network of blood vessels, is a tightly regulated process involved in tissue growth and maintenance. There is growing interest in the use of dietary factors as anti-angiogenic agents which may be effective as treatments for diseases such as cancer and age-related macular degeneration. There have been quite a few studies on the effects of dietary factors individually on angiogenesis. More recently, combinations of these factors as potential anti-angiogenic therapies have been investigated due to their possible synergistic interactions and relatively lower toxicity in the human body. Studies using these combinations are reviewed here.

KEY WORDS: angiogenesis, dietary factors, inhibitors, combinations


Angiogenesis, the development of new blood vessels from a previously existing network of blood vessels, is a natural process that occurs during embryonic and fetal development, wound healing, and menstruation. In the early stages of vascular development, a primary capillary plexus is formed de novo by angioblasts, which are endothelial cell precursors derived from mesodermal cells. This primary plexus is then remodeled into an organized network of arteries, veins, and capillaries (Hirashima and Suda, 2006).

Factors that promote angiogenesis include vascular endothelial growth factor (VEGF), the matrix-metalloproteinases (MMP), fibroblast growth factor (FGF), and the angiopoietins. VEGF is specific for the vascular endothelium and acts to increase vascular permeability allowing endothelial cells to infiltrate and proliferate. An important stimulus for VEGF expression and secretion is hypoxia. Not only does VEGF act as an angiogenesis inducer, but it may also play a role in promoting the survival of new vessels (McMahon, 2000). MMPs are enzymes that degrade the extracellular matrix (Raffeto and Khalil, 2008). FGF is a strong stimulator of angiogenesis and a recent review article suggests that it acts by coordinating various growth factors such as VEGF to induce angiogenesis (Murakami and Simons, 2008). Angiopoietins consist of a family of four growth factors. Angiopoietin(Ang)-1 and -4 are agonistic ligands, while Ang-2 and -3 can have antagonistic roles. Ang-1 can enhance angiogenesis through synergistic interactions with VEGF. On the other hand, Ang-2 can stimulate endothelial cell death when VEGF is inhibited (Methany-Berlow and Li, 2003).

In addition to its role in tissue growth and maintenance, angiogenesis is also associated with certain diseases. Excessive angiogenesis is a problem associated with malignant, ocular, and inflammatory disorders such as tumor growth, age-related macular degeneration, asthma, and endometriosis, while insufficient angiogenesis is associated with disorders such as ischemic heart disease and systemic sclerosis (Dulak, 2005; Pandya et al., 2006).

Folkman first hypothesized the link between tumor growth and the extent of angiogenesis. He found that a tumor implanted into a rabbit's cornea grew exponentially after the development of new blood vessels. Folkman's suggestion that depriving tumors of oxygen and nutrients would lead to their quiescent state and prevent tumor expansion gave rise to a search for angiogenic inhibitors. Many studies have demonstrated that the growth of solid tumors and metastases are dependent on angiogenesis (Folkman, 1971, 1974, 1989; Ausprunk and Folkman, 1977).

There are four steps involved in the growth of blood vessels within tumors: i) the release of angiogenic growth factors by cancerous cells, ii) the disintegration of the basement membrane of a pre-existing capillary through the action of MMPs, iii) the proliferation and migration of endothelial cells to form sprouts, and iv) the formation of a capillary tube through the eventual contact of sprouts (Li et al., 2000; Boik, 2001). Each of these four basic steps involves several mechanisms which anti-angiogenic agents may target.

Many anti-angiogenic agents have been discovered. Some inhibitors are platelet and plasma-derived such as angiostatin, endostatin, and platelet factor-4 (Daly et al., 2003). Despite the promise of using platelet and plasma derived anti-angiogenic agents, the anti-angiogenic potential of dietary factors is also being investigated because of their relatively lower toxicity (Manson et al., 2005). Some examples of dietary derived anti-angiogenic agents are isoflavones in soy such as genistein and daidzein and many flavonoids like quercetin or myricetin (Cao et al., 2002).

