Antioxidants in Cancer: A Little Knowledge Is a Dangerous Thing

Abstract

We ride on a tsunami of information about antioxidants and cancer in the 21st century. What is the significance? What are the connections? Do we know what lies ahead? Many answers and more questions emerge on the horizon as we unravel the mysteries of a paradox that intersects biochemical, cellular, and public health domains. It appears to be a tug of war on one side, with our physicians and health care providers trying to provide evidence-based answers, and on the other we have “Dr Professor Search Engine,” with its giant platter of colorful advice readily available always to all patients, fitness enthusiasts, and generally anybody who is passionate and curious on this topic. Antioxidants claim their fame as “biochemical trash collectors” in our cellular factory. They may be produced within our body as endogenous antioxidants or they may be outsourced as in exogenous antioxidants. Examples of exogenous antioxidants include vitamin A/ beta-carotene, vitamin C/ascorbic acid, vitamin E/tocopherol, etc, which may be obtained from food sources or supplements. Antioxidants play a major physiological role in neutralizing free radicals/reactive oxygen species. Free radicals are highly reactive elements that are continually produced during cellular metabolism and are implicated in molecular pathways of cancer promotion and progression. Now, reframing our initial query. “Should antioxidants be taken/prescribed in the prevention andmanagement of cancer?” we ponder over the largest body of evidence, which are the large randomized controlled trials conducted on national and global scales. To date, there have been 9 such studies. A 5-year nutrition intervention trail conducted in China with beta-carotene, alpha-tocopherol, and selenium revealed no significant effects. A systematic review and metanalysis by Pecollo and colleagues showed a paradoxical increased incidence of lung cancer in smokers who took beta-carotene supplements. However, no later effects were observed in gastrointestinal or hepatobiliary cancers. A similar increase in lung cancer incidence was observed with beta-carotene supplementation in smokers in the CARET study conducted in the United States. International studies such as HOPE-TOO showed no significant effect of alpha-tocopherol supplementation in cancer incidence or death from cancer in people diagnosed with cardiovascular disease or diabetes. Probing into the heart of the biochemical paradox of antioxidants in cancer promotion versus regression, we arrive at some scintillating cellular insights that explain the higher level of oxidative stress in the tumor microenvironment. Cancer cells are rapidly multiplying and hence have a higher level of basal oxidative stress compared to normal cells. Therefore, cancer cells rely on a greater concentration of antioxidants to counteract the lethal effect of reactive oxygen species and free radicals that would result in their demise. Antioxidants also play a role in modulating tumor immune-suppressive cells as elucidated in the research work of Lee Chang et al and Wang et al. Studies by Lee Chang et al showed that resveratrol, a dietary polyphenol compound possessing antioxidant properties at low doses that are nontoxic to immune cells, inhibits lung metastasis of breast cancer. Expanding on the paradox, resveratrol appeared to exhibit both antioxidant and pro-oxidant properties depending on its concentration and cell types used. Similarly, the studies of Wang et al showed that a combination of fish oil and selenium acted synergistically in boosting the host antitumor response against lung cancer. A literature review on 24 randomized controlled trials (RCTs) reported significantly decreased toxicities with concurrent supplementation of antioxidants with chemotherapy in patients with cancer compared to patients who were not on systemic antioxidants (controls). In contrast, 9 RCTs reported no differences in the toxicities by antioxidant supplementation and 1 RCT with vitamin A reported increased toxicity. In light of the paradoxical biochemical and cellular phenomena in cancer cells and preclinical models, the