Minnie Holmes-McNary, a molecular nutritionist, has an abiding interest in how the foods we eat affect our health—both positively and negatively. With Albert S. Baldwin, Jr., professor of biology, she has determined how trans-Resveratrol (Res) controls gene expression. A phytoalexin (an antibiotic compound produced by plants to combat pathogens such as fungal infections), Res is most abundant in red grapes, muscadine grapes, and grape products such as wine.

This is very exciting work because I believe it explains how diet modulates changes at the molecular level,” Holmes-McNary says.

As a doctoral student, she studied the deleterious effects of alcohol on the breast and alcohol’s role in the development of breast cancer. Intent on studying how diet affects gene expression, she joined Baldwin’s lab at the Lineberger Comprehensive Cancer Center as a postdoctoral fellow. It was 1997, and the discovery by University of Illinois scientists that Res, which is also found in mulberries, raspberries, and peanuts, has anticancer and anti-inflammatory attributes flooded both scientific and popular media. The scientists contended that Res was behind what has been dubbed the French paradox.

Much has been made of the observation that the French enjoy both a high-fat cuisine and lower rates of some cancers and coronary heart disease than Americans. The Illinois researchers proved that the French custom of taking Res-rich wine with meals was protecting them from the ravages of disease. But, they didn’t explain how Res worked its magic, and that missing piece to the puzzle intrigued Holmes-McNary.

The fact that trans-Resveratrol has both anticancer and anti-inflammatory potential made it very interesting,” she says. Holmes-McNary and Baldwin knew that to have those properties, Res had to be controlling gene expression. As she read the Illinois researchers’ findings, Holmes-McNary conjectured that Res was working through the protein NF-kB.

NF-kB is part of a delicate chemical cascade in which the activation of one protein initiates the successive activation of other proteins. For NF-kB to be released to a cell’s nucleus and function as a transcription factor (involved in proliferation and cell growth), the protein IkB kinase, which is upstream from NF-kB in the cascade, has to be activated—IkB kinase regulates NF-kB activation.

As a natural protective mechanism, NF-kB has a positive role—unless a cell is defective or damaged. Then, NF-kB’s role as a transcription factor takes on a sinister note. “If you look at cancer, NF-kB can play a negative role because it can promote the survival of cells that should die,” Holmes-McNary says. Ideally, if a cell is defective or damaged, it will initiate apoptosis (a process that the body uses to kill cancer and other defective cells), die, and be replaced by a normal cell. If a potential cancer cell is able to activate NF-kB, it will survive and proliferate.

After devoting considerable time to one assay, the researchers had their “eureka” moment. “The data were so clear that it was totally unmistakable,” Holmes-McNary says. “Trans-Resveratrol was inhibiting the function of IkB kinase, which inhibited the activation of NF-kB.” With NF-kB rendered inactive, a damaged or defective cell can initiate apoptosis.

Baldwin first reported several years ago that NF-kB appears to protect cultured cancer cells from attack by chemotherapies. “When NF-kB was switched off the chemotherapies were enhanced,” Holmes-McNary explains. She believes that dietary components such as Res increasingly will be used to augment cell sensitivity to chemotherapy.

Holmes-McNary finds the French paradox intriguing but not paradoxical. “Their dietary fat intake may be similar to ours in terms of type and amount consumed,” she says. But, there is one striking difference between our diets: The French have “the continuous dosing of Res from the wine they drink.” (According to the Wine Institute, in 1999, France ranked second in per capita wine consumption, while the United States ranked 33rd.) Holmes-McNary speculates that the French enjoy lower cancer rates “because daily dosing of Res may not allow their cancers the opportunity to progress as rapidly.”

To reap the benefits of Res, she includes Res-rich foods in her diet daily. Although red wines have some of the highest concentrations of Res, Holmes-McNary cautions against using Res as a license for overindulgence.

A twenty-year epidemiological study conducted in Nancy, France, showed that individuals who consumed more than four glasses of wine daily didn’t receive the anticancer benefit of Res,” she says.

The Carolina researchers’ findings are music to the ears of David Fussell, the owner of Duplin Winery in Rose Hill, North Carolina, which is the largest cooperative of scuppernong grape growers in North Carolina. The scuppernong, a muscadine grape that is native to North Carolina, tops the list of foods with high Res content.

Sales of his wines, which Fussell estimates at 35,000 cases annually, have picked up as awareness of the beneficial properties of Res and the scuppernong’s high Res content has grown. “That’s our biggest selling point,” he says.

The winery also produces a nonalcoholic elixir and is developing supplements made from the dried grape seeds and hulls, which should be available in early 2001. Land that supports tobacco is ideal for growing scuppernong grapes, so increased interest in the grapes could be a boon for North Carolina farmers.

For the study, Holmes-McNary used cultured cells from humans and animals because tissue culture allowed her “to really focus on how Res influences gene expression without the added complication of the whole body.” Cardiovascular, immune, and metabolic systems, for example, all affect dosing in studies using animals.

Holmes-McNary is putting the final touches on a grant proposal to duplicate the study in rats, whose genome is close to ours. “Animal studies will allow us to work out the quirks of dosing and will give us a good indication of what may happen in a clinical trial,” she explains. If the animal studies go as expected, the study will move to clinical trials in several years’ time.

Holmes-McNary and Baldwin’s findings have implications for heart disease because Res also inhibited the NF-kB-dependent gene MCP-1, which is involved in the development of atherosclerosis.

In the nutritional-science community, we’ve always known that fruits and vegetables are protective,” Holmes-McNary says. “Advances in molecular biology have made it possible to identify the mechanisms behind the protective attributes.”

Janet Wagner was formerly a staff writer for Endeavors.

This research appeared in the July 2000 issue of Cancer Research. The National Cancer Institute, PharmaScience, Inc., and the American Heart Association funded the research.