Combinations of dietary inhibitory compounds may be more effective in eliciting an anti-angiogenic response especially if each compound targets different steps of angiogenesis. Another advantage of using such compounds in combinations is that it may allow a dose reduction for each of the compounds used. For instance, Khafif et al. (1998) observed a dose reduction for (-)-epigallocatechin-3-gallate (EGCG) and curcumin when used in combination to inhibit the growth of oral epithelial cells. In addition, possible synergistic interactions may occur for example, when the result of combining the agents is greater than the sum of their individual effects (Tallarida, 2001).

There have been some, but not many, studies on the effectiveness of using dietary factors in combinations with each other against angiogenesis or in combination with chemotherapy or radiation therapy to combat tumor growth. According to our search of the literature, there has been no review focusing on the use of dietary factors in combinations to combat diseases associated with angiogenesis. In this paper we review these combinations and summarize their potential benefits.

A ay for angiogene i

There are quite a few in vitro and in vivo angiogenesis assays used to study both stimulatory and inhibitory compounds. These have been reviewed by Auerbach et al., 2003; Staton et al., 2004; and Norrby, 2006.

Cell proliferation, migration, and tube formation are assessed through the use of bovine aortic endothelial cells or human umbilical vein endothelial cells. The migratory response is tested by placing cells on one side of a cell-permeable filter and placing a test compound in the media below the filter. Tube formation, on the other hand, is a spontaneous process endothelial cells undergo and can be enhanced with the addition of Matrigel, a solubilized basement membrane mixture.

In vivo tests include the corneal assay, Matrigel plug, zebrafish and chorioallantoic membrane (CAM). The corneal angiogenesis assay involves creating a pocket in the cornea of a rabbit or mouse wherein test tumors or tissues are placed to induce the development of vasculature (Gimbrone et al., 1974; Muthukkaruppan and Auerbach, 1979; Muthukkaruppan et al., 1982). The Matrigel plug assay is a simpler assay wherein Matrigel mixed with test cells or compounds is subcutaneously injected into a mouse. This forms a solid plug and is then studied to assess blood vessel growth infiltration (Passaniti et al., 1982). Tumor microvessel density is detected by immunohistochemical staining of Factor VIII (Zhou et al., 1998). The zebrafish is a whole small angiogenesis model that can also be used to study blood vessel development. The optical transparency of the embryos allows a continuous observation of the effect of test substances on blood vessel development (Norby, 2006; Cross et al., 2003).

The CAM is a particularly widely used assay and an excellent model system for angiogenesis. It is employed using either windowed eggs or explanted embryos with test substances topically applied to the membrane using coverslips or filter discs. The chorioallantoic membrane develops from two extraembryonic structures: the chorion and allantois. The vascular system of the CAM consists of the capillary network close to the chorion epithelium as well as larger and deep free-floating vessels that move with movements of the embryo. Until day 8, immature blood vessels lacking a basal lamina and smooth muscle cells proliferate to give rise to a capillary plexus. Proliferation then declines after day 11 (Tufan and Satiroglu-Tufan, 2005). The CAM also produces FGF-2, which plays a role in the development of the CAM vasculature (Ribatti et al., 1996, 2001). Hence, the CAM assay also secretes endogenous vascular growth factors like tumor cells.

Although the CAM and other assays provide useful information the responses observed may be different from those seen in tumors and other pathological conditions. Hence, there is a need to use assays that have conditions most similar to the natural environment of tumors or other pathologic conditions.


Many individual dietary factors are anti-angiogenic. Reviews of these factors include those done by Losso (2003), Dulak (2005), Fan et al. (2006), Sagar et al. (2006 a, b) and Mojzis (2008). Tsuda et al. (2004) and Davis (2007) reviewed nutritional interactions in cancer prevention including some anti-angiogenic compounds.

These anti-angiogenic dietary factors are derived mainly from plant sources. Anti-angiogenic phytochemicals include genistein, curcumin, quercetin, EGCG, and resveratrol.

However there are some anti-angiogenic dietary factors from animal sources. For example, conjugated linoleic acid (CLA) from dairy or meat products, has been shown to be anti-angiogenic by Moon et al. (2003). Also CLA may be useful as an anti-cancer agent since it slowed down cell division in Xenopous laevis (Twersky et al., 2007).


