Antiangiogenic Substances in Blackberries, Licorice May Aid Cancer Prevention

Two recent studies suggest that naturally occurring antiangiogenic molecules present in black raspberries and licorice may have a role in preventing some types of cancer. In the first study published in the journal Cancer Prevention(1), researchers at the Ohio State Comprehensive Cancer Center found that anthocyanins, a class of flavonoids present in many types of berries, as well as red wine, inhibited tumor growth and angiogenesis, and stimulated cancer cell death in the experimental rats treated with a potent esophageal carcinogen.

Dr. Gary D. Stoner and colleagues fed rats an anthocyanin-rich extract of black raspberries and found that the extract was nearly as effective in preventing esophageal cancer in rats as whole black raspberries containing the same concentration of anthocyanins. In addition to reducing markers of inflammation and cell proliferation in the esophagus, the anthocyanins suppressed the expression of the angiogenic factors vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha (HIF-1alpha). The VEGF protein is a primary stimulator of tumor angiogenesis, and upregulation of HIF-1alpha is considered an initiating step in the angiogenesis cascade. Inhibitors of VEGF are already used, as drugs, to treat a variety of cancers as well as blinding disorders. According to the Angiogenesis Foundation, the opportunity to utilize dietary sources of naturally-occurring angiogenesis inhibitors to modify or prevent disease is an important new frontier for the angiogenesis field.

“Now that we know the anthocyanins in berries are almost as active as whole berries themselves, we hope to be able to prevent cancer in humans using a standardized mixture of anthocyanins,” said Dr. Stoner. “The goal is to potentially replace whole berry powder with its active components and then figure out better ways to deliver these components into tissues to increase their uptake and effectiveness. Ultimately, we hope to test the anthocyanins for effectiveness in multiple organ sites in humans.”

In the second study related to dietary antiangiogenesis, researchers at Vanderbilt University Medical Center showed that inhibiting an enzyme called 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) by treatment with a natural compound found in licorice prevents colorectal cancer progression in mice. The study was published in the April issue of the Journal of Clinical Investigation(2).

The Vanderbilt researchers examined expression of 11βHSD2 in human colon polyps and in the colons of mice predisposed to colon cancer. They found that 11βHSD2 was increased in polyps found in both mice and humans and correlated with COX-2 expression and activity. They then inhibited 11βHSD2 with glycyrrhizic acid, the main sweet-tasting component of licorice, and also by silencing the gene for 11βHSD2. Both treatments inhibited the production of prostaglandin E2 and prevented the development of polyps (adenomas) and tumor growth and metastasis. Because 11βHSD2, which modulates the inflammatory enzyme COX2-, is highly expressed only in kidney and colon, blocking the enzyme produces effects specific to those tissues.

“Since studies here and elsewhere have shown the importance of COX-2 and colonic carcinogenesis, we postulated that maybe one of the mechanisms by which the normal colon might prevent excessive expression of COX-2 is by 11βHSD2,” said Dr. Raymond Harris, the Ann and Roscoe R. Robinson Professor of Nephrology of Vanderbilt University Department of Medicine, and an author on the study.

Licorice, Dr. Harris noted, has been used as a nutraceutical for thousands of years for ailments ranging from coughs to constipation. In addition to inhibiting COX-2 through 11βHSD2, licorice also contains isoliquiritin, a flavonoid that has been shown to inhibit angiogenesis, vascular endothelial cell proliferation and capillary formation.

By Roderick Smith, M.S.

References: 1. Wang L-S, Hecht SS, Carmella SG, et al. Anthocyanins in black raspberries prevent esophageal tumors in rats. Cancer Prev Res 2009;2(1):84-93.

2. Zhang M-Z, Xu J, Yao B, et al. Inhibition of 11b–hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans. J Clin Invest 2009;119:876-885.


Consuming Soy Early in Life May Mitigate Later Breast Cancer Risk

Naturally-Occurring Angiogenesis Inhibitor in Soy May Be Key Component

Asian American women who ate higher amounts of soy during childhood had a 58% reduced risk of developing breast cancer, according to a National Cancer Institute study published in the April issue of Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research(1). The study focused on women of Chinese, Japanese and Filipino descent living in San Francisco-Oakland, Los Angeles and Hawaii. Researchers interviewed 597 women with breast cancer and 966 healthy women. If the women had mothers living in the United States, researchers interviewed those mothers to determine the frequency of soy consumption in childhood of their offspring.

