(This is part three of three articles with excerpts from
“Tumor Angiogenesis as a Target for Dietary Cancer Prevention”
by Dr. William Li.)

Natural Anti-Angiogenesis Inhibitors
for Prevention of Cancer

Green Tea Catechins

   After water, tea is the second most popular liquid in the world.  Its consumption is linked with a decreased risk of colon, prostate, lung, esophageal, and other cancers.(65-67)  Polyphenol catechins in tea, predominantly flavanols, possess antiangiogenic activity.(68-73)

   EGCG (epigallocatechin-3-gallate) is a potent tea flavonoid that specifically inhibits endothelial cell proliferation stimulated by bFGF.  Mice that consume the human equivalent of 2-3 cups of tea/day show inhibition of VEGF by as much as 70%, and reduction of tumor cell invasion by 50%.(73)

   An Italian study involving men with high-grade prostate showed 30% of the placebo group progressed to prostate cancer, while the EGCG demonstrated a low progression rate of 3%.(74)  A Japanese study had a 50% reduction in risk compared to lower green tea usage.(75)

Genistein

   Genistein is an isoflavonoid found in soybeans, has antiangiogenic activity including angiogenesis inhibition, induction of apoptosis, inhibition of bFGF- and VEGF-driven cell proliferation, PDGF, G2, c-fos expression, NF-κB activation and growth factor signaling pathways.(76-80)

   Historically, breast cancer incidence rates have been 4 to 7 times higher among white women in the US compared to in women in China or Japan.  In fact, among women with breast cancer, soy food consumption has now been shown in numerous, large-scale studies to be significantly associated with decreased risk of death and recurrence, regardless of estrogen receptor status or tamoxifen use.(81)  However, when Asian women migrate to the US, their breast cancer risk rises over several generations to reach that of US white women.(82-83)

   Likewise, Japanese men in Hawaii who consume a high soy diet have low mortality from prostate cancer.(84)

Resveratrol

   Resveratrol is a polyphenol found in more than 72 plant species, such as mulberries, peanuts, grapes, and grape products, including red wine of 1.5–3 mg/L.(85)  Resveratrol at 3-4 mg (equivalent to 3-4 glasses red wine/day), inhibits angiogenesis, suppresses VEGF-, bFGF, VCAM-1, COX-2, MMP-9 and inhibits tumor vascularization.(86-90)  That is quite a few benefits!

   Additionally, the Health Professionals Follow-up Study identified a protective effect for prostate cancer with a 36% risk reduction in men drinking 2–4 glasses of red wine per week.(91)

Lycopene

   Lycopene, a type of natural pigment in the carotenoid family, gives tomatoes and other fruits such as watermelon and papayas their bright red color. Lycopene is an angiogenesis inhibitor which suppresses signaling by PDGF and Platelet Activation Factor in vitro.(92)

   In the Health Professionals Follow-Up Study of over 51,000 men, the highest quintile of lycopene consumption was found to have a 15% risk reduction for developing prostate cancer compared to men in the lowest quintile.(93)  The risk reduction was even greater if tomato sauce was ingested; men consuming more than 2 servings/week had a nearly 23% risk reduction compared to men consuming less than 1 serving/month.

Omega-3 Polyunsaturated Fatty Acids

   The best known sources of the long-chain omega-3 fatty acids – docosahexaenoic acid (DHA) and eicosapentaenoic (EPA) – are cold water oily fish such as salmon, herring, mackerel, anchovies, sardines, and trout. Both preclinical and epidemiological studies suggest that omega-3 PUFAs are effective cancer preventative agents. Omega-3 fatty acids have been shown to suppress a variety of tumors.(94)  Intake of omega-3 PUFAs from seafood has been associated with a decreased risk for certain cancers, including pancreatic, colon, breast, and prostate cancer.

   (Oils are hard to mix with other nutrients and are a lot of bulk.  As a result, we recommend adding fish oil capsules to your diet if you do not eat much of the fish above.)

