University of North Carolina at Chapel Hill scientists have discovered why a compound found in grapes and grape products such as red wine shows natural cancer-fighting properties that might be important in preventing or treating the illness.

The work appears to explain the so-called "French paradox" -- the fact that French people experience lower rates of heart disease death and certain cancers despite drinking more wine on average than U.S. residents do.

Scientists found that the substance, trans-Resveratrol, or Res, modulates the activity of NF-kappa B, a protein that attaches to DNA inside cell nuclei and turns genes on and off like a switch, the scientists found. Res apparently helps turn off a natural protective mechanism in the body involving the protein that prevents cancer cells from being killed, as they should be.! r

A report on the work appears in the July issue of Cancer Research, a scientific journal. Authors are Dr. Minnie Holmes-McNary, a nutritional biologist and postdoctoral fellow at the UNC-CH School of Medicine’s Lineberger Comprehensive Cancer Center, and her mentor Dr. Albert S. Baldwin Jr., a biology professor who also works at the center.

"A couple of years ago, a group at the University of Illinois found that Res has both anti-inflammatory and anti-cancer properties," Holmes-McNary said. "The question then became how does it exert its effects, and that’s what we show in our paper."

Working with cultured human and rat cells, the scientists tested whether Res could inhibit both activation of NF-kappa B and NF-kappa B-dependent gene expression. They found that Res was a powerful inhibitor of the protein and appeared to work by controlling activity of another closely related protein called I-kappa B, which regulates NF-kappa activation.

! r "Using Res, we were able to promote apoptosis, a process that the body uses to kill cancer cells and other cells it needs to get rid of," Holmes-McNary said. "When Res was absent from the cell culture system, cancer cells continued to survive, but when Res was there under experimental conditions, we could successfully promote death of cancer cells by turning off NF-Kappa B."

Studies are now being planned to reproduce the findings in rodents, she said. If the animal experiments go well, the scientists may extend their work to humans within a few years. Epidemiological studies suggesting a protective effect of grapes and grape products such as red wine against heart disease and cancer began in the 1970s.

"This is very exciting work because we believe it explains how diet modulates changes at the molecular level," Homes-McNary said. "It provides a molecular rationale for the broad chemo-preventive properties of trans-Resveratrol and by extention, g! rapes and grape products."

Because the scientists also were able to inhibit a NF-kappa B dependent gene called MCP-1 that is involved in inflammation and development of atherosclerosis, the research also applies to cardiovascular disease, she added.

Res is found in many fruits and nuts, but is especially abundant in red grapes, mulberries, raspberries and peanuts, the scientist said. For that reason, she recommends that people consume more of them. Muscadine grapes, including scuppernongs, are rich sources of the compound.

Three years ago, Baldwin and other UNC-CH researchers first reported that NF-kappa B enables many cultured tumor cells to escape death when subjected to cancer-killing chemicals. After developing resistance to chemotherapy, cancer cells they studied continued reproducing and showed no ill effects from the treatment.

Last year, the scientists used a novel cancer gene therapy strategy to block NF-kappa B in mice with ! I-kappa B. Human tumors growing in the mice then became susceptible to chemotherapy and in some cases disappeared altogether following treatment.

Previously, no one had understood why many tumors become unresponsive to chemotherapy and radiation after a while, Baldwin said. NF-kappa B appears to be a front-line defense protecting both healthy cells -- and unfortunately cancer cells as well -- from chemical attack and other trauma.

In experiments reported last year, Baldwin and Dr. James C. Cusack Jr. of UNC-CH concentrated on human colorectal and fibrosarcoma tumors. They grew the tumors in mice and then treated them with a modified form of the inhibitor I-kappa B carried by a virus that could enter tumor cells. Treatment with a commonly used chemotherapy compound known as CPT-11 was far more successful, Baldwin said, when coupled with I-kappa B than when used by itself.

"These potential therapies, combined with dietary interventions such as in! corporation of Res into the diet, hold exciting possibilities for cancer treatment," Holmes-McNary said.

Support for the studies came from the National Cancer Institute and the N.C. affiliate of the American Heart Association.

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