Historically, breast cancer incidence rates have been 4 to 7 times higher among white women in the U.S. compared to in women in China or Japan. However, when Asian women migrate to the U.S., their breast cancer risk rises over several generations to reach that of U.S. white women, suggesting that modifiable factors, such as diet, rather than genetics, are responsible for the international differences. Previous studies have suggested a protective effect of soy consumption in adults, but the results have been inconsistent. This was the first study to examine the role of childhood soy intake and breast cancer risk.

Researchers divided childhood soy intake into thirds and compared the highest and lowest groups. High intake of soy (>1.5 times/week) during childhood (age 5-11 years) was associated with a 58% reduction in breast cancer. A high level of soy intake in adolescent and adult years was associated with a smaller reduction of 20-25%. The childhood relationship held for all three races (Japanese, Chinese, Filipino), all three study sites (San Francisco-Oakland, Los Angeles, Hawaii), and in women with and without a family history of breast cancer. “Since the effects of childhood soy intake could not be explained by measures other than Asian lifestyle during childhood or adult life, early soy intake might itself be protective,” said the study’s lead investigator, Larissa Korde, M.D., M.P.H., a staff clinician at the NCI’s Clinical Genetics Branch.

According to Dr. Korde, her study suggests early soy intake may have a biological role in breast cancer prevention. “Soy isoflavones have estrogenic properties that may cause changes in breast tissue. Animal models suggest that ingestion of soy may result in earlier maturation of breast tissue and increased resistance to carcinogens,” she said. “This study builds upon the evidence that the antiangiogenic molecules present in soy may be useful for preventing cancer,” said Dr. William W. Li, President and Medical Director of the Angiogenesis Foundation, Cambridge, Mass. “It was shown over a decade ago that the urine of Buddhist monks who consumed soy-based diets contained high levels of genistein, a naturally-occurring angiogenesis inhibitor.”

Notably, genistein exhibits a dose-dependent inhibition of vascular endothelial growth factor (VEGF), a potent angiogenesis stimulator, as well platelet-derived growth factor (PDGF), tissue factor, and matrix metalloproteases, which also promote angiogenesis(2).  Several antiangiogenic drugs designed specifically to inhibit VEGF and PDGF are already FDA-approved to treat colon, kidney, liver, brain, breast, and lung cancers. “This new study is the first to provide strong evidence for a preventative role of soy consumption during childhood,” said Dr. Li.

By Roderick Smith, M.S.

References: 1. Korde LA, Wu AH, Fears T, et al. Childhood soy intake and breast cancer risk in Asian American women. Cancer Epidemiol Biomarkers Prev

2. Su SJ, Yeh TM, Chuang WJ, et al. The novel targets for anti-angiogenesis and genistein on human cancer cells. Biochem Pharmacol 2005;69(2):307-18. 2009;18(4):1050-1059

A Purple Sweet Potato with Antiangiogenic Components Shows Increased Anti-Cancer Activity

A Kansas State University researcher is studying the potential health benefits of a specially bred purple sweet potato with anti-cancer properties. Soyoung Lim, a doctoral student, and Dr. George Wang, Associate Professor of Human Nutrition at Kansas State, bred purple sweet potatoes to contain unusually high amounts of anthocyanin, a pigment that renders the purple hue in the vegetable. Anthocyanins can be red, blue or purple depending on the source’s chemical structure, and are also found in foods such as blueberries, black raspberries, red grapes and red cabbage. Anthocyanins are known to have antiangiogenic properties, and high intake of foods containing this family of molecules has been associated with a reduced cancer risk in epidemiology studies.

Lim used a sweet potato with pronounced purple flesh and skin that was originally developed by Kansas State’s Ted Carey, Professor of Horticulture, at the University’s John C. Pair Horticultural Center in Haysville. Three different varieties of purple sweet potatoes, including Kansas State’s, were tested. Each contained varying amounts of anthocyanin. To quantify the amount of anthocyanin in each potato, Lim extracted the pigments from the vegetables and analyzed them via HPLC-MS Analysis, a method that separates the individual components. The potatoes were then segregated by flesh pigmentation and fiber content.

The study showed that the Kansas-bred potato had significantly higher anthocyanin contents compared to the other potatoes, and found two derivatives of anthocyanin that were dominant: cyanidin and peonidin. The potatoes’ total phenolic content as also determined. Phenols are naturally occurring chemical compounds that have anti-aging and antioxidant components. The specially bred purple sweet potato had a much higher total phenolic content and antioxidant capacity than the other purple sweet potatoes, said Lim.

To observe the specific tumor-preventing effects of cyanidin and peonidin—compounds called anthocyanidins that are chemically similar to anthocyanins—Lim treated human colon cancer cells with low concentrations of the pigment derivatives and also studied their effects on the cancer cell cycles. Both cyanidin and peonidin showed significant cell growth inhibition for the cancer cells, but they did not significantly affect the cell cycle. Lim said a better understanding of the underlying mechanisms in the Kansas-bred potato could provide scientific evidence of its health benefits.

