Antioxidants and Cancer Therapy: To Take or Not to Take: That Is the

Chapter 2

Antioxidants and Cancer Therapy: To Take or Not to Take: That Is the Question? 1

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N. A. Michael Eskin and Ranjanna Bird

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Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada Departments of Biology and Health Studies and Gerontology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada

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The development of chronic diseases such as cancer is attributed to oxidative damage by reactive oxygen species (ROS) to D N A . One way of reducing or minimizing the formation of ROS is by the addition of antioxidants in the diet. However, this strategy of supplementing cancer therapy with antioxidants is hotly debated because of the absence of clear data. Early studies indicated this could be detrimental in workers who smoke or are exposed to environmental carcinogens. Later studies showed ROS play a role in cell signaling and regulation which could lead to cell death or apoptosis. Thus supplementing with dietary antioxidants such as ascorbic acid would interfere with the formation of ROS and prevent apoptosis from occurring. Consequently, antioxidant supplements by cancer patients remains highly questionable.

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© 2007 American Chemical Society

In Antioxidant Measurement and Applications; Shahidi, F., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.


9 Reactive oxygen species (ROS) are normal metabolic by-products produced in the mitochondria (1-3). They are implicated in the genesis of atherosclerosis, diabetes, cancers as well as neurological disorders. Over 200 epidemiological studies point to a strong association between the low consumption of fruits and vegetables and the incidence of cancer (4-5). This is attributed to the presence of a wide array of antioxidants in fruits and vegetables capable of protecting normal cells from the damaging action of ROS. The latter includes free radicals such as superoxide, hydroxyl, peroxyl, alkoxyl, and hydroperoxyl radicals as well as nitric oxide and nitrogen dioxide. Consequently it would be safe to assume that the presence of antioxidants is essential for reducing oxidative damage and the development of cancers. For example, Thompson and co-workers (6) showed that increasing the consumption of fruits and vegetables in women with a family history of risk for breast cancer, significantly decreased urinary 8-hydroxyguanosine (8 OhdG) and 8-isoprostane F-2a (8EPG), both markers of oxidative cellular damage (Table I).

Table I. Overall Effect of the Vegetable and Fruit Intervention on Oxidative Indices* Parameter 8-OHdG" 8-EPG*"

Pre-Intervention 49.6 ± 12.4 3.7 ± 0.3

Post-intervention 21.4 ± 2 . 2 2.4 ± 0 . 1

Change (%) -52 -33

Antioxidants Antioxidants are organic compounds capable of neutralizing or detoxifying reactive oxygen or nitrogen species. These compounds can donate an electron to quench free radicals. In 2000, the National Academy of Sciences defined a dietary antioxidant as "A dietary antioxidant in food significantly decreases the adverse effects of ROS, reactive nitrogen species, or both on normal physiological functions in humans (7)." In addition there are a number of enzymes that are synthesized within the body to catabolize free radicals including superoxide dismutase, catalase, and glutathione peroxidase (8). A group of proteins which keeps metals such as iron and copper in the bound form also reduce the ability of these metal from catalyzing the production of free radicals. Vitamins E, C, A and β-carotene are generally classified as essential nutrients. Vitamin E is a fat-soluble vitamin associated with the cell membrane that works in conjunction with vitamin C, a water-soluble vitamin, to maintain its antioxidant potential. This is achieved by vitamin C regenerating vitamin E to its


10 reduced and active form. It is now recognized that many plant-derived compounds in the diet, such as flavonoids, carotenoids and steroids are also antioxidants (9-11).

Antioxidants and Cancer Treatment


β-Carotene and Vitamin E While supplementation with antioxidants may be an appropriate strategy for the normal population, a number of studies suggest this could detrimental in individuals who smoke or are exposed to environmental carcinogens. For example, three randomized clinical trials showed that β-carotene, alone or in combination with vitamins A and E, increased the incidence of lung cancer and mortality in heavy smokers and in asbestos workers (12-16). A review of the βcarotene data by Paolini and co-workers (17) showed it was particularly harmful to give β-carotene as the sole supplement to smokers or individuals exposed to such environmental carcinogens as asbestos. Under these conditions β-carotene acts as a cocarcinogen by inducing higher levels of cytochrome P450 isoforms which activate procarcinogens or increases ROS levels. As a consequence these individuals would be exposed to a greater risk for cancer. Vitamin E, the most popular antioxidant taken as a supplement has also been evaluated for its health benefits. Several reviews have appeared that present conflicting views on its anticarcinogenic and cardioprotective effects (18-25).

Vitamin C ROS are the major cause of cell damage but they also play an important physiological role in intracellular signaling and regulation (26). As a result ROS influences redox status and depending on their concentration can cause cell proliferation or arrest and cell death (apoptosis). Thus the production of ROS can play an important role in bringing about the death of cancer cells or apoptosis.Thus addition of antioxidants could inhibit apoptosis and prevent the destruction or elimination of precancerous and cancerous cells. Wenzel et al. (27) found ascorbic acid interfered with apoptosis of HT-29 human colon carcinoma cells induced by the drug camptothecin or the flavonoid flavone. The reduction of ROS by ascorbic acid inhibited disintegration of the plasma membrane of these cancer cells. Ascorbic acid reduced or prevented stimulation of caspase 3, downregulation of the mitochondrial antiapoptotic protein b c l - X l as well as N K - k B mRNA levels. This study clearly showed that an increase in


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Figure. 1. Effect of ascorbic acid (ΛΑ) on protein oxidation (A) and lipid Peroxidation (B). Both processes were significantly reduced by A A. Values were assessed 16 h after ALA-PDT treatment. Results represent means ± SD of at least six independent experiments. *p < 0.05, **p

Antioxidants and Cancer Therapy: To Take or Not to Take: That Is the

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