Who doesn’t take antioxidant supplements nowadays? The ads promise a longer and happier life, bigger muscles, great sexual performance, and miracle cures for arthritis symptoms.

To be sure, some specific antioxidant formulations are useful in the treatment of certain conditions. The most prominent of these is the AREDS (for age-related eye disease study) formula for age-related macular degeneration. The original formula contains vitamin C, vitamin E, beta-carotene, zinc, and copper. However, because of an association to increased risk of lung cancer in smokers (more on this later), beta carotene was replaced with lutein and zeaxanthin in the subsequent formulation (AREDS2).

But despite evidence for benefit in a limited number of conditions, it is now becoming increasingly clear that antioxidant supplements can cause serious harm—and it is all about the free radicals.

 

What are free radicals?

Although I have written about this before in my August 2015 post, Are Antioxidant Supplements Worth the Price, it is worth reviewing the details here.

oxygen free radical
Graphic credit: HonChemistry | CC SA 3.0 license

A free radical is a molecule that is missing one electron from its complete, neutral state. Since an electron is negatively charged, the free radical is positively charged. For instance, when oxygen is missing one electron it becomes an oxygen free radical, also called ROS, for Reactive Oxygen Species, and that’s how we’ll refer to them in this article.

One and a half billion years ago, eukaryotic (i.e. possessing a nucleus) single cells in the primordial soup were invaded by parasitic bacteria. But they co-opted the invaders by providing them with nutrients in exchange for the bountiful energy they produced by using oxygen to metabolize glucose. With time, these bacteria lost their capacity to survive independently and became part of the cells they parasitized. These are the mitochondria of today’s cells.

 

Nothing comes without a price

The aerobic metabolism of glucose (also called oxidative phosphorylation) produces a by-product: ROS. These pesky radicals can be injurious to the cell. They can attack DNA and produce mutations. They can also attack the cell’s proteins and its membrane lipids.

Let’s focus on the important damage to DNA. As we said, the oxidative stress exerted by ROS can lead to enhanced mutation rates, promoting the transformation of a normal cell into a tumor cell. So, it was a ‘no-brainer’ to postulate that if we could quench the voracious ROS, perhaps we could use antioxidants to prevent, and even treat, cancer.

 

Surprise!

On this basis, large-scale multicenter clinical trials of antioxidant supplementation were carried out. However, this supplementation not only failed to benefit patients but was associated with a significant increase in cancer incidence.

Dietary supplementation with vitamin E, for example, significantly increases the risk of prostate cancer in healthy adults. Another study showed that dietary supplementation with vitamin E and beta-carotene (a vitamin A precursor) increases the incidence of lung cancer in male smokers.

Doesn’t make sense, right? If antioxidants eliminate molecules that promote tumor growth, how can they also cause tumor growth? Well, this is a classic case of when a little bit of knowledge is dangerous.

 

The wily tumor cell

How can normal cells withstand the oxidative stress exerted by ROS? Evolution saw to it that we survive by equipping the cell with molecules and enzymes that are antioxidants, protecting the cell from damage. Now, consider that tumor cells are actually normal cells that had undergone certain deleterious mutations. So what happens there?

Elena Piskounova and her coworkers studied human melanoma cells in mice to investigate the oxidative stress and the antioxidant system in these cells. She found that as a tumor starts to grow, the elevated metabolic activity of the mutated cells, as well as their uncontrolled proliferation, displaces cells from their normal environmental niches, and that can cause enhanced production of reactive oxygen species (ROS).

These highly reactive molecules create a state of oxidative stress that can kill the cells. Successful tumor cells combat this stress by producing antioxidant molecules that neutralize ROS.

However, tumor cells that detach from a primary tumor experience high ROS levels again, both in the bloodstream and at distant sites where they attempt to form metastatic tumors. The increase in oxidative stress should kill those cells, and indeed most of them die. But the few successful tumor cells that establish metastases have undergone metabolic changes that allow them to better withstand oxidative stress, including upregulating metabolic pathways that produce antioxidants.

 

Add in antioxidant supplements

(By FDA graphic by Michael J. Ermarth ("Miracle Cure!" Health Fraud Scams) [Public domain], via Wikimedia Commons)
“Miracle Cure!” Health Fraud Scams | Michael J. Ermarth | Wikimedia Commons
So, what are we doing when we take megadoses of antioxidant supplements? We are aiding and abetting the very antioxidant system that allows the tumor cell to withstand the attack of the free radicals in the first place.