The following studies of anti-angiogenic combinations of dietary factors are the only ones we have found in our search. Some of these experiments demonstrated synergistic interactions of the dietary compounds on angiogenesis; other combinations need to be further investigated to determine possible synergistic interactions.

Unique nutrient mixture: ly ine, proline, arginine, a corbic acid, and EGCG

Roomi, et al. (2005a, b) demonstrated that their unique mixture of nutrients containing lysine, proline, arginine, ascorbic acid, and EGCG inhibited the secretion of MMPs and VEGF, two factors involved in angiogenesis, by human osteosarcoma cells. The anti-angiogenic activity of EGCG can be attributed to inhibition of both tyrosine kinase and ephrin-A1-mediated endothelial cell migration (Tang et al., 2007). The study did not compare the effectiveness of the individual components at inhibiting angiogenesis compared to the combination.

Berry extract tudie

Roy et al. (2002) and Bagchi et al. (2004) examined the anti-angiogenic properties of six berry extracts (wild blueberry, bilberry, cranberry, elderberry, raspberry seed, and strawberry). A profile of each berry extract shows that each contains different concentrations of the following flavonoids: gallic acid, epigallocatechin, catechin, EGCG, epicatechin, rutin, ferulic acid, scopoletin, and quercetin. Each berry extract inhibited [H.sub.2][O.sub.2] and TNF[alpha]-induced VEGF expression by human keratinocytes. Further experimentation demonstrated that it was the flavonoid component (ferrulic acid, catechin, and rutin) and not the antioxidant properties of the extracts that contributed to VEGF inhibition. A berry mix, the Mix 1-optiBerry IH141, was more effective than the individual extracts in inhibiting [H.sub.2][O.sub.2]-induced VEGF expression by human keratinocytes. Using a Matrigel assay, the researchers also showed that two berry mixes, Mix 1-optiBerry IH141 and Mix 2-optiBerry IH151 (InterHealth Nutraceuticals, Inc.), inhibited endothelial cell tube formation as compared to controls. However, individual berry extracts were not tested with the Matrigel assay so no comparison could be made with the two optiBerry mixes.

Pomegranate fractions

Pomegranate (Punica granatum) juice and peels are rich in flavonoids such as luteolin, while its seed oil is rich in punicic acid, a three-double-bond conjugated linoleic acid (CLA). Bagli et al. (2004) have shown that luteolin inhibits VEGF-induced neovascularization in a rabbit cornea assay as well as tumor growth and angiogenesis in a routine model. It was discovered that luteolin mainly targets phosphotidylinositol 3'-kinase, which is involved in the apoptotic pathway. Toi et al. (2003) conducted a number of both in vivo and in vitro assays that demonstrated the anti-angiogenic properties of different pomegranate fractions, namely, pomegranate fermented juice polyphenols, pomegranate pericarp polyphenols, and pomegranate seed oil fractions. Pomegranate fermented juice and pericarp polyphenols, and seed oil fractions decreased the amount of VEGF secreted by estrogen-sensitive human breast cancer cells and immortalized normal human breast epithelial cells. Pomegranate polyphenols also exhibited an anti-proliferative effect in fibroblasts of myometrial and amniotic fluid origins. Finally, a CAM assay showed that treatment with pomegranate pericarp polyphenols is able to decrease the amount of new blood vessel formation. The authors suggest that the CLA and punicic acid components of pomegranate seed oil may explain the anti-angiogenic activity of the various pomegranate fractions. Previous studies have shown CLA blocks bFGF, a pro-angiogenic factor in fibroblasts while punicic acid inhibits prostaglandin synthesis leading to inhibition of cyclooxygenase (COX) synthesis (Nugteren and Christ-Hazelhof, 1987; Takei et al., 2002). COX is an enzyme that converts arachidonic acid into prostanoids, some of which play a role in angiogenesis (Wang et al., 2007).

Grape seed extract

A grape seed extract, patented as Traconol, was tested for its anti-tumor properties using athymic mice implanted with human prostate carcinoma DU145 cells. Traconol contains a mixture of different catechins, flavonoids, and proanthocyanidins. The mice were fed with Traconol at 100 and 200 mg/kg/day for 7 weeks. Compared to a control group, the Traconol-fed mice contained tumors with decreased microvasculature. An in vitro assay also showed that Traconol inhibited VEGF secretion by DU145 cells (Singh et al., 2004). Traconol also inhibits human umbilical vein endothelial cell (HUVEC) growth and MMP-2 secretion (Agarwal et al., 2004).

