Digging for Ginseng's Secretsby Marilyn Davis
Ginseng is on Laura Murphy's mind—and in her tea. Should it be in yours? It's too soon to say. Ginseng may prove useful against cancer—someday. This is a road story, not a story about a medical breakthrough. The destination remains beyond the horizon.
Ginseng has been used for centuries in Asian medicine as an aphrodisiac, a tonic for well-being, and a curative. The root, legendary for the uncanny resemblance it sometimes bears to the human body, grows slowly and should be several years old before harvesting. In the United States, where collectors have decimated many wild populations, growers cultivate ginseng in the woods or commercially farm it, and supplement makers peddle it as a stimulant and an energy booster.
"Truck stops now have concentrated ginseng extract near the cash registers, where they used to have the caffeine pills," says Murphy, an associate professor of physiology.
As an herbal remedy, ginseng is largely untested in the West. Because of the extravagant claims made for many supplements, research into such alternative remedies sometimes is dismissed as non-mainstream. But Murphy could have the last laugh. Her research may eventually show that ginseng can help prevent or treat breast and prostate cancer.
Back in the early 1990s, the Illinois Ginseng Growers Association contacted Murphy to inquire about the pharmaceutical properties of American ginseng (Panax quinquefolium), a different species from Asian ginseng. "They were wondering why the Asians were buying so much of their ginseng," she says. U.S. ginseng exports top 1.4 million pounds. The wild-cultivated root can fetch $300 to $600 per pound; the commercially farmed variety, about $30 per pound.
Murphy had been studying the effects of drugs such as marijuana on reproduction and female neuroendocrinology. The growers' query, she thought, would make an ideal research project for some high school students who were working in her lab, courtesy of a School of Medicine summer program funded by the Howard Hughes Medical Institute.
"There were reports that ginseng has effects on hormones and may itself act like a hormone, which piqued my interest," she says.
Under Murphy's supervision, the high school students fed male and female rats ground-up ginseng root in oil, then looked for hormonal changes in those animals compared with rats not consuming ginseng. In the male rats, one of the things they looked at was libido. To Murphy's surprise, ginseng "enhanced libido significantly," yet the team found no changes in male sex hormones. (These findings were later published in Physiology and Behavior.)
Nor did ginseng seem to affect hormones in the female rats, other than to decrease blood levels of prolactin (a hormone needed for milk production). All of the females reproduced and nursed normally, and their offspring were normal.
"Ginseng has been used for thousands of years by humans and reported to have very minimal side effects," says Murphy. "Our rat studies were the first to look for any possible toxicological effects of high doses in the female during a very vulnerable time [reproduction]. We tested some really high doses of American ginseng, and it seemed very safe."
Around this same time, Murphy ran across several Korean studies looking at Asian ginseng and cancer. "The Korean scientists found that Asian ginseng inhibits cancer cell proliferation in a variety of cancers, such as lung cancer, melanoma, and colon cancer," she says. "They knew what component in the ginseng was responsible—and this component is not found in American ginseng."
She wondered if American ginseng might have the same effect on cancer cells. She was also struck by the fact that the Korean scientists hadn't yet studied any hormone-dependent cancers, such as breast or prostate cancer.
So she and her undergraduate students exposed cultured human breast cancer cells to a water extract of American ginseng. They found a nice dose/response relationship: the higher the concentration of ginseng, the more it slowed down the rate of cell proliferation.
"It doesn't kill the cells, but you can raise the dose to completely inhibit proliferation," says Murphy. "It arrests the cell in a certain state of development."
These pilot studies, funded by small grants from the School of Medicine, were promising enough to win Murphy a $295,701 grant from the U.S. Defense Department, which administers some funds for breast cancer research.
Breast cancers are not all alike. Many tumors have cells with estrogen receptors; they grow rapidly in the presence of estrogen. Other tumors have cells with no estrogen receptors; their growth is not spurred by the hormone. So Murphy expanded the petri-dish studies to compare two different human breast cancer cell lines: one that has estrogen receptors and one that doesn't. Ginseng inhibited the growth of both types of cells within three to seven days. But it was about twice as effective with the estrogen-sensitive cells.
"I'm hesitant to say yet whether there's a steroid component" to the response, says Murphy. Nonetheless, she got a similar result with two types of human prostate cancer cells, one that is testosterone-dependent and one that isn't.
Murphy's team next turned to animal studies. They injected female mice with human breast cancer cells. Some of the mice had been drinking regular water for the previous two weeks; the rest had been drinking water with 1 percent ginseng extract. (The human equivalent would be 2-3 grams of ginseng per day.) This procedure was continued after the mice were injected with the cells.
"This strain of mice has a compromised immune system that doesn't allow them to reject foreign tissue," Murphy explains. "After two weeks you see tumors form at the site of the inoculation. There's no difference at first [between the mice on ginseng and the controls]. But after five weeks, when the tumors are big enough to start growing their own blood supply, ginseng has an effect."