So now we can explain the seemingly paradoxical observation that although ROS can cause mutations, inhibiting them actually promotes tumor survival and metastatic spread. And as we know, it is not the primary tumor that kills that patient. It is the metastases to distant organs.

 

Is it all ‘academic’?

You probably wonder, “Yes, antioxidants promote metastases of pre-existing tumors.” But what happens in healthy people?

The answer is twofold. First, cells undergo mutation all the time, day in and day out. Fortunately, thanks to the natural metabolic and immunological defenses perfected by eons of natural selection work, the vast majority of such cells are eliminated. But no system is perfect, and every so often some cells escape the defense mechanisms and proliferate. These nascent tumors will welcome an added boost to their proliferation provided by antioxidants.

Second, it has been shown that about 30% of males over 50 have resting prostate tumor cells when they die of unrelated causes. Is it any wonder then that the antioxidant vitamin E, promoted as a preventative of prostate cancer, actually promotes it?

In a commentary on the melanoma study in Nature, the authors conclude:

“These findings, taken together, necessitate a revised perspective of the role of ROS in cancer, and force us to view it as an unlikely ally in our quest to treat this deadly disease.”

 

The extent of the problem

It is estimated that about half the U.S. adult population takes dietary supplements. The increase in the number of nutritional supplements has assumed epidemic proportion from 4,000 in 1994 to 55,000 in 2012.

In 2007, out-of-pocket expenditures for herbal or complementary nutritional products reached $14.8 billion. Obviously, an unregulated lucrative business, inviting both fraud and enabling senators, the likes of Republican Senator Hatch (UT) and Democratic senator Harkin (IA), who authored legislation to prohibit meaningful oversight by the FDA. Why would these public servants do something so patently harmful to the public? Follow the money, it always works!

As long as the problem was ‘only’ ~23,000 emergency department visits per year attributed to adverse events related to dietary supplements, it was ‘no big deal’. But now that the relationship to cancer deaths is not just an association but causal, are we finally going to do something about it? Knowing how big money politics works, I suggest none of us hold our breaths.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

7 COMMENTS

  1. There is an error in your explanation:

    > A free radical is a molecule that is missing one electron from its complete, neutral state

    This is false. What this sentence describes is not a radical, but a (positive) ion. A radical, in fact need not be electrically charged (for example OH or CH3). What would really, albeit somewhat imprecisely, describe a radical is “a molecule that has free space in its orbitals.” It has nothing to do with charge or “neutral state”.

    For example, Na is a radical (very reactive), it has one electron in the outermost orbital, Na+ is a ion which isn’t quite as reactive (because it has lost that inconvenient electron), you drink it with water.

    • Your definition is of course correct. Except that neither OH nor CH3 nor Na+ are biologically relevant. Oxygen, missing an electron, is. It becames reactive, hence the name Reactive Oxygen Species (ROS).

  2. Hi Dr. Dov.
    I am currently taking Alpha Lipoic Acid 600 mg.
    I am a Breast Cancer survivor feeling weak and dizziness my Oncologist recommend ALA and I felt good immediately my question is how long should I keep taking them?
    Thank you for your help.

  3. Hi Dr. Dov, This is a useful article. Thank you. It is also worrisome! We were always led to believe that supplements help. This article shows anti-oxidant supplements can be dangerous. Elsewhere (on nutritionfacts.org), I read that Fish Oil supplements may actually be dangerous as well. Now I wonder if all supplements are harmful. Can you point out which others, if any, we should strictly avoid.

    • I don’t think you should take ANY of them, because a well-balanced diet provides them all. Excess vitamin D, for instance, can cause bone abnormalities. As I mentioned in the article, beta carotene and vitamin E have been shown to promote cancer spread. Vitamin C was claimed to prevent the common cold -in fact, mega doses worsen the symptoms.

  4. I have been on “mega vitamin” therapy for over 30 years, specifically to avoid prostate cancer and to delay the onset of ailments that come with old age. Vitamins A-B-C-D-E, zinc, saw palmetto, flaxseed oil, and many others. At 69yrs old, Im in great health with no hbp, diabetes, prostate, cancer. Is cancer in my limited future now?

    • Hard to tell. These studies are based on populations, and their results are averages. Very few people are exactly the average; some are higher, some are lower. as Yogi Berra famously said: It’s tough to make predictions, especially about the future.

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