How antioxidants can accelerate cancers, and why they don't protect against them

Drs. Tuveson and Chandel explain why eating foods rich in antioxidants, as well as taking antioxidant supplements, can actually promote cancer, rather than fight or prevent it, as conventional wisdom suggests. Credit: CSHL

For decades, health-conscious people around the globe have taken antioxidant supplements and eaten foods rich in antioxidants, figuring this was one of the paths to good health and a long life.

11 july 2014--Yet clinical trials of antioxidant supplements have repeatedly dashed the hopes of consumers who take them hoping to reduce their cancer risk. Virtually all such trials have failed to show any protective effect against cancer. In fact, in several trials antioxidant supplementation has been linked with increased rates of certain cancers. In one trial, smokers taking extra beta carotene had higher, not lower, rates of lung cancer.

In a brief paper appearing today in The New England Journal of Medicine, David Tuveson, M.D. Ph.D., Cold Spring Harbor Laboratory Professor and Director of Research for the Lustgarten Foundation, and Navdeep S. Chandel, Ph.D., of the Feinberg School of Medicine at Northwestern University, propose why antioxidant supplements might not be working to reduce cancer development, and why they may actually do more harm than good.

Their insights are based on recent advances in the understanding of the system in our cells that establishes a natural balance between oxidizing and anti-oxidizing compounds. These compounds are involved in so-called redox (reduction and oxidation) reactions essential to cellular chemistry.

Oxidants like hydrogen peroxide are essential in small quantities and are manufactured within cells. There is no dispute that oxidants are toxic in large amounts, and cells naturally generate their own anti-oxidants to neutralize them. It has seemed logical to many, therefore, to boost intake of antioxidants to counter the effects of hydrogen peroxide and other similarly toxic "reactive oxygen species," or ROS, as they are called by scientists. All the more because it is known thatcancer cells generate higher levels of ROS to help feed their abnormal growth.

Drs. Tuveson and Chandel propose that taking antioxidant pills or eating vast quantities of foods rich in antioxidants may be failing to show a beneficial effect against cancer because they do not act at the critical site in cells where tumor-promoting ROS are produced – at cellular energy factories called mitochondria. Rather, supplements and dietary antioxidants tend to accumulate at scattered distant sites in the cell, "leaving tumor-promoting ROS relatively unperturbed," the researchers say.

Quantities of both ROS and natural antioxidants are higher in cancer cells – the paradoxically higher levels of antioxidants being a natural defense by cancer cells to keep their higher levels of oxidants in check, so growth can continue. In fact, say Tuveson and Chandel, therapies that raise the levels of oxidants in cells may be beneficial, whereas those that act as antioxidants may further stimulate the cancer cells. Interestingly, radiation therapy kills cancer cells by dramatically raising levels of oxidants. The same is true of chemotherapeutic drugs – they kill tumor cells via oxidation.

Paradoxically, then, the authors suggest that "genetic or pharmacologic inhibition of antioxidant proteins" – a concept tested successfully in rodent models of lung and pancreatic cancers—may be a useful therapeutic approach in humans. The key challenge, they say, is to identify antioxidant proteins and pathways in cells that are used only by cancer cells and not by healthy cells. Impeding antioxidant production in healthy cells will upset the delicate redox balance upon which normal cellular function depends.

The authors propose new research to profile antioxidant pathways in tumor and adjacent normal cells, to identify possible therapeutic targets.

More information: "The Promise and Perils of Antioxidants for Cancer Patients" appears in The New England Journal of Medicine on July 10, 2014.

Provided by Cold Spring Harbor Laboratory

Vitamins can damage the body's own defences

Each year, we spend billion of dollars on dietary supplements. New research indicates that vitamin pills may upset the fragile balance in our cells and thus cause more harm than good.

29 nov 2013--Vitamin supplements are a billion-dollar industry. We want to stay healthy and fit and help our bodies with this. But perhaps we are achieving precisely the opposite?

"We believe that antioxidants are good for us, since they protect the cells from oxidative stress that may harm our genes. However, our bodies have an enormous inherent ability to handle stress. Recent research results show that the body's responses to stress in fact are important in preventing our DNA from eroding. I fear that the fragile balance in our cells can be upset when we supplement our diet with vitamin pills," says Hilde Nilsen to the research magazine Apollon. Nilsen is heading a research group at the Biotechnology Centre, University of Oslo.

Maintenance of genes

Our DNA – the genetic code that makes us who we are – is constantly exposed to damage.

