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June 2003

Selenium for better DNA repair

Carmia Borek Ph.D.

Selenium's anticancer effects have been appreciated for over 20 years with no clue about the mechanism of its cancer preventive activity. Shown to reduce human risk of colon, lung and prostate cancer and now in clinical trials for prostate cancer-prevention, selenium, as one of the most promising cancer preventive agents, has challenged scientists to discover its ways. Researchers have generally focussed on two modes of action that could explain its protective effects; selenium prevents cancer through its antioxidant activity, by scavenging DNA-damaging, cancer-causing free radicals; or, selenium has a corrective function in cancer prevention, by selectively inducing genetically programmed cell suicide (apoptosis) that rids the body of DNA damaged cells that are potentially cancerous.

New research now offers an additional and compelling mechanism. In a recent report, in the Proceedings of the National Academy of Sciences, Seo and colleagues at Indiana University show that selenomethionine, the form of selenium found in food, prompts human cells whose DNA has been damaged to switch on DNA repair, a key requirement in preventing cancer.

Selenomethionine, through a series of steps, modifies a regulatory cellular protein called p53 (functional in normal but lost in tumor cells), which turns on a DNA repair pathway.

Using ultraviolet light to damage cellular DNA, the research team found that treatment of the cells with selenomethionine activated a protein called Ref-1 that switched on p53 causing a three fold increase in p53 activity and a doubling of DNA repair in the cells. As a result, cells with functional p53 can tolerate higher doses of ultraviolet light if grown and maintained in the presence of selenomethionine.

Because cancer originates from an accumulation of DNA damage and cancer-causing mutations, any natural mechanism that would provide a stable repair system would contribute to cancer prevention. The likely protective action of selenium is that as long as selenomethionine is present in the normal cells it causes a permanent p53-directed stimulation of DNA repair; this reduces the accumulation of cancer-causing mutations in the cell and prevents the onset of the disease. This mechanism of action may be central to selenium's anticancer powers.

The investigators treated the cells with selenomethionine in the range used in previous chemoprevention clinical trials. As the authors explain "Cancer prevention use of selenium consists of 200 micrograms per day, exceeding the {recommended dietary allowances} by four fold with no toxicity." Indeed, the landmark 1996 randomized clinical trial, led by the late Larry Clark, showed that a daily intake of 200 micrograms selenium reduced the overall risk of developing cancer by 40%, compared to placebo.

The new work underscores the importance of selenium in the diet; it raises an exciting possibility that people with normally functioning p53 could boost their capacity for DNA repair and reduce cancer risk by increasing selenomethionine dietary intake. The importance of this idea hinges on earlier findings that some people are naturally more proficient than others in repairing DNA, and that these differences in repair-capacity can be correlated with cancer risk.

Fat that may benefit diabetics
reduces weight, blood sugar

New research suggests that supplementing the diet with conjugated linoleic acid (CLA) may lead to better weight control and disease management in diabetics.

A new study published in the January issue of the Journal of Nutrition has found that diabetics who add CLA - an essential fatty acid made up of various fatty acid isomers - to their diet had lower body mass as well as lower blood sugar levels by the end of the eight-week study. Hyperglycemia, or high blood sugar, is a hallmark of diabetes. Researchers also found that higher levels of this fatty acid in the bloodstream meant lower levels of leptin, a hormone thought to regulate fat levels. Scientists theorize that high leptin levels may play a role in obesity, one of the biggest risk factors for adult-onset diabetes.

"In previous work, we found that CLA delayed the onset of diabetes in rats," said Martha Belury, the senior author of the study and an associate professor of human nutrition at Ohio State University. "In this study, we found that it also helped improve the management of adult-onset diabetes in humans."

According to researchers, in the current study they have found that one particular CLA isomer, t10c12-CLA (10-12 isomer) helped to control both body weight and leptin levels. In that study, the researchers asked 21 people with adult-onset diabetes to take either a supplement containing a mixture of rumenic acid and 10-12 isomer or a safflower oil supplement as a control daily for eight weeks. Rumenic acid is the predominant isomer in foods that contain CLA, while the 10-12 isomer is less abundant.

"The amount of CLA, how long it's taken and the type all impact the fatty acid's ability to affect obesity in humans and therefore help manage diabetes," Belury said.

At the study's conclusion, blood samples from the participants revealed that fasting blood glucose levels had decreased in nine of 11 people taking the CLA supplement, but only in two of the 10 taking the safflower supplements, suggesting that CLA was helping to control certain symptoms of diabetes.

In addition, the researchers also examined the impact each isomer had on changes in body weight and leptin levels. According to their results, it was the 10-12 isomer, and not rumenic acid, that was linked to a reduction of body weight and leptin levels. Also, the average weight loss among patients taking CLA supplements was low - on average 3.5 pound - while the group taking the safflower supplement had no weight change. In addition, leptin levels decreased in the CLA group and rose slightly in the safflower group.

"The effect of the 10-12 isomer on reducing body mass and leptin levels was key," Belury said. "Other researchers have shown the 10-12 isomer to be helpful in reducing body mass in animals."

A promising new treatment for Parkinson's disease

A new treatment for Parkinson's disease recently yielded impressive results as all of the patients in a preliminary trial showed measurable progress. According to the findings reported in a recent online issue of the journal Nature Medicine, the new bioengineered medication - called glial cell line-derived neurotrophic factor (GDNF) - is a potential breakthrough in combating the degenerative effects of Parkinson's disease. "All five patients showed improvement, some more than others. Some symptoms were more affected," said neuroscientist and trial researcher Clive N. Svendsen of the University of Wisconsin-Madison.

Parkinson's disease is a progressive disorder of the nervous system that affects an estimated 1.2 million people in the United States and Canada. Symptoms include tremors, body rigidity and problems in movement. While the disease's cause is unknown, most symptoms stem from a lack of the neurotransmitter dopamine. Currently, most drugs used to treat the disease restore dopamine or mimic its action, but do not act permanently.

In the new trial, however, a miniature battery-driven pump implanted into the chest delivers a continuous dose of GDNF deep into the substantia nigra region of the brain where dopamine is produced. Results thus far suggest that GDNF shields healthy brain cells from the disease and causes damaged cells to regenerate.

"The drug eliminated the periods of immobility that had occurred as much as 20% of the time before treatment and reduced or stopped the involuntary movements common to the disease," said Dr. Svendsen. "Also, the senses improved for three patients who had lost the ability to taste or smell."

Typically, the first stages of human testing are limited in scope - using only a small pool of subjects to examine the safety issues associated with a new medication. Only then can larger, double-blind tests be set up to examine how effective the medication is. According to Dr. Svendsen this phase one test has continued for nearly two years with no side effects to the patients.

"Our main concern was the safety issue, and it is important to keep in mind the limited scope of the trial - but the clinical results we observed were impressive. The results show that the drug GNDF is worth studying very carefully as a possible treatment for Parkinson's disease."