Natural chemical in liquorice hints at new cancer prevention strategy
Scientists at Vanderbilt University Medical Center in Nashville, Tennessee, sought to use glycyrrhizic acid, the main sweet-tasting component of liquorice, to inhibit the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2) that is thought to play a crucial role in bowel cancer growth.
Bowel cancer is the number two and number three killer in the US and the UK respectively.
The potential benefits of liquorice may be related to another enzyme, called cyclooxygenase 2 (COX-2), which is reported to promote colorectal cancer progression “via the action of the enzyme's inflammatory products, the prostaglandins," wrote Raymond Harris and Ming-Zhi Zhang in the Journal of Clinical Investigation.
Harris and Zhang – nephrologists who are also members of the Vanderbilt-Ingram Cancer Center – have been investigating COX-2 regulation in the kidney. They previously found that inhibiting 11-beta-HSD2 in the kidney suppresses COX-2 expression in that organ.
Long use of liquorice
Long before the term 'nutraceutical' entered today's vocabulary, Man has consumed liquorice for thousands of years for ailments ranging from coughs to constipation. But identifying the role liquorice could potentially play in preventing in bowel cancer may pave the way for nutraceutical applications rooted in liquorice’s natural chemical glycyrrhizic acid.
And while inhibiting COX-2 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, both types of drugs "cause serious adverse side" effects that limit their utility for chemoprevention. Side effects not witnessed with the liquorice compound.
So in a departure from these treatments, Harris and Zhang investigated the role glycyrrhizic acid could play in inhibiting 11-beta-HSD2.
"The colon is one of the only other organs (besides the kidney) with high expression of 11-beta-HSD2, suggesting that this enzyme might play a role in colorectal cancer progression," wrote the scientists.
"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 11-beta-HSD2," said Harris, director of the division.
Natural chemical in liquorice fights cancer progression
The researchers examined expression of 11-beta-HSD2 in human colon polyps and in the colons of mice predisposed to colon cancer. They found that 11-beta-HSD2 was increased in polyps found in both mice and humans and correlated with COX-2 expression and activity.
They then inhibited 11-beta-HSD2 with the natural liquorice component glycyrrhizic acid, and by silencing the gene for 11-beta-HSD2.
"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 tumour growth and metastasis," reported the scientists.
Further, because 11-beta-HSD2 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.
But the researchers noted that even liquorice 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 11-beta-HSD2.
"These are relatively minor compared to the cardiovascular side effects of COX-2 inhibitors," Harris said. "We didn't see these side effects in the mice we treated…but it would be something to be aware of, and something that could easily be treated with a diuretic."
Harris and colleagues are continuing to investigate the mechanism of 11-beta-HSD2 inhibition. Zhang, an assistant professor of Medicine and of Cancer Biology, also plans to look at the enzyme's role in lung cancer and other tumours.
And although this natural chemical is "an appealing drug lead in itself", the researchers are also working with the Vanderbilt Institute for Chemical Biology to develop more specific and potent inhibitors of 11βHSD2.
"We think we can make an inhibitor that is more specific and has better delivery to the target tissues," said Zhang.
Source: Journal of Clinical InvestigationApril 2009, Volume 119, Issue 4 "Inhibition of 11-beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans"Authors: Ming-Zhi Zhang , R C. Harris