The following four studies have shown that some anti-angiogenic compounds used in combinations act synergistically.

Alliin in combination with vitamins C and E

In a study done by Mousa and Mousa (2005), vitamins C and E together significantly enhanced the anti-angiogenic properties of alliin, a compound derived from garlic. A Matrigel assay demonstrated that the addition of 5 [micro]g each of vitamins C and E significantly improved the inhibitory effect of alliin on fibroblast growth factor-2 (FGF-2)-induced human endothelial cell tube formation by a five-fold shift. The addition of vitamins C and E at 2.5 [micro]g each enhanced the anti-angiogenic efficacy of alliin in FGF-2-induced angiogenesis in the chick embryo chiorioallantoic membrane (CAM) assay by a three- to four-fold improvement compared to alliin alone. Finally, vitamin C, vitamin E, and alliin also synergistically inhibited the growth of a human fibrosarcoma implant in the CAM model. The same synergistic interaction was seen with human colon carcinoma. The anti-angiogenic properties of alliin can be attributed to its increase of nitric oxide (NO) release. High concentrations of NO can inhibit angiogenesis while low concentrations of NO promote it (Isenberg et al., 2005). The authors did not test the addition of vitamin C or E individually with alliin to know whether either vitamin contributed more to the observed synergistic effect. Mikirova et al. (2008) have shown that vitamin C at dosages greater than 100 mg/dl suppressed endothelial cell tube formation in Matrigel. They attributed the anti-angiogenic mechanism of vitamin C to inhibition of NO production. The anti-angiogenic property of tocotrienol (T3), the unsaturated form of vitamin E, is due to its ability to inhibit the growth factor-dependent activation of phosphatidylinositol-3' kinase (PI3K)/PDK/Akt signaling system. This signaling system is responsible for phosphorylating substrates within a cell involved in proliferation and apoptosis. Also, T3 acts via the induction of apoptosis in endothelial cells (Nakagawa et al., 2007; Shibata et al., 2008).

1,25-dihydroxyvitamin D3 in combination with retinoids

Majewski et al. (1995, 1996) demonstrated, using the tumor cell-induced angiogenesis assay, that 1,25-dihydroxyvitamin D3 (1,25[[OH].sub.2]D3), a derivative of vitamin D3, acted synergistically with retinoids, derivatives of vitamin A, to inhibit angiogenesis in mice. Each of these dietary factors individually was shown to elicit a similar anti-angiogenic response, which was significantly enhanced when retinoids and 1,25[(OH).sub.2]D3 were combined. Other studies have shown that the anti-angiogenic properties of 1,25-dihyroxyvitamin D3 are due to its inhibition of endothelial cell sprouting and morphogenesis. It also causes the regression of sprouting elongated endothelial cells, suggesting apoptotic activity (Mantrell et al., 2000). In fact, it was shown that 1,25-dihydroxyvitamin D3 acts to increase p53 expression in breast cancer cells thus causing cell death (James et al., 1996). The anti-angiogenic properties of retinoic acid (RA) have been investigated in a number of studies (Diaz et al., 2000; Hoffman et al., 2007; and Pal et al., 2000). Hoffman et al. (2007) found that RA decreases in vitro VEGF secretion by thyroid cancer cell lines and inhibits HUVEC proliferation, which was dose-dependent. The application of RA also decreased microvessel density in two thyroid cancer cell lines, FTC236 and C643, by 25% and 15% respectively.

Soy phytochemical extract in combination with green tea

Combination of a soy phytochemical extract and green tea inhibited tumor angiogenesis in SCID female mice infected with MCF-7, a breast cancer tumor, showing synergestic effects (Zhou et al., 2004). To quantitatively assess angiogenesis, microvessel density was determined in the implanted tumors by staining of Factor VIII. The soy phytochemical extract alone and normal blood levels (<1 [micro]mol) of genistein and EGCG, active components in tea, did not significantly decrease microvessel density. However, when the soy phytochemical extract was combined with either green tea or black tea, significant inhibition of tumor angiogenesis was observed. The study suggested that the observed effects were due to the bioactive components in soy and tea such as soy isoflavones and tea polyphenols.


