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.

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

Antiangiogenic component of broccoli inhibits growth of breast cancer cells

Numerous scientific studies have shown the cancer protective effects of increasing intake of cruciferous vegetables, including broccoli, cauliflower, Brussels sprouts, kale and cabbage. Among the beneficial chemical components of these vegetables is sulforaphane, a naturally occurring compound that suppresses both cancer cell growth and the growth of new tumor blood vessels (angiogenesis). The antiangiogenic properties of sulforaphane have been studied, and it downregulates the production by cancer cells of key angiogenesis-promoting factors, including vascular endothelial growth factor (VEGF), HIF-1α, matrix metalloproteinase-2 and matrix metalloproteinase-9.

Using an extract of sulforaphane, a group of researchers led by Yanyan Li and Duxin Sun at the Department of Pharmaceutical Sciences, University of Michigan, were able to inhibit the growth of breast cancer stem cells both in laboratory cultures and in mice. A growing body of research indicates that many types of cancer, including breast cancer, are initiated and maintained by a small fraction of tumor stem cells—characteristics that make them an attractive target for therapy.

Reporting their findings in the journal Clinical Cancer Research, the scientists found that sulforaphane reduced the size breast cancers in mice by more than 50%. Further, sulforaphane was able to reduce the numbers of breast cancer stem cells by 65-80% in mice implanted with human breast tumors. These findings provide rationale for future clinical evaluation of sulforaphane for breast cancer chemoprevention, and as an antiangiogenic intervention.

By Roderick Smith, M.S.