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Natural Product

Goat’s rue (Galeaga officinalis). Photo credit: Epibase

June 13, 2012

If you live in the Cache Valley of northern Utah, just south of the Idaho border, overgrown patches of the same distinctive weed have rustled along the creeks and pastures between Logan and the town of Richmond as long as anyone can remember. The tap-rooted perennial stands roughly four-feet high, has bright green, frond-like leaves, produces purple, white, and blue blooms, and looks from afar like a poor man’s snapdragon. In Latin, the plant is Galeaga officinalis. In France, it is French lilac, a more lyrical reference to its therapeutic qualities in the hands of medieval herbalists. In Sweden, the plant is called getruta (“ruta” a genus of medicinal and culinary herbs with finely cut leaves). In English-speaking countries, getruta morphed into Goat’s rue.

But in Cache Valley, the primary place in the United States where Galega officinalis grows wild, farmers have always jokingly called it professor weed. And therein lies an unfortunate historical tale. In 1891, the professors at the Utah Agricultural Experiment Station in Logan (today, Utah State University) sought a suitable feed source for the livestock foraging in this arid, tumbleweed-rich region. Having heard the Europeans were sanguine about a possible new feed source called Goat’s rue, the professors imported the plant and entered it, along with alfalfa and a variety of clovers and grasses, into a three-year experiment to determine the best of the bunch. By 1893, Goat’s rue flunked the test, producing underwhelming yields and drawing rueful looks from livestock at its bitter taste. The professors declared alfalfa as the hands-down winner and mowed their experimental plots to the ground.

That was the end of the story for thirty-plus years until the 1920s. That’s when farmers and botanists began to see Goat’s rue cum professor weed growing wild about a mile from the experiment station and heading north along the Logan-Richmond Canal. By the 1970s, the getaway plant had become a frank infestation. An estimated 60-square-mile swath of Cache County was under invasive purple, white, and blue blooms. In 1981, state and federal agencies launched Utah Goatsrue Eradication Project to prevent what was now classified as a noxious weed from escaping into neighboring counties and bordering states. The dragnet came following reports that Galega officinalis had killed a few grazing sheep in Europe. By 1996, the Utah eradication program had removed about 85 percent of the blooms in Cache Valley. Then funding for the program ceased. The purple, white, and blue flowers reappeared.

The new blooms were symbolic of a new era for Galega officinalis and its medicinal past. In December 1994, the Food and Drug Administration had approved metformin, a drug modeled after a compound in Galega officinalis, to treat Type II diabetes. And therein lies another historical tale.

In the early 1920s, European scientists sought the active compound in Galega officinalis responsible for its centuries-old use among herbalists to treat the polyuria (excessive urination) associated with Type II diabetes. The initial answer was the plant contains guanidine, the nucleic acid guanine in oxidized form and a presumed blood sugar-lowering agent. However, when guanidine proved toxic as a diabetes drug, attention turned by the middle of the decade to one of the plant’s better tolerated extracts called galegin, a chemical intermediate of guanidine. Subsequent work to design a better tolerated galegin-like molecule led to the testing of various synthetic compounds, including one synthesized a few years earlier in Scotland called metformin. By the end of the decade, researchers had established the antihyperglycemic effects of metformin in clinical studies. Then, as sometimes happens, metformin sat on the investigative shelf for two-plus decades, overshadowed by the miracle of insulin.

In 1956, the shadow finally lifted when a French scientist heard a guanidine-based influenza treatment also seemed inexplicably to lower blood sugar levels. Intrigued, the scientist tested metformin and other guanidine-based compounds as possible treatments for Type II diabetes. Metformin scored well in these initial studies and emerged in 1959 as a new blood sugar-lowering medication in Europe. Thirty-plus years and multiple clinical trials later, metformin entered the American market with a therapeutic and economic bang. In 2008, an estimated 40 million prescriptions were filled in the United States for metformin. Worldwide, over 120 million people use the medication, the only diabetes drug modeled on an herbal design.

Now, a new and equally exciting chapter is unfolding in oncology for metformin and, by association, Galega officinalis . Previous studies have reported that people who control their diabetes with metformin have more than a 40 percent lower rate of cancer than those who use other diabetes medications. This spawned laboratory work to look for hard-wired explanations written into our cells. Researchers discovered that metformin activates the LKB1-AMPK pathway, a molecular chokepoint that links cell metabolism to growth control and cell polarity. But in turning on LKB1-AMPK, another related cellular pathway known as mTOR complex 1 (mTORC1) powers down and so does protein synthesis. When that happens, cells lower their energy expenditure and slow their rates of proliferation.

That’s where things got interesting, especially for those who study head and neck cancer. Recent work shows that head and neck squamous cell carcinoma (HNSCC) cells commonly turn up mTORC1 to fuel their abnormal growth. Was it possible for metformin to shut down mTORC1 in premalignant HNSCC cells and prevent their progression to metastatic disease?

A team of NIDCR scientists and colleague answer in the affirmative in the April issue of Cancer Prevention Research. The scientists found in a range of standard HNSCC cell lines that metformin prevents their progression, but the compound may do so independent of the LKB1-AMPK. They then showed in mice that metformin acts primarily on the basal proliferating layer of premaliganant lesions, significantly reducing their size and number. The authors concluded, “Collectively, our data underscore the potential clinical use of metformin as a targeted chemopreventive agent in the control of HNSCC development and progression.”

  • Vitale-Cross L, Molinolo AA, Martin D, Younis RH, Maruyama T, Patel V, Chen W, Schneider A, Gutkind JS, “Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions,” Cancer Prev Res (Phila) 2012 Apr;5(4):562-73.

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This page last updated: February 26, 2014