Plant compounds slow the growth of tumor cells

Researchers at UW–Madison report in the current issue of the Journal of Nutrition that small concentrations of two compounds from plants we eat suppress the growth of three kinds of human cancer cells in the laboratory.

The two compounds we studied suppress an enzyme. We think that this deprives tumor cells of chemical intermediates they need to multiply. The two compounds even work on human tumor cell lines that have mutations known to promote cancer. Charles Elson Nutritional scientist

“Our studies showed that cancer cells were more sensitive to these compounds than normal cells and that the two compounds had a stronger effect when combined than we would have expected from the action of either alone,” says Charles Elson, a nutritional scientist in the College of Agricultural and Life Sciences. “Our findings strengthen the idea that a diet rich in plants is beneficial because of the large array of plant compounds rather than the singular action of one kind of plant or one compound in plants.”

Elson suggests that the anticarcinogenic activity of these and similar plant compounds differs from the mechanism of other agents that block or suppress cancer cell growth. Unless controlled, cancer cells typically live and divide indefinitely.

“The two compounds we studied suppress an enzyme,” Elson says. “We think that this deprives tumor cells of chemical intermediates they need to multiply. The two compounds even work on human tumor cell lines that have mutations known to promote cancer.”

Studies consistently have shown that people who eat a diet high in fruits, vegetables and grains have a reduced risk of many types of cancer, including lung, alimentary tract, liver, pancreas, bladder, kidney, breast, endometrium, cervix and prostate.

What is it about these foods that limits cancer? In a quest reminiscent of the search for vitamins begun in the last century, scientists are trying to identify the beneficial compounds in the fruits, vegetables and grains we eat that control tumor growth.

Plants contain many beneficial compounds including fiber and micronutrients such as vitamins and their precursors. According to Elson, research initially focused on compounds such as vitamin A, vitamin E and folic acid. But clinical trials with them have been inconclusive at best, he says.

Other scientists have been examining non-nutritive compounds in plants. Elson has been studying compounds he calls isoprenoids, a group that includes more than 22,000 compounds. All are derived from a parent compound called mevalonic acid. Limonene and lycopene are examples of isoprenoids that inhibit cancer.

Many isoprenoids contribute to plants’ distinctive flavors and fragrances, Elson says. In plants, isoprenoids help regulate germination, growth, flowering and dormancy while attracting pollinators and protecting plants from insects and fungi.

Elson began working with isoprenoids because some can reduce cholesterol levels in animals. Initially he hoped that depriving tumor cells of cholesterol would make them susceptible to cancer treatments. But Elson’s early experiments showed he could not lower the cholesterol in tumor cells by feeding animals isoprenoids. However, he noticed that the isoprenoids slowed tumor growth.

To screen isoprenoids for those with anticarcinogenic activity, Elson tests them against a cell line developed from an extremely aggressive form of mouse melanoma. He has identified many isoprenoids that can slow the growth of this cell line. The tricky part has been finding isoprenoids that suppress cancer growth at the low concentrations that might occur in diets.

One such isoprenoid is gamma-tocotrienol, a compound found in cereal grains; it has a chemical structure related to vitamin E. In research published in 1997, Elson’s group showed that substituting gamma-tocotrienol for vitamin E in a diet fed to mice slowed the growth of tumors transplanted to those mice. It was the first research demonstrating that an isoprenoid slowed cancer growth and prolonged the life of mice when fed at a level that an animal might consume.

In the current paper, Elson and his graduate student, Huanbiao Mo, found that gamma-tocotrienol slowed the growth of cell lines from human leukemia and breast cancer. They also tested beta-ionone — an isoprenoid found widely in fruits and vegetables. Beta-ionone is related structurally to beta carotene, the precursor of vitamin A. Elson and Mo showed that beta-ionone also suppressed the growth of cell lines for human leukemia and breast cancer, as well as human colon cancer. The human cell lines were even more sensitive to the action of the isoprenoids than the mouse melanoma cells, according to Elson.

“We found that the human cancer cell lines were three times more sensitive to the isoprenoids than a non-cancerous cell line,” Elson says. “This raises the issue of why cancer cells might be more sensitive to these plant compounds than non-cancerous cells.”

Mo and Elson found that the isoprenoids interfered with the maturation of lamin B, a material cells need when they divide. Many of the tumor cells treated with the isoprenoids accumulated in a pre-division phase while many others entered apoptosis, or programmed cell death. The researchers showed that the isoprenoids suppressed the activity of 3 hydroxy-3-methyglutaryl coenzyme A (HMG CoA) reductase, an enzyme critical for the maturation of lamin B as well as the synthesis of cholesterol.

“We’ve known since the 1950s that tumor cells are more sensitive to reductions of HMG CoA reductase than healthy cells,” Elson says. “When isoprenoids inhibit the activity of this enzyme they disrupt the processing of mevalonic acid via the mevalonate pathway. We think the tumor cells need chemical intermediates produced from the breakdown of mevalonic acid for lamin B maturation and that isoprenoids slow tumor growth by depriving tumor cells of those intermediates.”

The nutritional scientist does not anticipate that his research will lead to a single critical isoprenoid or vegetable that people can eat to protect themselves from cancer. “These compounds act as a group to inhibit cancer growth,” he says, “with some enhancing the effectiveness of others.”

Nor does Elson believe in an exclusively vegetarian diet.

“I don’t think that it’s the presence of meat in diets that leads to health problems, but the lack of enough fruits, grains and vegetables. The people who eat a lot of animal products are often the same individuals that don’t eat enough fruits and vegetables,” he says.