“This type of scientific study can lead to important advances in understanding how dietary strategies may impact on cancer and other diseases linked to angiogenesis,” said William W. Li, M.D., president and medical director of the Angiogenesis Foundation. “By comparing the different levels of anti-tumor activity in different strains of the same type of food, it may be possible to identify the specific strain that might confer the greatest health benefits in terms of disease modification.”

The Angiogenesis Foundation is actively studying the antiangiogenic activity of various dietary-derived natural compounds as part of its disease prevention research program.

By Roderick Smith, M.S.

First human study of oral anthocyanins, antiangiogenic compounds found in certain foods, shows activity for colorectal cancer chemoprevention

Anthocyanins are naturally occurring pigmented chemicals belonging to the group of molecules called polyphenols found in green tea, many kinds of berries and fruits, and spices, such as curcumin.

These compounds have been shown to possess chemopreventive activity against a variety of cancerous tumors in preclinical studies, including tumors of the gastrointestinal tract. The cancer preventive properties are believed to be attributable to both their antiangiogenic effect, preventing tumors from developing a blood supply, as well as direct anti-tumor activity.

Researchers at the University of Leicester in the UK have conducted a first-in-human pilot study of mirtocyan, an anthocyanin-rich standardized extract from bilberries, in a small group of patients with colorectal cancer (CRC) to determine whether its administration can also impact existing large tumors.

The study also examined whether oral intake of mirtocyan generates measurable levels of bilberry anthocyanins in the blood, urine, and tumor tissue. Fifteen patients with colorectal adenocarcinomas and 10 with CRC liver metastases were enrolled in this British study1.The patients that were scheduled to undergo surgical removal of a primary colon tumor or liver metastases were given oral mirtocyan at 3 different doses — 1.4, 2.8, or 5.6 grams (containing 0.5-2.0 grams anthocyanins) — on a daily basis for 7 days before surgery. The amount of bilberry anthocyanins present in body tissue and fluids after oral intake was analyzed by high performance liquid chromatography (HPLC) with visible or mass spectrometric detection. The researchers measured the rate by which the cancer cells divide by immunohistochemistry (Ki67) in tumor samples taken during surgery.

They also measured concentrations of insulin-like growth factor (IGF-I) in the patients’ plasma — IGF-1 stimulates angiogenesis through its upregulation of VEGF (vascular endothelial growth factor), a potent angiogenesis factor that stimulates the tumor blood supply. Tumor proliferation from colorectal tumor samples taken from all patients who received mirtocyan was significantly decreased by 7% compared with pre-intervention values. There was also a small reduction in circulating IGF-I concentrations across all patients/doses and a small increase in apoptosis in colorectal tumor samples. Mirtocyan anthocyanins and its metabolites were identified in plasma, colorectal tissue, and urine of patients, but not in the liver.

Anthocyanin concentrations in the plasma and urine were roughly dose-dependent, based on the amount taken by mouth, reaching approximately 179 ng/gram in tumor tissue at the highest dose of mirtocyan. While this was a small study, involving only 25 cancer patients, and lacked a control group, it demonstrates the feasibility of measuring the anti-tumor effects of antiangiogenic molecules from food sources in cancer patients2. It is possible that higher concentrations of anthocyanin would lead to even more pronounced anti-tumor effects.

The levels of anthocyanin metabolites detected in the tumor samples in this study were much lower than those previously published in mice experiments, suggesting that testing higher doses of mirtocyan should be done to identify a dose-dependent effect.

However, the evidence this study generates, showing biological activity against colorectal tumors in cancer patients suggests that foods and their extracts containing anthocyanins, and mirtocyan, specifically, have potential to improve cancer treatment through non-pharmaceutical means. Larger randomized, controlled studies would be required to establish this benefit.

By Roderick Smith, M.S.


1. Thomasset S, Berry DP, Cai H, et al. Pilot study of oral anthocyanins for colorectal cancer chemoprevention. Cancer Prev Res 2009;2(7):625-33.

2. Meyskens Jr. FL. Food extracts for chemoprevention: Quo Vadis? Cancer Prev Res 2009;2(7):608-10.

Squid Ink Discovered to be Antiangiogenic

Squid Ink Discovered to be Antiangiogenic

Squid ink is used as a defense mechanism in many species of marine cephalopods, and is also considered a delicacy in Spanish and other cuisines.  It now joins a growing number of marine-derived sources of naturally occurring inhibitors of angiogenesis.