In each of the hundred trillion cells in our body, up to two hundred thousand instances of damage to the DNA take place every day. These may stem from environmental causes such as smoking, stress, environmental pathogens or UV radiation, but the natural and life-sustaining processes in the organism are the primary sources of damage to our DNA.

How can the repair of damage to our DNA help us stay healthy and live long lives?

A small worm provides the answer

To answer this question, Hilde Nilsen and her group of researchers have allied themselves with a small organism – a one millimetre-long nematode called Caenorhabditis elegans (C. elegans). This roundworm, which lives for only 25 days, is surprisingly sophisticated with its 20 000 genes; we humans only have a couple of thousand more.

"C. elegans is a fantastically powerful tool, because we can change its hereditary properties. We can increase its ability to repair DNA damage, or we can remove it altogether. We can also monitor what happens when damage to DNA is not repaired – in several hundred specimens and through their entire lifespan."

Different "repair proteins" take care of various types of damage to the DNA. The most common ones are repaired by "cutting out" and replacing a single damaged base – by itself or as part of a larger fragment.

Affecting lifespan with the aid of genes

In some specimens that do not have the ability to repair the damage, the researchers observe that the ageing process proceeds far faster than normal. Is it because the damage accumulates in the DNA and prevents the cells from producing the proteins they need for their normal operation? Most researchers have thought so, but Hilde Nilsen doubts it.

One of the genes studied by the researchers has a somewhat shortened lifespan: on average, this mutant lives three days less than normal. Translated into human terms, this means dying at the age of 60 rather than at 70.
– We were surprised when we saw that these mutants do not in fact accumulate the DNA damage that would cause ageing. On the contrary: they have less DNA damage. This happens because the little nematode changes its metabolism into low gear and releases its own antioxidant defences. Nature uses this strategy to minimize the negative consequences of its inability to repair the DNA. So why is this not the normal state? Most likely because it comes at a cost: these organisms have less ability to respond to further stress ‒ they are quite fragile.

Hilde Nilsen and her colleagues have now –for the very first time – shown that this response is under active genetic control and is not caused by passive accumulation of damage to the DNA, as has been widely believed.

This provides an opportunity to manipulate these processes. And that's exactly what we have done: we have re-established the normal lifespan of a short-lived mutant by removing other proteins that repair damage. Hence, the cause could not be accumulation of damage, since there is no reason to assume that a mutant with no other alternative ways to repair its DNA will be less exposed to damage. There must be something else.

The researchers have gone on to discover that this "something else" in fact is the other repair proteins. They believe that the proteins inhibit damage that they fail to repair completely.

"The consequence is that they establish a barrier – a road block. This triggers a cascade of signals that reprogram the cell.

"Wouldn't this imply that the repair proteins defy their own purpose – after all, the result is a shorter lifespan?

"We need to remember that most likely, the purpose of the DNA repairs is to ensure that we produce healthy offspring – not necessarily that we live as long as possible after our reproductive age interval. Initiating a survival response that reinforces the antioxidant defences means that a lack of ability to repair the DNA has less impact than it would otherwise have on our reproduction. To the species as a whole, it's a small cost that some individuals will be less good at handling stress and have a shorter life."

Because this is an active process within the cells, the researchers refer to it as reprogramming.

"We have found several proteins that trigger this reprogramming. The process has the same effect as a reduction in caloric intake, which we know helps increase the lifespan in many species. In other words, there are two routes to a long life. When we stimulate both of these two routes in our nematode at the same time, we can quadruple its normal lifespan," Nilsen says.

Can do great harm

The balance between oxidants and antioxidants is crucial to our physiology, but exactly where this equilibrium is situated varies from one person to the next.

"This is where I start worrying about the synthetic antioxidants. The cells in our body use this fragile balance to establish the best possible conditions for themselves, and it is specially adapted for each of us. When we take supplements of antioxidants, such as C and E vitamins, we may upset this balance," the researcher warns.

"It sounds intuitively correct that intake of a substance that may prevent accumulation of damage would benefit us, and that's why so many of us supplement our diet with vitamins. Our research results indicate that at the same time, we may also cause a lot of harm. The health authorities recommend that instead, we should seek to have an appropriate diet. I'm all in favour of that. It's far safer for us to take our vitamins through the food that we eat, rather than through pills," Hilde Nilsen states emphatically.

