Licorice compound offers cancer prevention strategy
A chemical component of licorice may offer a new approach to preventing colorectal cancer without the adverse side effects of other preventive therapies, Vanderbilt University Medical Center researchers report.
In the study published in the Journal of Clinical Investigation, Raymond Harris, M.D., Ming-Zhi Zhang, M.D., and colleagues show that inhibiting the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11ßHSD2) — either by treatment with a natural compound found in licorice or by silencing the 11ßHSD2 gene — prevents colorectal cancer progression in mice predisposed to the disease.
One promising target for colorectal cancer chemoprevention is the enzyme cyclooxygenase 2 (COX-2), which promotes colorectal cancer progression via the action of the prostaglandins. Inhibiting this enzyme — with non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or with selective COX-2 inhibitors like Vioxx or Celebrex — reduces the number and size of colon polyps in mice and in patients with an inherited predisposition to colon cancer. However, both types of drugs cause serious adverse side effects that limit their utility for chemoprevention.
Harris and Zhang have been investigating COX-2 regulation in the kidney. They previously found that inhibiting 11ßHSD2 in the kidney suppresses COX-2 expression in that organ.
The colon is one of the only other organs (besides the kidney) with high expression of 11ßHSD2, suggesting that this enzyme might play a role in colorectal cancer progression.
The researchers examined expression of 11ßHSD2 in human colon polyps and in the colons of mice predisposed to colon cancer. They found that 11ßHSD2 was increased in polyps found in both mice and humans and correlated with COX-2 expression and activity.
They then inhibited 11ßHSD2 with glycyrrhizic acid, the main sweet-tasting component of licorice, and by silencing the gene for 11ßHSD2.
Both treatments inhibited the production of prostaglandin E2 (an inflammatory molecule produced by the COX-2 enzyme) and prevented the development of polyps (adenomas) and tumor growth and metastasis.
Because 11ßHSD2 is highly expressed only in kidney and colon, blocking the enzyme produces effects specific to those tissues — unlike NSAIDs, selective COX-2 inhibitors, and steroid treatments that can prevent cancer progression but also cause serious side effects like gastrointestinal irritation, cardiovascular events, and immunosuppression, respectively.
Licorice, Harris noted, has been used as a nutraceutical for thousands of years for ailments ranging from coughs to constipation.
But even licorice is not without side effects; long-term consumption can lead to low blood potassium and increases in blood pressure — side effects linked to the inhibition of 11ßHSD2.