Antioxidants and cancer – Of men and mice (1)

Antioxidants are good for your health. Such a statement seems to be popular wisdom these days, and the belief is certainly encouraged by the food and supplement industry. Even better: antioxidants protect against cancer (and according to the heavy advertising surrounding us, they also protect against a whole bunch of other diseases). But do they, really?

Antioxidants and cancer prevention: does taking supplements make a difference?

Let’s go back to why we entertain the idea that antioxidants protect against cancer in the first place. The rationale is simple: free radicals are highly reactive chemicals that can damage DNA; DNA damage can in turn lead to tumor formation; antioxidants are molecules capable of neutralizing free radicals; therefore, antioxidants can prevent tumor formation. It seems very logical, but unfortunately, biology is often more complex than a series of logical steps.

When scientists began to understand that free radicals were involved in the development of atherosclerosis (and possibly other diseases) in the 1990s, the word “antioxidant” left the chemistry labs and invaded the public stage. Intrigued by the potential benefits, the scientific and medical community set up clinical trials to determine whether dietary supplementation with antioxidants could have an impact on preventing heart disease or cancer. Meanwhile, the food and supplement industry and the media went directly on to praise the benefits of antioxidants, be it the newest kind of berry on the market, green tea, dietary pills or additives to breakfast cereals (forget about all the sugar, look at the amount of antioxidants we packed in here!).

However, antioxidant supplements have not delivered the hoped-for benefits. When it comes to cancer and heart disease prevention, the largest randomized clinical trials (which provide the most reliable evidence) have yielded negative results. For example, in1996, the Physician Health’s Study conducted in the US with about 22,000 men followed-up for 14 years found no difference in rates of cancer, cardiovascular disease, or overall mortality, between men who had taken beta-carotene supplements (50 mg every other day) and men who had taken a placebo over the 13-14 years of study (1). Other trials have led to similar conclusions: antioxidants supplements have no substantial impact on healthy people in terms of important things such as preventing cancer or premature death (here is a blog post pointing at several of these studies).

Antioxidant supplements vs fruit and vegetables

Of course, the fact that antioxidant supplementation does not seem to make a difference in preventing cancer or heart disease does not mean that antioxidants in general are useless.

First, it’s important to remember that the word antioxidant does not represent just a few precious vitamins, but actually a chemical property shared by many different molecules. Antioxidants are not just beta-carotene, vitamin E, or selenium, but many other chemicals that we can get from food or that our own bodies can make. So, even if potentially harmful free radicals are constantly made in our bodies, we are equipped to deal with them.

Secondly, the absence of detectable benefits from antioxidant supplementation does not mean that a diet rich in antioxidant-containing foods (fruit and vegetables notably) is not associated with benefits. Taking a given antioxidant isolated in a pill is not likely to provide the same benefits as eating fruits and vegetables, which contain not only different antioxidants, but also lots of other useful substances. The absence of benefits from supplementation may also simply mean that humans already derive benefits from antioxidants obtained from a balanced diet and that adding a pill here or there does not make a substantial difference.

What about taking supplements, “just in case”?

It could be argued that not all antioxidant supplements nor all combinations of antioxidants have been studied in large trials, and that trials may not have been long enough yet to see potential benefits of antioxidant supplementation. So why not take a few vitamin supplements, just in case? Surely there is no harm in doing that?

If we were sure that antioxidants are harmless in all situations, then it would not matter much indeed – except perhaps to your wallet. However, a few studies have raised potential red flags against the indiscriminate use of antioxidant supplementation (see next section). A Cochrane review published in 2012 even reported that the use of supplements (beta-carotene, possibly vitamin E and vitamin A) was associated with a slight increase in mortality (2).

There is a growing tendency in our society to equate “natural” with “safe”. Most people would agree that snake’s venom, though perfectly “natural”, is not quite “safe”. However, when the conversation turns to food, vitamins or dietary supplements, the distinction between “natural” and “safe” does not seem straightforward anymore. The logic goes that if one is already getting antioxidants from the diet without experiencing any adverse effect, and antioxidants protect from damage induced by free radicals, then there can be no harm in taking a little bit more. But again, biology is more complex than that. Context matters. Subtle variations in quantities matter. A whole lot of other factors come in to complicate the apparently simple initial equation.