A new paper in the journal Carbohydrate Polymers illuminates the potential anti-cancer properties of a sulfated polysaccharide isolated from the ink of the squid Ommastrephes bartrami. Ommastrephes bartrami, known as the neon flying squid, is a species found in the western Pacific Ocean. In laboratory experiments, squid ink polysaccharides (SIPs) inhibited angiogenesis, the growth of new capillary blood vessels, and the invasion and migration of tumor cells. Angiogenesis is critical for the growth and development of cancerous tumors. This is the first study to show that substances derived from squid ink could form the basis of new therapies for the prevention of tumor metastasis and possibly angiogenesis.

By Roderick Smith, M.S.

High-tech delivery of common spice into tumors holds promise for cancer prevention

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Curcumin, a dietary polyphenol derived from the root of the plant Curcuma longa, has shown potential as a chemopreventive (cancer-preventing) substance, with beneficial effects affecting different stages of cancer development. Curcumin has an anti-tumor effect by modulating the multiple genes involved in tumor cell proliferation, programmed cell death, invasion, and new blood vessel growth (angiogenesis). The poor absorption of orally ingested curcumin, however, has been considered a limitation of its use in cancer prevention.

Researchers at Wayne State University, Detroit, and the University of Minneapolis, have now developed an injectable, sustained-release formulation of curcumin microparticles that dramatically inhibited the growth of tumors in laboratory mice. The microparticles, consisting of microscopic spheres of curcumin in a biodegradable polymer, were injected into mice bearing human breast cancer tumors. Mice that received the curcumin microparticles had significantly less tumor growth and a reduction in markers of tumor angiogenesis, including the development of microscopic tumor capillaries and expression of a key angiogenic protein, compared with mice that received a placebo.

Notably, steady blood levels of curcumin were maintained for 4 weeks following a single injection of microparticles. The levels of curcumin were significantly higher in the lungs and brain, common sites of breast cancer metastasis, than in the blood. This would suggest that the microparticle approach might also potentially have a protective effect to keep metastases from forming in those organs.

The research group also studied repeated injections of curcumin microparticles and speculated that the steady blood concentrations of curcumin provided by the microparticles may provide a “metronomic chemotherapy”-like effect, in which regular, low-dose chemotherapy suppresses tumor growth by inhibiting angiogenesis. While requiring validation in human studies, these results suggest that new ways to deliver a dietary-derived antiangiogenic molecule as a drug. The findings were reported in the journal Cancer Research (2010;70(11):4443–52).

By Roderick Smith, M.S.

Cinnamon Joins Growing Number of Herbs with Proven Antiangiogenic Activity

Cinnamon, the dry bark and twig of Cinnamomum spp., is one of the world’s most popular and oldest spices. Cinnamon extract has been found to possess potent antioxidant, antimicrobial, and antipyretic (fever reducing) properties. Several recent studies have found that cinnamon extract also has anticancer activity. Cinnamon extract was shown to inhibit blood cancer cell proliferation in laboratory experiments and melanoma tumor growth in mice. New research now shows that cinnamon extract also inhibits vascular endothelial growth factor (VEGF), a potent angiogenesis-stimulating protein.

As a critical factor in tumor angiogenesis—the process by which cancerous tumors develop their own blood supply—VEGF is a primary target for antiangiogenic cancer treatment. The identification of naturally occurring VEGF inhibitors derived from diet offers a potential approach for cancer prevention. Using laboratory tests, scientists associated with the US Department of Agriculture and the Beckman Research Institute found cinnamon extract to be a potent inhibitor of the primary receptor for VEGF, VEGF receptor-2, on endothelial cells—the cells that line the inner walls of blood vessels and that are activated during tumor angiogenesis. In cell cultures and in mice, cinnamon extract inhibited VEGF-induced endothelial cell proliferation and the formation of tumor blood vessels.

The research identified compounds called procyanidins, types of polyphenols, as the active components in cinnamon extract that inhibit angiogenesis. It has been well established that polyphenols, especially flavonoids, are beneficial active components found in many natural food products, including red wine, tea, coffee, fruits, vegetables, beans (soy), grains, seeds and spices. Recently, polyphenols extracted from various plants, including soy, berry, pomegranate, grape seed extract and green tea, have been found to be potent inhibitors of angiogenesis.

The new study, published in the journal Carcinogenesis, revealed a novel activity in cinnamon and identified a natural VEGF inhibitor that could potentially be useful in cancer prevention and/or treatment. These new data are in agreement with other studies in which several natural products were shown to inhibit VEGF receptor-2, including catechins from green tea extract, delphinidin, ellagic acid, as well as grape seed extract.

By Roderick Smith, M.S.

Research published in Carcinogenesis 2010;31(3):481-8