Cruciferous Vegetables  –  Glucosinolates, Isothiocyanates, and Indole-3-carbinol

   This includes cabbage, broccoli, cauliflower, collard greens, mustard greens, radishes, Brussel sprouts, bok choy, and kale.  There are tons of studies showing the value of these things but this is more a matter of including these things in your veggie diet than supplements.

Flavonoids

  Flavonoids are a family of polyphenols that serve as important plant pigments. They are subcategorized by chemical structure into:

flavonols (such as quercetin),
anthocyanidins,
proanthocyanidins,
ellagic acid,
ellagitannins, and
isoflavones (such as genistein),

   Flavonoids are antiangiogenic through a variety of mechanisms; they inhibit VEGF expression, inhibit endothelial cell migration, and decrease matrix metalloproteinases MMP-2 and MMP-9.(95-99)

   The U.S. Department of Agriculture identifies spinach, onions, parsley, beets, and thyme among high flavonoid-containing vegetables and herbs.(100) Fresh salad greens such as lettuce, chicory, arugula, and red lettuce are also rich in polyphenolic flavonoids.(101)

Quercetin  

   Its antiangiogenic properties include inhibition of PDGF and Platelet Activation secretion from tumor cells and inhibition of endothelial cell proliferation and migration.(102) For example, quercetin has been shown to reduce VEGF as much as 40%.(103)  A large prospective study of 41,000 women living in Iowa between the ages of 55 and 69 found a number of flavonoid-containing leafy greens (abundant in quercetin) was associated with a significant risk reduction for lung cancer.(104)

   One of the richest sources of dietary flavonoids is red onion, which has particularly high levels of quercetin. There was a nearly 73% risk reduction for ovarian cancer in the population when comparing those who frequently consumed onion. Similarly, there was an 88% risk reduction for esophageal cancer in the group with highest versus lowest onion intake. In a separate Dutch cohort study, consumption of at least half an onion/day was associated with 50% risk reduction in gastric cancer.(105)

Anthocyanins  

   These are pigments that are present in many types of berries and grapes as well as red wine. They exhibit a purple color at neutral pH, red in acidic, and blue in alkaline conditions. They have been shown to inhibit angiogenesis and tumor growth in experimental animals.(106)

   Animals fed an anthocyanin-rich extract (5% in diet) obtained from black raspberries (BRB), blackberries, or strawberries showed a reduced number of esophageal tumors as compared to controls –41% less by BRB, 46% less by blackberries, and 24% less by strawberries.(107)

   Berries are also rich in other natural polyphenols such as ellagic acid, which contributes to bioactivity.

Proanthocyanidins

   These are a type of tannin—large polymeric chains of flavonoids—found in many plants and fruits, notably cacao, cinnamon, cranberry, apples, grapes, black current, chokeberry, and persimmon. Proanthocyanidins are thought to be the major source of flavonoids ingested in the Western diet.(108)

   Proanthocyanidins constitute 60% of the polyphenol content in cacao, the source of chocolate(109) with a (–)-epicatechin, similar to green tea.(110)  Cocoa extract downregulates the expression of ErbB2 tyrosine kinase and inhibits TNF-alpha-induced VEGF secretion in vitro.(111)

   Procyanidins are also found in cinnamon, which have been found to inhibit angiogenesis and tumor growth. Cinnamon extract inhibits VEGF receptor-2 on endothelial cells and suppresses endothelial cell proliferation, migration, and tube formation in vitro.(112)  The cinnamon extract suppressed the expression of angiogenic factors VEGF, FGF, and TGF-? as well as COX-2 and HIF-1alpha, which promote angiogenesis. In addition, the cinnamon extract suppresses melanoma metastasis as measured by the size and weight of the spleen and draining lymph nodes of mice bearing melanoma in vivo.(113)

   Many edible berries also contain proanthocyanidins, including the American cranberry, black currants, and grapes. Chokeberries, named because of their extreme astringency, contain among the highest levels of proanthocyanidins detected.(114)