Antioxidant supplements and the particular case of lung cancer

In 1994, a large trial conducted in Finland and following about 29,000 male smokers for 5 to 8 years reported that beta-carotene supplementation actually increased the incidence of lung cancer by 18% (3). A similar trial conducted in the US and involving about 18,000 smokers, former smokers, or workers exposed to asbestos (all three conditions known to increase the risk of lung cancer) also found that supplementation with a combination of beta-carotene and vitamin A increased the risk of lung cancer: the risk of developing lung cancer for men taking the supplement was 28% higher than that for men taking a placebo (4). As a result of these findings, the trial was in fact stopped earlier than planned, for obvious ethical reasons.

One difficulty with such trials is of course how to interpret the results. Although there was a statistically significant increase in the incidence of lung cancer in the group of men taking beta-carotene in the Finnish study, there was at the time no plausible biological explanation for such a finding, and the researchers wondered whether their findings were indeed representative of a true clinical phenomenon. The American study, by also reporting an adverse effect of antioxidant supplementation, gave additional weight to the possibility that antioxidants were indeed detrimental in the particular case of people already at high risk of developing lung cancer. However, a biological explanation was still missing.

A study recently published in Science Translational Medicine now shows that antioxidant supplementation accelerates lung cancer progression in mice (5). The researchers also suggest a potential molecular mechanism to explain how antioxidants may be detrimental in this setting, thereby providing clues as to what the missing biological link (or at least part of it) may be. (If you want to know more about this study, look here.)

A few take-home messages

– So far, reliable large-scale studies have not detected any substantial positive impact of antioxidant supplementation on cancer or heart disease prevention.

– Some clinical trials have actually detected the possibility that antioxidant supplements increase the risk of lung cancer in certain individuals already at risk. A study recently published in Science Translational Medicine brings support to these clinical trials by providing experimental data and suggesting a potential biological mechanism to explain how high amounts of antioxidants may increase lung cancer risk.

– Important note: a link between cancer risk and antioxidant supplements for certain people does not mean that fruits and vegetables would be harmful for these people. Indeed, supplementation means getting antioxidants in amounts much higher than what is contained in a normal diet.

– Fruit and vegetables contain many substances of potential benefit beyond antioxidants, so for now, the bottom line seems to be: eat fruit and veggies, and don’t waste time and money on searching for the wonder supplement pill.

Further reading (a selection of what I’ve stumbled upon while preparing this post):

Antioxidants: Beyond the Hype. Harvard School of Public Health
The antioxidant myth is too easy to swallow. Henry Scowcroft. The Guardian
Cancer Research UK:
– Science blog – Series: Antioxidants
– Science blog – Vitamin supplements do not reduce the risk of cancer. Ed Yong
Diet and cancer: the evidence (links to many scientific studies)
Down with antioxidants. Ariel Fenster. McGill University, Office for Science & Society blog.
Enough is enough: stop wasting money on vitamin and mineral supplements. Editorial, Annals of Internal Medicine (American College of Physicians).

References

1. Lack of Effect of Long-Term Supplementation with Beta Carotene on the Incidence of Malignant Neoplasms and Cardiovascular Disease. Hennekens CH, Buring JE, Manson JE, et al. N Engl J Med 1996; 334:1145-1149. doi: 10.1056/NEJM199605023341801

2. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD007176. doi: 10.1002/14651858.CD007176.pub2

3. The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers. The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994; 330:1029-1035. doi: 10.1056/NEJM199404143301501

4. Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease. Omenn GS, Goodman GE, Thornquist MD, et al. N Engl J Med 1996; 334:1150-55. doi: 10.1056/NEJM199605023341802

5. Antioxidants accelerate lung cancer progression in mice. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO. Sci Transl Med. 2014 Jan 29;6(221):221ra15. doi: 10.1126/scitranslmed.3007653
PMID: 24477002

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