At the end of the experiment, the tumors in the treated mice were 50 percent smaller than those in the untreated mice.
If ginseng actually interferes with angiogenesis—the tumor's ability to generate blood vessels—that is potentially important news. Stopping tumor angiogenesis is one key strategy for cancer researchers.
But there are other possible explanations. Ginsenosides—the biologically active compounds in ginseng—are fat-soluble. "My theory is that they accumulate in the fat slowly and that with everyday usage of even small doses you may accumulate therapeutic levels in your body," Murphy says.
That could explain why it takes a few weeks for ginseng to kick in with the tumor-bearing mice—and why ginseng takes several days to slow the growth of cancer cells in culture, whereas many drugs have a much faster effect.
"No studies have looked at ginseng metabolism, so we don't know if it does hang around in the body very long," she adds. "There's so much research we need to do. But Asians who take ginseng regularly as part of a tonic take it every day. I think that may be important."
A junior in physiology, Jennifer Rice, won a Chancellor's Undergraduate Research Award to tackle the next step: isolating the compound responsible for Murphy's promising findings. Rice found it by testing different purified ginsenosides (there are at least 10 in American ginseng) in cell studies. A ginsenoside dubbed Rc works faster than whole ginseng, checking cancer cell growth within 48 hours.
"None of the other ginsenosides had any effect," says Murphy. "But with Rc, there's a very rapid suppression of prostate and breast cancer cell proliferation."
She adds, "Rc is quite different from the ginsenoside in Asian ginseng [that has similar effects]. It looks like they act through different mechanisms, because the Asian compound induces cell death and Rc doesn't. I'd like to combine them to see if they have an additive or synergistic effect on cell proliferation."
Murphy and Rice, who has since graduated and now works as a technician in Murphy's lab, are trying to determine how Rc acts. " We know so little about it," says Murphy. "Does it stimulate a receptor? Does it get inside the cell? What's it triggering or turning off in the cell? You have to have an idea of how [a substance] is acting before you can get into clinical trials."
By measuring the amount of DNA in a cell, an instrument called a flow cytometer can pinpoint the stage at which the cell's development has been arrested. From these tests, Murphy has found that Rc acts on the cells when they're relatively young—before they've begun to make new DNA in preparation for cell division. This narrows her search for the proteins and cellular mechanisms involved.
Murphy wants to test Rc in animals just as she's tested whole ginseng. But she's run into her first big obstacle: Rc is very expensive—about $100 per milligram—because it's hard to purify and no one has synthesized it. Even if she could afford the large quantities needed for animal studies, they aren't yet available.
"I'm in a corner," she says. She may try to find a chemist with whom she can collaborate to purify the substance.
In the meantime, there are other avenues to explore. Brian Williams, a student in SIUC's Medical Education Preparation program, is testing Rc in combination with various chemotherapy drugs to see if it boosts their effectiveness against cancer cells. Joseph Gonzalez, a senior in biological sciences, is comparing the effect of different doses of Asian and American ginseng extract on human prostate cancer cells. And Murphy is beginning to test whether American ginseng might prevent the onset of breast cancer.
Her team gave female rats ginseng-laced water for 2 weeks. Then they injected the rats with a carcinogen that, within 6-20 weeks, triggers the development of mammary tumors. The test rats are continuing to get ginseng in their water. A group of control rats also injected with the carcinogen are drinking plain water.
Murphy is eager to see how this experiment pans out. Her hunch is that American ginseng will ultimately "make more sense" as a preventive agent than as a cure, in part because of how expensive Rc is and in part because it doesn't kill cancer cells.
"Ginseng may turn out to be useful as a food supplement you can take to decrease the chances of onset of certain types of cancer," she says—just as we may choose to eat soy or broccoli for their phytoestrogens, antioxidants, and other substances.
Murphy does not suggest that people make a run on their local health food store. Reni Hill, a junior in physiology, has proved that this is a risk, if nothing else, to the wallet. Hill has been testing different ginseng supplements on cancer cells and finding that some are duds in terms of effectiveness. Her work squares with recent reports that some nutrition supplements contain next to none of the active ingredient touted on the label.
Ginseng has potential health risks, too. It appears to interfere with certain medications, and some people are allergic to it.
Beyond that, Murphy's findings, though promising, are very preliminary. American ginseng has not been used in a clinical trial—a rigorous process of testing on humans—to check safety and effectiveness against cancer. The path from the lab bench to the patient is a long one, and promising research often dead-ends. But Murphy is sufficiently convinced about ginseng's safety and its potential that she thinks the research "could move relatively quickly to clinical trials."
Murphy's work to date, which she presented at the American Society for Cell Biology's national meeting in December 2000, has attracted the interest of other scientists, some of whom now also want to test Rc. She welcomes the competition.
"If people want to jump on board and start getting results out, fantastic. The more people do, the more validated ginseng will become. I think it's important to alter our thinking about alternative treatments."
For more information, contact Laura Murphy, Ph.D., Dept. of Physiology, at (618) 453-8212.
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