   Both apples and apple juice are rich sources of procyanidins in addition to other polyphenols previously described such as quercetin and catechins. Based on the USDA Continuing Survey of Food Intakes by Individuals (CSFII), apples are a major source of proanthocyanidins in the U.S. diet.(115)

   In the Nurses Health Study involving 77,000 women, a statistically significant 37% risk reduction for lung cancer was observed among women for increases of 1 serving per day of apples or pears.(116)  An analysis of case-control studies conducted in Italy found that people who consumed at least one apple per day had a significantly reduced risk of colorectal cancer and cancers of the oral cavity, larynx, breast, and ovary relative to those who ate less than an apple a day.(117)

Ellagitannins

   These are glycosides of the flavonoid ellagic acid and can be found in numerous types of fruits and nuts including pomegranate, strawberries, blackberries, raspberries, muscadine grapes, walnuts, and pecans.(118) Upon consumption, ellagitannins are hydrolyzed to ellagic acid which is antiangiogenic.

   All parts of the pomegranate contain high levels of ellagitannins, have been shown to inhibit the growth of prostate cancer in both in vitro and in vivo laboratory experiments.  Interestingly, pure pomegranate juice has been found to be more potent than its separated individual polyphenol components – suggesting that this might be a good drink to have around vs a supplement.(119)

Menaquinone

   Menaquinone (vitamin K2) is associated with a reduced risk for developing several forms of cancer, suppresses angiogenesis, enhance tumor apoptosis, and inhibit the proliferation of cancer cells.(120)  Food containing menaquinone were associated with significantly lower incidences of lung cancer and 62% less prostate cancer.

Curcumin (Tumeric)

   Curcumin (diferuloylmethane), a flavonoid derived from the plant Curcuma longa, is present in tumeric spice.  There are some people that name curcumin as their #1 nutrient of all time for all purposes!  It certainly has its place here also.  It has chemopreventive and anti-angiogenic activity.  It also inhibits carcinogenesis in skin, stomach, intestines, and liver.

   Dietary ingestion of curcumin has been shown to prevent the formation of colon polyps, suppress proliferation of colon cancer and prostate cancer cells, and decrease intra-tumoral microvessel density.(121-123)  Since curcumin takes a lot of volume (500 – 2,000 mg/day), it makes since to include it in your diet in addition to some supplementation.

Beta-cryptoxanthin

   Papaya is a rich source of carotenoids, with the same lycopene content as tomatoes, but twice the beta-cryptoxanthin content.  In the Singapore Chinese Health Study, 63,257 Chinese men and women participated in a prospective study of diet and cancer.(124)  In the first 8 years of follow-up there was a 27% risk reduction among all subjects, and a 37% risk reduction among current smokers.

   In a study of women, diet, and breast cancer risk from the Nurses’ Health Study, total carotenoids were associated with a 50% reduction in breast cancer risk.

Other Dietary Inhibitors

We have identified antiangiogenic activity other dietary-derived chemopreventive molecules. These include:

brassinin         – a phytoalexin found in Chinese cabbage;
hesperidin and naringenin    – the citrus-derived bioflavonoids
ellagic acid      – from berries, pomegranate, and grapes;
silymarin        – from milk thistle and artichoke;
organosulfur allyl disulfide   – from garlic.(125-129)

Conclusion and Future Directions

   Angiogenesis  limits the development of all known cancers.  Its early intervention and inhibition suppresses tumor growth, progression, and metastases.  As such, tumor angiogenesis is a critical target for cancer prevention.

   Natural anti-angiogenic molecules are present in many dietary sources.  They have a wide spectrum of abilities that can suppress the growth of microscopic tumors. The key is to have a blend of the most important ingredients!

   With that in mind, controlling blood vessel growth through nutrient extracts may help redefine the prevention throughout an individual’s lifetime, from infancy through adulthood.  It may also be a leap forward in the suppression of early stage cancer – all through what nature has to offer!

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