Antioxidants and Cancer Prevention

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What are free radicals, and do they play a role in cancer development? 

Free radicals are highly reactive chemicals that have the potential to harm cells. They are created when an atom or a molecule (a chemical that has two or more atoms) either gains or loses an electron (a small negatively charged particle found in atoms). Free radicals are formed naturally in the body and play an important role in many normal cellular processes (1, 2). At high concentrations, however, free radicals can be hazardous to the body and damage all major components of cells, including DNA, proteins, and cell membranes. The damage to cells caused by free radicals, especially the damage to DNA, may play a role in the development of cancer and other health conditions (1, 2).

Abnormally high concentrations of free radicals in the body can be caused by exposure to ionizing radiation and other environmental toxins. When ionizing radiation hits an atom or a molecule in a cell, an electron may be lost, leading to the formation of a free radical. The production of abnormally high levels of free radicals is the mechanism by which ionizing radiation kills cells. Moreover, some environmental toxins, such as cigarette smoke, some metals, and high-oxygen atmospheres, may contain large amounts of free radicals or stimulate the body’s cells to produce more free radicals.

Free radicals that contain the element oxygen are the most common type of free radicals produced in living tissue. Another name for them is “reactive oxygen species,” or “ROS” (1, 2).

What are antioxidants?

Antioxidants are chemicals that interact with and neutralize free radicals, thus preventing them from causing damage. Antioxidants are also known as “free radical scavengers.”

The body makes some of the antioxidants that it uses to neutralize free radicals. These antioxidants are called endogenous antioxidants. However, the body relies on external (exogenous) sources, primarily the diet, to obtain the rest of the antioxidants it needs. These exogenous antioxidants are commonly called dietary antioxidants. Fruits, vegetables, and grains are rich sources of dietary antioxidants. Some dietary antioxidants are also available as dietary supplements (1, 3).

Examples of dietary antioxidants include beta-carotene, lycopene, and vitamins A, C, and E (alpha-tocopherol). The mineral element selenium is often thought to be a dietary antioxidant, but the antioxidant effects of selenium are most likely due to the antioxidant activity of proteins that have this element as an essential component (i.e., selenium-containing proteins), and not to selenium itself (4).

Can antioxidant supplements help prevent cancer?

In laboratory and animal studies, the presence of increased levels of exogenous antioxidants has been shown to prevent the types of free radical damage that have been associated with cancer development. Therefore, researchers have investigated whether taking dietary antioxidant supplements can help lower the risk of developing or dying from cancer in humans.

Many observational studies, including case–control studies and cohort studies, have been conducted to investigate whether the use of dietary antioxidant supplements is associated with reduced risks of cancer in humans. Overall, these studies have yielded mixed results (5). Because observational studies cannot adequately control for biases that might influence study outcomes, the results of any individual observational study must be viewed with caution.   

Randomized controlled clinical trials, however, lack most of the biases that limit the reliability of observational studies. Therefore, randomized trials are considered to provide the strongest and most reliable evidence of the benefit and/or harm of a health-related intervention. To date, nine randomized controlled trials of dietary antioxidant supplements for cancer prevention have been conducted worldwide. Many of the trials were sponsored by the National Cancer Institute. The results of these nine trials are summarized below.    

Trial name, country (reference) Intervention Study subjects Results
Linxian General Population Nutrition Intervention Trial, China (6, 7) 15 milligrams (mg) beta-carotene, 30 mg alpha-tocopherol, and 50 micrograms (µg) selenium daily for 5 years Healthy men and women at increased risk of developing esophageal cancer and gastric cancer

Initial: no effect on risk of developing either cancer; decreased risk of dying from gastric cancer only Later: no effect on risk of dying from gastric cancer

Later: no effect on risk of dying from gastric cancer

Alpha-Tocopherol/Beta-Carotene Cancer Prevention Study (ATBC), Finland (812) Alpha-tocopherol (50 mg per day) and/or beta-carotene (20 mg per day) supplements for 5 to 8 years Middle-aged male smokers

Initial: increased incidence of lung cancer for those who took beta-carotene supplements

Later:  no effect of either supplement on incidence of urothelial, pancreatic, colorectal, renal cell, or upper aerodigestive tract cancers
Carotene and Retinol Efficacy Trial (CARET), United States (1315) Daily supplementation with 15 mg beta-carotene and 25,000 International Units (IU) retinol People at high risk of lung cancer because of a history of smoking or exposure to asbestos

