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Environmental Factor, April 2012

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High-throughput screening finds surprising properties for antioxidants

By Larry Thompson

Kyungjae Myung, Ph.D.

Myung's laboratory investigates genome instability, which is a characteristic of cancer and many genetic disorders, by examining the mechanisms of DNA repair and replication, as well as their roles in the production and suppression of gross chromosomal rearrangements. (Photo courtesy of NHGRI)

Raymond Tice, Ph.D.

Tice is the lead coordinator for the NTP High Throughput Screening (HTS) Initiative and plays a key role in the efforts of the Tox21 community. (Photo courtesy of Steve McCaw)

Antioxidants have long been thought to have anti-aging properties, primarily by protecting a person’s genetic material from damaging chemicals. The story, however, now appears to be much more complicated.

National Institutes of Health researchers from two institutes and one center have demonstrated that some anti-oxidants damage DNA and kill cells instead of protecting them. The findings, published March 19 in the Proceedings of the National Academy of Sciences, also suggest that this surprising capability may be good for treating cancer, but may prove cautionary when using antioxidant-based medicines to treat other disorders, such as diabetes.

An unexpected discovery

“It’s an unexpected discovery,” said Kyungjae Myung, Ph.D., a senior researcher in the Genetics and Molecular Biology Branch of the National Human Genome Research Institute (NHGRI), and the senior author on the report.

“This report demonstrates the ability of the high throughput screening program to generate findings that may impact on human health,” said co-author Raymond Tice, Ph.D., chief of the NIEHS/NTP Biomolecular Screening Branch. “In this case, the technology is helping to identify potential drug candidates for treating cancer.”

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Many people attempt to boost their levels of antioxidants by eating fruits and vegetables, nuts and grains, or by taking supplements. By adding antioxidants to the diet, many people hope to slow down the process that some believe contributes to the normal process of aging.

DNA repair

Myung did not set out to challenge this anti-aging strategy. His lab studies DNA repair, the enzyme systems within a cell that fix mistakes and other damage accumulating routinely in DNA as cells live and divide. Researchers know that naturally occurring defects in DNA repair can lead to a number of disorders, including cancer.

Myung’s group sought a new way to easily identify chemicals that damage DNA and then use those chemicals to study cellular repair mechanisms, a basic research question. Using a laboratory-grown cell line from human kidneys, the team developed a novel laboratory test that readily shows when a chemical exposure damages DNA.

With the test developed, Myung’s team formed collaborations with two other NIH research groups. The first was with what is now the NIH National Center for Advancing Translational Sciences (NCATS). Over the last several years, a team lead by Christopher Austin, M.D., head of the NCATS labs, has developed high-throughput chemical screening systems using robotics. Austin agreed to use Myung’s test to screen thousands of chemicals for their ability to damage DNA. But what chemicals should they test?

Tox21 — testing chemicals faster and more efficiently

In 2008, NCATS (then part of NHGRI), NIEHS/NTP, and the U.S. Environmental Protection Agency (EPA) formed the Tox21 initiative to develop high-throughput screening tests that measure cellular harm caused by environmental chemicals. The Tox21 team created a library of some 2,000 compounds and agreed to test them against Myung’s assay. The NHGRI researchers also added a commercially available chemical collection to the screening runs for a total of some 4,000 chemicals.

The screening runs produced surprises, identifying 22 antioxidants that damaged DNA. Three of the antioxidants — resveratrol, genistein, and baicalein — are currently used or being studied as an anti-aging intervention, as well as a treatment for several disorders, including heart disease, type 2 diabetes, osteopenia and osteoporosis, and chronic hepatitis.

Not only did the antioxidants damage the DNA, the researchers found, but, in dividing cells such as in tumors, the antioxidants could be lethal, killing the disease-causing cells. Despite their ability to damage DNA, the chemicals did not cause genetic mutations, making them particularly good candidates for improved cancer drugs.

Cool biology — new research avenues

“This is what’s cool about biology,” Austin said. “Just when we think we understand something, it turns out to be more complex than we thought. Not only did the NHGRI team produce a novel way to measure DNA damage, but their test has given us insights into the effects of chemical compounds that were not seen in more conventional strategies.”

The discovery opens up several new lines of research. As a first step, the collaborators are dramatically expanding the number of compounds — more than 300,000 — to be screened with the new test. The Tox21 team also has decided to include the test in its standard screen for biological harm produced by environmental chemicals.

Citation: Fox JT, Sakamuru S, Huang R, Teneva N, Simmons SO, Xia M, Tice RR, Austin CP, Myung K. 2012. High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death. Proc Natl Acad Sci U S A; doi:10.1073/pnas.1114278109 [Online 19 March 2012].

(Larry Thompson is the communications director for the National Human Genome Research Institute.)

Findings about compounds that damage DNA, but may treat cancer

The clinical implications for these findings are more complicated. This initial discovery is only in lab-grown cell lines, not even in intact organisms. The relevance for humans has yet to be demonstrated.

Still, there is plenty of work already underway. Other research teams have launched various studies of these DNA-damaging antioxidants in various diseases. For example, 44 studies are currently listed in for resveratrol, which is found in many foods, including red grapes and wine, peanuts, and chocolate. The studies focus on treating Alzheimer’s disease, type 2 diabetes, obesity, inflammation, colon cancer, multiple myeloma, and testing other anti-aging strategies, among others. The newly reported study does not suggest that resveratrol in red wine is harmful, because the dose is probably too low to be significant, Myung said.

Researchers also have launched 43 studies on genistein, including trials to treat cancers of the prostate, pancreas, bladder, breast, kidney, and skin (metastatic melanoma) and as adjunct treatments for rare diseases, such as cystic fibrosis.

Even though the antioxidants damaged the DNA, the researchers reported that the chemicals did not cause genetic mutations — another surprise. “Because they don’t cause genetic mutations, antioxidants may be useful for treating cancer,” Myung said. “Standard chemotherapy mutates the tumor’s DNA, speeding its evolution and sometimes allowing it to escape the toxic treatment intended to kill it. This leads to multidrug resistance in some cancer patient’s disease.”

To test whether the antioxidants might help, the NHGRI team borrowed some multidrug resistant cancer cells from Michael Gottesman, Ph.D., a National Cancer Institute researcher and NIH Deputy Director for Intramural Research. Although these cells are very resistant to anticancer drugs, treatment with resveratrol appeared to sensitize the cancer cells, leading to their death. “Resveratrol,” Myung said, “could prove useful in treating multidrug resistant cancers.”

The findings do raise concerns about using antioxidants to treat disorders, as treatment with high doses may cause unexpected DNA damage that leads to other problems. “Clearly,” Myung said, “much more study will be needed.”

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