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Supplement-size doses of antioxidants hasten lung cancer progression

By Anette Breindl, Science Editor

It is an article of faith among many health-conscious individuals that antioxidants are good for you – an article of faith that leads to a lot of vitamin sales. And in the typical “more is better” rationale that fuels many of those sales in the first place, most supplements provide many times the U.S. recommended daily allowance (RDA).

For example, “virtually every vitamin E supplement will give you at least fourfold the recommended daily dose for humans,” Per Lindahl told reporters at a press conference, and “10 to 15 percent of population is thought to take doses that are 15-20 fold of the RDA.”

But Lindahl and his colleagues at the Swedish University of Gothenburg have found that in mice, two separate antioxidants – the chronic obstructive pulmonary disorder (COPD) drug N-acetylcysteine and vitamin E – sped up the progression of lung tumors. Animals receiving either compound once they had lung cancer developed more tumors, and those tumors were more aggressive and ultimately killed the animals sooner than control animals who did not receive the vitamin.

The researchers published their findings in the Jan. 30, 2014, issue of Science Translational Medicine.

Vitamin E is touted specifically for its ability to prevent cancer. And those cancer prevention claims may, as a matter of fact, be true.

“Vitamin E might be beneficial for cancer prevention in normal, healthy people,” Martin Bergo told reporters at the press conference. “We are only able to say what happens to an existing tumor when you feed that antioxidant.”

The scientific rationale for why antioxidants should protect against cancer remains sound. Antioxidants scavenge free radicals, which damage cells in multiple ways. One of those ways is by inducing DNA damage, which can, beyond a doubt, lead to cancer.

Nevertheless, clinical trials addressing whether antioxidants do protect against cancer have been mixed. And “very few of them addressed the impact of antioxidants in people that may already have a tumor,” prompting Bergö and his team to address this question experimentally.

The team first induced lung tumors in mice by activating the oncogenes BRAF or KRAS, and then fed them one of two antioxidants: vitamin E or N-acetylcysteine.

Animals receiving either antioxidant lived, on the average, only half as long as those that were spared the treatment.

Perhaps ironically, the molecular reason appeared to be that antioxidants did what they are meant to do – they lowered cellular levels of reactive oxygen species or free radicals.

“A normal cell needs to protect itself from those free radicals,” Bergö explained. But “tumor cells also has free radicals inside them, and they might have quite high levels, because they metabolize fast and they proliferate fast. So it’s also in the tumor cells’ interest to lower levels of free radicals. And that’s what we’re doing” with the antioxidant treatment.

Lindahl elaborated that ultimately, the lower levels of antioxidants lead to lower levels of the tumor suppressor p53, allowing tumor cells to grow. “P53 can sense when DNA has been damaged by reactive oxygen species,” he told reporters, and when p53 levels are lower because antioxidant levels are lower, “it allows the cancer cells to escape their own defense system.”

The results are likely to receive the most – and the most histrionic – attention by people taking (or selling) antioxidant supplements, and they may ultimately prove broadly applicable to different antioxidants and different tumor types.

Both Bergö and Lindahl repeatedly cautioned at the press conference that it is too early to make any clinical recommendations. Instead, they said the most urgent consequence of their findings is the need to take a closer look at the effects of acetylcysteine on COPD patients.

Given the relationship between smoking, COPD, and lung cancer, many COPD patients may have small undiagnosed tumors whose growth could be accelerated by antioxidants.

“We need to find out quickly whether their use of the drug acetylcysteine will accelerate [COPD patients’] chances of developing lung cancer,” Bergö said, adding that his team is now looking at trial registries to see whether there is epidemiological evidence for such an increased risk.

Although the work was done mostly in mice, it was designed to be relevant to humans.

Lindahl said that his team chose to study lung tumors driven by activation of the oncogenes BRAF and KRAS, which are established players in human lung cancer. As a result, the tumors that the mice developed were genetically and microscopically “very similar” to human tumors. In their paper, the authors also showed that vitamin E and acetylcysteine accelerated the growth of cancer cells that had been isolated from human lung tumors. Finally, although the vitamin E doses the team tested were higher than the RDA for vitamin E, they are typical of what a person taking a supplement would actually ingest.

For that matter, vitamin E is not the only antioxidant supplement taken at high doses. Megadoses of vitamin C are popular for their supposed health benefits – and some doctors specifically recommend them for smokers, since smoking depletes vitamin C.

Bergo was circumspect in his interpretation of how his team’s results affect the risk-benefit ratio of vitamin supplements for smokers. “Our study doesn’t really let us make general recommendations,” he said. “But certainly, it needs to be studied . . . since vitamin C has antioxidant properties and patients who smoke may have a small undiagnosed tumor, it is certainly possible” that vitamin C supplements could increase the cancer risk for smokers.

Another thing his team wants to look at is how broad the antioxidant effect on tumors is. Although the team focused on lung cancer in the current study, he noted that other studies have found warning blips in other types of cancers. In 2009, for example, results from the SELECT (the Selenium and Vitamin E Cancer Prevention Trial) showed a slight increase in prostate cancer rates for men taking vitamin E.

The findings of the SELECT trial did not reach statistical significance. But, Bergo said, in combination with the data now published in Science Translational Medicine, as well as other data from research and clinical trials, it supports his belief that “this is going to be applicable to other types of cancer.”