Curcumin, quercetin, and resveratrol in combinations

The anti-angiogenic potential of various combinations of curcumin, quercetin, and resveratrol, three known anti-angiogenic compounds, was tested using the CAM assay (Arriola and Twersky, 2007). Explantation was done according to Dugan et al. (1991). This method of explantation allows for multiple treatments to be placed on one membrane, as compared to egg windowing.

Curcumin is the main component found in the rhizome turmeric (Curcuma longa) and is a direct inhibitor of angiogenesis (Bhandarkar and Arbiser, 2007). It is commonly used in Indian and Chinese herbal medicine. In a study done by Hahm et al. (2004), 10 [micro]g/chorioallantoic membrane resulted in a 68% angiogenesis inhibition. Gururaj et al. (2002) related the anti-angiogenic activity of curcumin to its role in downregulating the gene expression of VEGF and the angiogenic ligands, ang -1 and -2. A recent review article on curcumin discusses curcumin's numerous molecular targets related to tumor formation such as VEGF and COX-2 (Kunnumakkara, et al. 2008).

Quercetin is a flavonoid present in olive oil, red wine, tea, and in many fruits and vegetables. Quercetin was shown to exhibit anti-angiogenic properties due to its inhibition of tyrosine kinase and its role in decreasing the activity and expression of MMP-2 (Tan et al., 2003). MMP-2 is involved in a number of angiogenic steps, namely, migration, invasion, and tube formation. Using a CAM assay, Tan et al. (2003) found that 50-100 nmol/10 [micro]l/egg was the effective dose in eliciting an anti-angiogenic response while the concentration of 25 nmol exhibited no effect. Chen et al. (2008) showed that quercetin was able to inhibit choroidal and retinal angiogenesis. Quercetin inhibited endothelial cell proliferation and tube formation in a dose-dependent manner at concentrations of 10 to 100 [micro]M and induced slight apoptosis at concentrations of 100 [micro]M.

Resveratrol, found in wine and grapes, is a potent anti-angiogenic compound, as only 25 [micro]g/0.16 [cm.sup.2] is needed to result in a 100% acapillary zone with a CAM assay (Li et al., 2000). Resveratrol directly inhibited human umbilical vein endothelial cell growth and decreased the activity of MMP-2. Resveratrol has also been shown to suppress the action of COX-1 (Igura et al., 2001). COX-1 is produced by endothelial cells and plays an important role in regulating angiogenesis; hence, resveratrol probably acts to restrain this enzyme (Jang et al., 1997; Igura et al., 2001). A study by Mousa et al. (2005) demonstrated that resveratrol inhibited FGF-2-induced angiogenesis using a CAM assay and also inhibited tumor growth in tumors that were implanted into the CAM.

Since curcumin, quercetin, and resveratrol each acts differently to inhibit angiogenesis, Arriola and Twersky (2007) hypothesized that combinations of these compounds would be as effective as or more effective than using an individual compound alone. They tested curcumin, quercetin, and resveratrol individually and in various combinations at a concentration range of 1.5 to 20 [micro]g/10 [micro]l. Preliminary results showed that the most effective combinations were: curcumin + resveratrol at 5 [micro]g/10 [micro]l each and curcumin + quercetin + resveratrol at 10 [micro]g/10 [micro]l, 5 [micro]g/10 [micro]l, and 5 [micro]g/10 [micro]l, respectively (Figure 1). Results indicate that there is noticeably less fine vessel growth in the experimental groups compared to controls. Further investigation is recommended to analyze the molecular targets of the combined use of these three compounds as well as a more quantitative analysis of anti-angiogenic response. These may help elucidate whether there is a true synergistic interaction among the compounds, which would help dictate proper dosages needed to elicit an anti-angiogenic response.


There have also been studies on the effectiveness of using dietary factors in combination with chemotherapy drugs such as tamoxifen and cyclophosphamide in inhibiting the growth of tumors in immune-deficient mice.

