Antioxidants Accelerate the Growth and Invasiveness of Tumors in Mice

November 12, 2015, by NCI Staff

Evidence from two new studies in mice shows that antioxidants—dietary supplements commonly used in the belief that they may help prevent disease—may actually promote tumor growth and metastasis. 

The new findings, authors from both studies said, suggest that cancer patients and people with an increased risk of cancer should avoid taking antioxidant supplements.

It had long been hypothesized that antioxidants might be able to protect against cancer because they neutralize reactive oxygen species (ROS) that can damage DNA. In laboratory and animal studies, the presence of increased levels of exogenous antioxidants has been shown to prevent the types of free radical damage that have been associated with cancer development. 

However, multiple large randomized, placebo-controlled prevention clinical trials failed to substantiate this idea. Some of the largest clinical trials, in fact, had to be aborted because the patients receiving antioxidants had a higher incidence of cancer than patients who did not receive them.

To investigate how antioxidants might affect cancer progression, Martin Bergö, Ph.D., of the University of Gothenburg in Sweden, led a 2014 study in mouse models of human lung cancer. The researchers found that adding the antioxidants N-acetylcysteine (NAC) or vitamin E to the diet of mice with small lung tumors substantially increased the number, size, and stage of the tumors. Additional work showed that the NAC and vitamin E reduced levels of ROS and DNA damage in cancer cells, and essentially eliminated expression of the gene p53—a tumor suppressor gene that is typically activated by DNA damage.

These findings, Dr. Bergö said, provided a plausible explanation for why the male smokers who received antioxidants in the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study in Finland had a higher incidence of lung cancer than those who received a placebo. The simplest explanation, Dr. Bergö said, is that when the trial recruited patients, many of them had small, undiagnosed lung tumors, which progressed more rapidly when they were given antioxidants.

In their most recent study, published October 7 in Science Translational Medicine, Dr. Bergö’s team examined the effects of antioxidants on melanoma. They chose to study melanoma because the incidence of melanoma is increasing in the United States and Europe, melanoma cells are sensitive to oxidative stress, and a good mouse model of melanoma already exists, Dr. Bergö explained.

Although supplementation of drinking water with NAC didn’t increase the number and size of the primary melanoma tumors in the mice, the researchers found that it doubled the number of lymph node metastases.

To understand what the antioxidants were doing in the mice, the researchers measured how the antioxidants were affecting glutathione—the main antioxidant that is naturally produced by the body. The ratio of reduced glutathione to oxidized glutathione is an indicator of how much oxidative damage cells are experiencing. This ratio increased only a little in the primary tumors but increased greatly in the metastases, suggesting that the antioxidant was reducing oxidative stress specifically in the metastatic cancer cells of the mice.

In human melanoma cell lines, the researchers found, treatment with NAC and the soluble vitamin E analogue (Trolox) didn’t affect cell proliferation, but it did increase the cells’ ability to invade and migrate.

In the other recent study, published October 14 in Nature, Sean Morrison, Ph.D., of the University of Texas Southwestern Medical Center, and his colleagues provided additional evidence that antioxidants can promote cancer metastasis. In mouse models of melanoma, the researchers found, levels of oxidative stress were higher in circulating cancer cells than in cancer cells in primary tumors. Oxidative stress actually interfered with the formation of metastatic tumors, they found. Treating these mice with antioxidants decreased oxidative stress in the circulating cancer cells and increased their ability to metastasize.

“Administration of antioxidants to the mice allowed more of the metastasizing melanoma cells to survive, increasing metastatic disease burden,” Dr. Morrison said in a press release.

The findings support the idea that antioxidants, by reducing oxidative stress, benefit tumor cells more than they benefit normal healthy cells, Dr. Morrison added. The results also support the idea that treating patients with pro-oxidants might be a way to prevent metastasis, he said.

In fact, methotrexate, a commonly used cancer drug, has pro-oxidant properties. The drug works by inhibiting an enzyme called dihydrofolate reductase (DHFR), which plays a key role in the metabolic pathways that produce glutathione, as well as the pathways that produce new DNA bases. By blocking DHFR, methotrexate interferes with DNA replication and increases oxidative stress.

Based on the available evidence, Dr. Bergö said he was extremely concerned with the aggressive marketing of antioxidants to cancer patients. The data strongly suggest that using antioxidants “could be really dangerous in lung cancer and melanoma, and possibly other cancers,” he said. “And because there’s no strong evidence that antioxidants are beneficial, cancer patients should be encouraged to avoid supplements after they have a diagnosis.”