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.