ANTIOXIDANTS PROBABLY HARMFUL IN CANCER

While alternative health gurus often encourage increasing antioxidants in the diet and the taking of antioxidant nutritional supplements such as beta-carotene, vitamins A, C, and E, and selenium, new research findings suggest that antioxidants could do more harm than good, especially in cancer patients.

The idea is discussed in a perspective article on the promise and perils of antioxidants for cancer patients in the July 10 issue of the New England Journal of Medicine.

Coauthor David Tuveson, MD, PhD, professor and deputy director of the Cold Spring Harbor Laboratory Cancer Center in New York, explained in an interview with Medscape Medical News that the idea that antioxidants could be useful in cancer goes back to Linus Pauling, and is based on observations that oxidation within cells is needed for cell growth. "As cancer cells growth rapidly, a cancer cell would have more oxidation within it than a normal cell," he added, and the hope was that antioxidants would interfere with these cellular oxidative processes and would suppress the growth.

"Although some early preclinical studies supported this concept," the authors write, there have now been several clinical trials that have shown no effect of antioxidants on reducing the incidence of cancer, and there have even been suggestions of harm in persons who are at risk for cancer.

Dr. Tuveson noted a clinical trial from Scandinavia in the early 1990s, which found that high doses of antioxidants, particularly beta-carotene, were associated with more lung cancer rather than less as had been hoped for.

There was a similar finding from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which found that the antioxidants did not reduce the risk for prostate cancer, as had been hoped, and in fact increased the risk in some men.

Dose-dependent Harmful Effect

The perspectives article was prompted by new findings reported earlier this year, he said. An animal study carried out by Swedish researchers showed that the harm from antioxidants was dose-dependent (Sci Transl Med. 2014;6:221ra15). The study was conducted in a genetically engineered mouse model that mimics early human non-small-cell lung cancer. The researchers studied N-acetylcysteine (which is used in patients with chronic obstructive pulmonary disease) and also derivatives of vitamin E, and they found that these antioxidants "actually increased cancer burden and mortality in a dose-dependent manner."

"The mice got lung cancer faster and they died more quickly of the disease," Dr. Tuveson said.

In their perspective article, Dr. Tuveson and coauthor Navdeep Chandel, PhD, from Northwestern University in Chicago, address the question of why.

It turns out that all cells have not only oxidative mechanisms producing reactive oxygen species, they also have a mechanism by which they produce antioxidants, and so there is a balance between the 2 in each cell. "And cancer cells, because they make more oxidants, also make more antioxidants," Dr. Tuveson explained.

"So when adding an antioxidant as a supplement, all you are doing is increasing a pool of what is already there," he said. "But you are not actually stopping the oxidative mechanisms, and you are not stopping the production of oxidants in the first place, and the pathways that are fuelling cell growth," he added."All you are doing is helping the cancer cell deal with the toxic effects of the oxidants, and by doing so you may be actually making the cancer cell even stronger," Dr. Tuveson said."The antioxidants that we take as a supplement or in our diet don't go after the root cause of how oxidants promote cancer cell biology,...and our suggestion is that we need to look much more carefully at these mechanisms if we are to truly develop strategies to prevent cancer," he said.

In their article, the authors propose 2 strategies for further research — the development of antioxidants that target specific intracellular sites of oxidant production, and also a synthetic lethal strategy directed at antioxidants produced within the cell. Both of these strategies are currently at the research stage, with work focused on developing compounds that could be tested in humans.

As for the clinical implications of the research so far, Dr. Tuveson said: "We don't firmly say that taking antioxidants is dangerous for cancer patients...but I do believe that our article will cause those discussions to begin."

However, others have already warned cancer patients not to take antioxidants; for instance, prostate cancer patients have been warned against taking selenium, as previously reported by Medscape Medical News.

In addition, there is a question of whether antioxidants may interfere with common cancer treatments, such as chemotherapy and radiotherapy, as these work by increasing oxidation within cancer cells, Dr. Tuveson commented. This is an area that needs to be studied more, he said.

This issue of antioxidants being harmful to cancer patients was raised last year by Nobel laureate James Watson, PhD, who is chancellor emeritus at the Cold Spring Harbor Laboratory. He described a new hypothesis on reactive oxygen species that he considers is "among my most important work since the double helix."

Dr. Watson proposed that antioxidant levels within cancer cells are a problem and are responsible for resistance to treatment, and that the untreatability of late-stage cancer might be the result of "its possession of too many antioxidants."

"The time has come to seriously ask whether antioxidant use more likely causes than prevents cancer," Dr. Watson said. Nutritional intervention trials have shown no obvious effectiveness in preventing cancer or in lengthening mortality, and, "in fact, they seem to slightly shorten the lives of those who take them."

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