Quercetin and tamoxifen

Ma et al. (2004) reported that tamoxifen and quercetin acted synergistically to reduce tumor volume, VEGF expression, and microvessel density in prostate tumor xenograft mice. The combination was more effective than using either compound alone.

Ginsenoside Rg3 and cyclophosphamide

Ginsenoside Rg3, the main component of ginseng, and cyclophosphamide synergistically acted to inhibit VEGF expression and micro-vessel density in human ovarian cancer in athymic mice (Xu et al., 2007). Also, a study by Yue et al. (2006) has shown that ginsenoside Rg3 can inhibit the proliferation, invasion, and capillary tube formation of endothelial cells in a dose dependent manner, possibly by suppressing the action of proteases like MMP.


Omega-3 fatty acids and ionizing irradiation

Hardman et al. (2005) examined the possible synergistic effects of a diet rich in omega-3 fatty acids and ionizing irradiation (IR) on mice infected with human breast cancer cells. A diet of omega-3 fatty acids alone was found to be effective in decreasing tumor growth rate through its action on angiogenesis. The researchers did not observe any synergistic effects in combining IR therapy with omega-3 fatty acid consumption in decreasing tumor growth. However, the combination therapy did continue to inhibit blood vessel tumor infiltration for 22 days after IR exposure. Omega-3 fatty acids act to decrease the expression of COX-2. The authors propose that their whole body IR treatment was so effective at combating tumor growth that any effect of the addition of omega-3 fatty acid consumption was difficult to measure.


Only a handful of studies have examined the potential of using dietary compounds in combinations to combat angiogenesis, which is surprising considering their great potential as angiotherapy agents. In our search of the literature, many of the studies used extracts of fruits or herbs and found such extracts contained anti-angiogenic properties. There is a need to compare the anti-angiogenic effects of the various extracts, which contain numerous dietary compounds, with the single active compound, if any. Certainly future investigation is needed to identify and isolate the active anti-angiogenic components in such extracts. For instance, ginger was found to regulate angiogenic factors and 6-shogaol was found to be its most active component (Rhode et al., 2007). Also, further studies with animal models need to be done since our review found only two studies using animal models for testing possible anti-angiogenic agents in combination (Singh et al., 2004; Zhou et al., 2004).

Using such compounds in combinations is advantageous especially when the compounds exhibit synergistic interactions. Alliin in combination with vitamins C and E, 1,25-dihydroxyvitamin D3 in combination with retinoids, and soy phytochemicals in combination with green tea are most effective when used in combinations compared to using each compound alone to fight angiogenesis. The synergistic outcomes of using such compounds together may be due to the fact that each individual compound inhibits angiogenesis at different steps, thus providing a more effective mode of action.

Results of these anti-angiogenesis studies may indicate the effectiveness of using dietary factors in combinations against angiogenesis in tumor growth and in retinal pathologic conditions. The use of dietary factors as anti-angiogenic agents is favorable due to their relatively low toxicity. This quality is important if any of the anti-angiogenic agents result in severe side effects in the long run. Using compounds in combinations is also practical, as this is how they are found in our normal diets. The health benefits of fruits and vegetables are due to the synergistic interactions of such chemicals (Tsuda et al., 2004). Studies on the anti-angiogenic potential of dietary factors in combinations warrant their study in human clinical trials. When this occurs then it becomes possible to understand the proper dosages necessary to exhibit an anti-angiogenic response that is applicable to the cure for tumors and retinal pathologic conditions.

Studies have also shown that dietary factors may also improve current treatments for cancer such as the use of synthetic drugs or radiation. Hence, investigating dietary factors in relation to angiogenesis proves useful and their use has great potential whether they can be used together or with other types of cancer therapies. More rigorous studies, especially with animal models, are needed before the use of anti-angiogenic factors is a common practice clinically. In our search there have not been any human clinical trials investigating the use of dietary factors alone or in combinations to specifically target angiogenesis. Thus, information from various in vivo and in vitro assays on angiogenesis is critically important and may lead to a better understanding of how dietary anti-angiogenic agents can be applied to human trials.


Part of this work was aided by a grant from the TriBeta Research Foundation. We would like to thank Dr. Katherine Lyser, Professor Emeritus, Biological Sciences, Hunter College, CUNY for helpful comments.


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