Resveratrol, it seems, is turning into the duct tape of the biopharmaceutical industry. The compound is a much-touted anti-aging ingredient of red wine and dark chocolate, a metabolism health food supplement and experimental therapy – and now a possible chemotherapy drug.

That's the upshot of work published by scientists at the National Human Genome Research Institute, who have developed a new, high-throughput screen for genotoxins. With that assay, they have identified several compounds, including resveratrol, which might make good chemotherapeutic agents because they are genotoxic – that is, they damage DNA – without being mutagenic.

Resveratrol and two other compounds highlighted in the paper, baicalein and genistein, might make good chemotherapy drugs, senior author Kyungjae Myung told BioWorld Today, because they can damage DNA and induce cell death without introducing additional mutations into the genome.

Such additional mutations are a frequent result of DNA damage, with the consequence that chemotherapy, even as it kills most cancer cells, can put itself out of business by introducing resistance mutations into some of those cells.

Resveratrol, baicalein and genistein do not lead to mutations, Myung explained, because of the specific DNA polymerase that is recruited to repair the DNA damage they cause. One form of DNA damage is the specific chemical modification of a DNA base. When the DNA strand with the modified base is replicated, the cell's regular DNA replication machinery cannot replicate the modified base, and calls in specific repair polymerases.

Some of those polymerases replace the damaged bases nearly at random, introducing many mutations during their repairs. But the polymerase that repairs resveratrol-induced damage, pol-eta, is high-fidelity. As a result, even those cells that do not go into apoptosis after treatment with those agents at least are unlikely to sport new mutations that make them resistant to other treatments.

In their experiments, which were published in the March 19, 2012, online issue of the Proceedings of the National Academy of Sciences, Myung and his team described an assay they have developed that allows them to quickly screen agents for DNA-damaging agents.

Myung and his team developed the assay by making a cell line that contains a fusion between the ATAD5 gene, which is induced by DNA damage, and luciferase, the firefly protein that gives off a greenish glow. ATAD5, Myung explained, "is important to suppress genomic instability" after DNA damage.

ATAD5 could – and has been – used by itself as a biomarker of DNA damage. But its detection is fairly laborious. Fusing it to luciferase, Myung said, "makes measurements much more high-throughput" and allowed his team to screen nearly 4,000 compounds for the work reported in PNAS. (By now, that number has reached 300,000, and the assay also is being used by the National Institute of Environmental Health to screen for environmental toxins.)

Of the 4,000 compounds, just about 100 induced DNA damage in the assay. And the largest single group of those compounds – roughly a quarter of the total – consisted of antioxidants, prompting Myung and his team to look at the mechanism of antioxidant DNA damage in more detail.

They found that because cells use the high-fidelity pol-eta to repair such damage, resveratrol, baicalein and genistein all induced DNA damage without leading to mutagenesis. Furthermore, resveratrol and genistein were particularly effective at killing a multidrug-resistant cancer cell line.

Myung said that "some of our institute's clinicians are interested" in bringing the work to the clinic. His team currently is looking at the molecular mechanisms of the compounds in greater detail to see whether it is possible to identify cells that might be most vulnerable to those agents.

Many tumors are defective in specific aspects of DNA repair – for example, about 5 percent of breast tumors harbor mutations in one of the BRCA genes, and 10 percent to 15 percent of colorectal tumors are deficient in another repair mechanism, DNA mismatch repair. Myung, whose research team specializes in DNA repair, has about a dozen otherwise isogenic cell lines that are defective in specific DNA repair pathways. He and his colleagues plan to test whether any of those cell lines are especially vulnerable to certain ways of DNA damaging agents.

As for resveratrol's other roles in health, it may not be mutagenic. But the notion that it can cause DNA damage could be disconcerting enough for those who take the compound as a supplement or in clinical trials for metabolic disorders. Myung said, however, that resveratrol's ability to damage DNA does not necessarily mean that it cannot also be successful at improving metabolism.

The difference, he said, lies in the dose and the route of administration. "Our intestine cannot absorb [oral resveratrol] to the level that can cause cell death," he said. Even if a patient were to take oral resveratrol at a very high level, the compound might enter some of the intestinal cells lining the gut, but those cells are not replicating – and resveratrol can cause cell death "only when it goes into replicating cells."