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.
What are antioxidants?
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
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 (8–12)||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 supplementsLater: 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 (13–15)||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 earlyLater: 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 supplementationLater: no benefit or harm associated with 2 years of vitamin E supplementation
|Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) Study, France (19–22)||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 (
||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 earlyLater: 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
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