Initial: increased risk of lung cancer and increased death from all causes—trial ended early

Later: higher risks of lung cancer and all-cause mortality persisted; no effect on risk of prostate cancer
Physicians' Health Study I (PHS I), United States (16) Beta-carotene supplementation (50 mg every other day for 12 years) Male physicians No effect on cancer incidence, cancer mortality, or all-cause mortality in either smokers or non-smokers
Women’s Health Study (WHS), United States (17, 18) Beta-carotene supplementation (50 mg every other day), vitamin E supplementation (600 IU every other day), and aspirin (100 mg every other day) Women ages 45 and older

Initial: no benefit or harm associated with 2 years of beta-carotene supplementation

Later: no benefit or harm associated with 2 years of vitamin E supplementation
Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) Study, France (1922) Daily supplementation with vitamin C (120 mg), vitamin E (30 mg), beta-carotene (6 mg), and the minerals selenium (100 µg) and zinc (20 mg) for a median of 7.5 years Men and women

Initial: lower total cancer and prostate cancer incidence and all-cause mortality among men only; increased incidence of skin cancer among women only

Later: no evidence of protective effects in men or harmful effects in women within 5 years of ending supplementation

Heart Outcomes Prevention Evaluation–The Ongoing Outcomes (HOPE–TOO) Study, International (23) Daily supplementation with alpha-tocopherol (400 IU) for a median of 7 years People diagnosed with cardiovascular disease or diabetes No effect on cancer incidence, death from cancer, or the incidence of major cardiovascular events
Selenium and Vitamin E Cancer Prevention Trial (SELECT), United States (24, 25) Daily supplementation with selenium (200 µg), vitamin E (400 IU), or both Men ages 50 and older

Initial: no reduction in incidence of prostate or other cancers—trial stopped early

Later: more prostate cancer cases among those who took vitamin E alone
Physicians' Health Study II (PHS II), United States (26) 400 IU vitamin E every other day, 500 mg vitamin C every day, or a combination of the two Male physicians ages 50 years and older No reduction in incidence of prostate cancer or other cancers

Overall, these nine randomized controlled clinical trials did not provide evidence that dietary antioxidant supplements are beneficial in primary cancer prevention. In addition, a systematic review of the available evidence regarding the use of vitamin and mineral supplements for the prevention of chronic diseases, including cancer, conducted for the United States Preventive Services Task Force (USPSTF) likewise found no clear evidence of benefit in preventing cancer (27).

It is possible that the lack of benefit in clinical studies can be explained by differences in the effects of the tested antioxidants when they are consumed as purified chemicals as opposed to when they are consumed in foods, which contain complex mixtures of antioxidants, vitamins, and minerals (3). Therefore, acquiring a more complete understanding of the antioxidant content of individual foods, how the various antioxidants and other substances in foods interact with one another, and factors that influence the uptake and distribution of food-derived antioxidants in the body are active areas of ongoing cancer prevention research.

Should people already diagnosed with cancer take antioxidant supplements?

Several randomized controlled trials, some including only small numbers of patients, have investigated whether taking antioxidant supplements during cancer treatment alters the effectiveness or reduces the toxicity of specific therapies (28). Although these trials had mixed results, some found that people who took antioxidant supplements during cancer therapy had worse outcomes, especially if they were smokers.

In some preclinical studies, antioxidants have been found to promote tumor growth and metastasis in tumor-bearing mice and to increase the ability of circulating tumor cells to metastasize (2931). Until more is known about the effects of antioxidant supplements in cancer patients, these supplements should be used with caution. Cancer patients should inform their doctors about their use of any dietary supplement.                      

Selected References
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    [PubMed Abstract]
  2. Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry & Cell Biology 2007; 39(1):44-84.

    [PubMed Abstract]
  3. Bouayed J, Bohn T. Exogenous antioxidants—double-edged swords in cellular redoc state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxidative Medicine and Cellular Longevity 2010; 3(4): 228-237.

    [PubMed Abstract]
  4. Davis CD, Tsuji PA, Milner JA. Selenoproteins and Cancer Prevention. Annual Review of Nutrition 2012; 32:73-95.

    [PubMed Abstract]
  5. Patterson RE, White E, Kristal AR, et al. Vitamin supplements and cancer risk: the epidemiologic evidence. Cancer Causes and Control 1997; 8(5):786-802.

    [PubMed Abstract]
  6. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. Journal of the National Cancer Institute 1993;85:1483–91.