Huge consumption of dietary supplements

The National Research Centre in Complementary and Alternative Medicine (NAFKAM) has investigated the volume of dietary supplements consumed in Norway in 2012:

• Last year, 70 per cent of the population purchased dietary supplements.
• In total, Norwegians spent nearly NOK 3 billion on pills or beverages intended to supplement our diet.
• Many of us use dietary supplements as elements of an alternative diet or in dosages that exceed the recommendations given in the instruction leaflet.

Provided by University of Oslo

Regimens: Antioxidants Don’t Lessen Strokes for at-Risk Women

By NICHOLAS BAKALAR
Supplements of the antioxidants beta carotene, vitamin C and vitamin E may be good for you, but a new study reports that they have no effect, either alone or in combination, in preventing heart attack, stroke or death among women at risk for cardiovascular disease.
Researchers randomly assigned more than 8,000 women to take regular doses of vitamin E, vitamin C, beta carotene or placebos, and followed them for more than nine years. All the women, whose average age was 60, either had had cardiovascular disease or were at high risk for it. During the nine years, 1,450 women had a heart attack, a stroke or cardiac surgery, and there were 395 deaths from heart disease.
Women in the vitamin E group had a slight decrease in disease compared with the placebo group, but it was not statistically significant. Neither beta carotene nor vitamin C had any statistically significant effect compared with placebo.
Combinations of the antioxidants had no effect either, except for a slight reduction in stroke among those taking both vitamins C and E together. The study appears in the Aug. 13 issue of The Archives of Internal Medicine.
“While the individual supplements may not decrease risk,” said Nancy R. Cook, the lead author and an associate professor of epidemiology at Harvard, “it does seem that diets high in fruits and vegetables that contain these antioxidants are helpful. It may be that we haven’t identified the particular nutrients or combinations of nutrients that might be beneficial.”

Antioxidant Supplements May Raise Women's Skin Cancer Risk

By Kathleen DohenyHealthDay ReporterMon Aug 20, 7:02 PM ET
MONDAY, Aug. 20 (HealthDay News) -- Taking antioxidant supplements won't protect against skin cancer and may actually boost the risk, at least in women, according to a new French study.
"Taking into consideration our results, we are particularly concerned by the use of long-term supplementation, notably in sun-seekers and people wanting to look tanned [using beta-carotene]," said researcher Dr. Serge Hercberg, professor of nutrition at the Medical University of Paris.
The new findings come on the heels of a study, published in mid-August in the Archives of Internal Medicine, that found that antioxidants don't prevent heart disease risk in high-risk women.
In the new French study, published in the September issue of The Journal of Nutrition, Hercberg's team looked at the effects of antioxidant doses on skin cancer. The research was conducted as part of a larger study that looked at the effects of antioxidants on cancer and ischemic heart disease.
Antioxidant nutrients are thought to reduce disease risk by cutting down on the unhealthy effects of "free radical" molecules that damage cells.
The researchers assigned almost 7,900 women and more than 5,100 men to take either an oral daily capsule of antioxidant or a placebo that looked the same. The antioxidants included 120 milligrams of vitamin C, 30 milligrams of vitamin E, 6 milligrams of beta-carotene, 100 milligrams of selenium and 20 milligrams of zinc.
"They are not high doses," Hercberg said. "They are at a level below a lot of pills you can find to buy over the counter."
The men and women were followed for about 7.5 years. In that time, 157 cases of any form of skin cancers were reported, including 25 melanomas, the most deadly form.
The team found that, in women, the incidence of all types of skin cancer combined was actually higher in the antioxidant group, and so was their incidence of melanoma.
But the incidence of non-melanoma skin cancers, when evaluated separately, did not differ between the antioxidant and placebo groups in men or women. In men, there was no difference in any form of skin cancer (including melanoma) between the two groups.
In the antioxidant group, 51 women developed skin cancer, while 30 in the placebo group did. Among the men, 43 in the placebo group and 33 in the antioxidant group got skin cancers.
As for melanoma, the incidence did not differ significantly between the men's treatment group -- 6 in the placebo group and 3 in the antioxidant group got it. But 3 women on placebo and 13 on antioxidants got melanoma -- a significant difference, the researchers said.
Antioxidant studies have yielded mixed results, Hercberg stressed. For example, in previous studies, researchers saw a higher risk of lung cancer in heavy smokers who regularly took high doses of beta-carotene.
Studies have suggested that antioxidant supplements might protect against prostate cancer incidence in men with low blood levels of prostate specific antigen (PSA), Hercberg said. But research has also suggested that the nutrients might increase prostate cancer risk in men with a high PSA. PSA levels are a marker for pre-existing prostate cancer risk.
That could also be happening in the women who got more skin cancers after taking antioxidants, he theorized. If their skin cancer had already been developing, taking an antioxidant might not help, Hercberg speculated.
While the study is interesting, further research is needed to confirm it, said Dr. Ariel Ostad, a spokesman for the Skin Cancer Foundation and a New York City dermatologist not involved in the study.
He said the study did have one serious limitation. "It does not take into account sunscreen use," he said. If the participants tended not to use sunscreen, that could have affected the results.
Meanwhile, Ostad added, taking care in the sun is important, and "sunscreens are by far the most powerful" weapon to prevent skin cancers.
More information
To learn more about preventing skin cancer with sunscreens, visit the Skin Cancer Foundation.