    [PubMed Abstract]
  7. Qiao YL, Dawsey SM, Kamangar F, et al. Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. Journal of the National Cancer Institute 2009;101(7):507-518.

    [PubMed Abstract]
  8. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effects of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New England Journal of Medicine 1994;330:1029–35.

    [PubMed Abstract]
  9. Rautalahti MT, Virtamo JR, Taylor PR, et al. The effects of supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer 1999; 86(1):37-42.

    [PubMed Abstract]
  10. Virtamo J, Edwards BK, Virtanen M, et al. Effects of supplemental alpha-tocopherol and beta-carotene on urinary tract cancer: incidence and mortality in a controlled trial (Finland). Cancer Causes and Control 2000;11(10):933-939.

    [PubMed Abstract]
  11. Albanes D, Malila N, Taylor PR, et al. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer. Cancer Causes and Control 2000; 11(3):197-205.

    [PubMed Abstract]
  12. Wright ME, Virtamo J, Hartman AM, et al. Effects of alpha-tocopherol and beta-carotene supplementation on upper aerodigestive tract cancers in a large, randomized controlled trial. Cancer 2007; 109(5):891-898.

    [PubMed Abstract]
  13. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New England Journal of Medicine 1996;334(18):1150-1155.

    [PubMed Abstract]
  14. Goodman GE, Thornquist MD, Balmes J, et al. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. Journal of the National Cancer Institute 2004;96(23):1743-1750.

    [PubMed Abstract]
  15. Neuhouser ML, Barnett MJ, Kristal AR, et al. Dietary supplement use and prostate cancer risk in the Carotene and Retinol Efficacy Trial. Cancer Epidemiology, Biomarkers & Prevention 2009;18(8):2202-2206.

    [PubMed Abstract]
  16. Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. New England Journal of Medicine 1996;334:1145–9.

    [PubMed Abstract]
  17. Lee IM, Cook NR, Manson JE. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: Women’s Health Study. Journal of the National Cancer Institute 1999;91:2102–6.

    [PubMed Abstract]
  18. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005;294(1):56-65.

    [PubMed Abstract]
  19. Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Archives of Internal Medicine 2004;164(21):2335-2342.

    [PubMed Abstract]
  20. Hercberg S, Kesse-Guyot E, Druesne-Pecollo N, et al. Incidence of cancers, ischemic cardiovascular diseases and mortality during 5-year follow-up after stopping antioxidant vitamins and minerals supplements: a postintervention follow-up in the SU.VI.MAX Study. International Journal of Cancer 2010;127(8):1875-1881.

    [PubMed Abstract]
  21. Hercberg S, Ezzedine K, Guinot C, et al. Antioxidant supplementation increases the risk of skin cancers in women but not in men. Journal of Nutrition 2007;137(9):2098-2105.

    [PubMed Abstract]
  22. Ezzedine K, Latreille J, Kesse-Guyot E, et al. Incidence of skin cancers during 5-year follow-up after stopping antioxidant vitamins and mineral supplementation. European Journal of Cancer 2010;46(18):3316-3322.

    [PubMed Abstract]
  23. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;293(11):1338-1347.

    [PubMed Abstract]
  24. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009;301(1):39-51.

    [PubMed Abstract]
  25. Klein EA, Thompson IM, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306(14):1549-1556.

    [PubMed Abstract]
  26. Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA 2009;301(1):52-62.

    [PubMed Abstract]
  27. Fortmann SP, Burda BU, Senger CA, et al. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: an updated systematic evidence review for the U.S. Preventive Services Task Force. Annals of Internal Medicine 2013.

    [PubMed Abstract]
  28. Lawenda BD, Kelly KM, Ladas EJ, et al. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? Journal of the National Cancer Institute 2008;100(11):773-783.

    [PubMed Abstract]
  29. Sayin VI, Ibrahim MX, Larsson E, et al. Antioxidants accelerate lung cancer progression in mice. Science Translational Medicine 2014; 6(221):221ra15.

    [PubMed Abstract]
  30. Le Gal K, Ibrahim MX, Wiel C, et al. Antioxidants can increase melanoma metastasis in mice. Science Translational Medicine 2015; 7(308):308re8.

    [PubMed Abstract]
  31. Piskounova E, Agathocleous M, Murphy MM, et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 2015; 527(7577):186-191.

    [PubMed Abstract]
  • Reviewed: February 6, 2017

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