Antioxidants Don't Reduce Risk of MI, Stroke, or Cardiovascular Death in High-Risk Women

BOSTON, Aug. 14 -- Antioxidant vitamins C and E and beta carotene did not reduce the risk of cardiovascular events in more than 8,000 high-risk women, reported researchers here.
Neither Vitamin C (ascorbic acid), vitamin E, or beta carotene reduced the combined primary end point of myocardial infarction, stroke, coronary revascularization, or cardiovascular death, reported Nancy R. Cook, Sc.D., of Brigham and Women's Hospital and Harvard, and colleagues, in the Aug. 13/27 issue of Archives of Internal Medicine.
"For stroke, we found a significant 2-way interaction between ascorbic acid and vitamin E (P=0.03). Those in the active groups for both agents experienced fewer strokes compared with those in placebo groups for both agents (RR 0.69; 95% CI 0.49-0.98 [P=0.04])," they wrote.
And, they noted, there was also "a marginally significant reduction in the primary outcome with active vitamin E among a prespecified group of women with [cardiovascular disease] (RR, 0.89; 95% CI, 0.79-1.00, P=0.04)."
The Women's Antioxidant Cardiovascular Study recruited 8,171 women, average age 61, in 1995 and 1996. All participants had a history of cardiovascular disease or had at least three risk factors for it.
Women were randomized to 500 mg of vitamin C or placebo daily, 500 IU of vitamin E or placebo every other day, and 50 mg of beta carotene or placebo every other day. The study design allowed researchers to assess the efficacy of the vitamins as monotherapy or in combination with other antioxidants.
The women were followed for a mean of 9.4 years during which time 1,450 women had one or more cardiovascular events-274 myocardial infarctions, 298 strokes, and 889 coronary revascularization procedures. There were 995 deaths, 395 of which were from cardiovascular causes.
No additional adverse effects were observed among those taking the vitamins, although there was a small increase in reports of upset stomach among those taking active beta carotene.
Limitations of the study noted by the authors included a lack of complete follow-up and compliance, although, they said, it was above 90% through 2003. Mortality follow-up was 99% complete and compliance was comparable to other trials.
"While additional research into combinations of agents, particularly for stroke, may be of interest, widespread use of these individual agents for cardiovascular protection does not appear warranted," the researchers concluded.
This study was supported by an investigator-initiated grant from the National Heart, Lung, and Blood Institute. Vitamin E and its placebo were supplied by Cognis Corporation. All other agents and their placebos were supplied by BASF Corporation. Pill packaging was provided by Cognis and BASF. The authors disclosed no financial conflicts. Primary source: Archives of Internal MedicineSource reference: Cook NR et al "A Randomized Factorial Trial of Vitamins C and E and Beta Carotene in the Secondary Prevention of Cardiovascular Events in Women Results from the Women's Antioxidant Cardiovascular Study" Arch Intern Med. 2007;167:1610-1618.

Some Antioxidant Supplements May Increase Mortality, Meta-Analysis Finds

Beta carotene, vitamin A, and vitamin E supplements were associated with increased mortality in a large meta-analysis and systematic review reported in today's JAMA.
Researchers examined randomized, controlled trials of antioxidants used for primary or secondary disease prevention. When the researchers focused in on the trials that used high-quality methodology -- 47 studies comprising about 180,000 patients -- they found recipients of supplements had increased mortality compared with controls (relative risk, 1.05). Used singly or in combination with other supplements, beta carotene, vitamin A, and vitamin E increased mortality in high-quality trials. Vitamin C did not have a significant effect on mortality.
The authors conclude: "Our results extend previous reviews and guidelines, suggesting that antioxidant supplements may not be beneficial."

http://www.medpagetoday.com/PrimaryCare/DietNutrition/dh/5152