Anti Ox

French 1 Lindsey French NTR 302 Zemel 6 March, 2008 The Role of Antioxidants and Cancer: Beneficial and Detrimental . Worldwide, cancer is the second leading cause of premature death in adults (1). When cancer develops, the most common treatment used to fight the disease is chemotherapy. Although chemotherapy has proven to be the most effective treatment for cancer, it releases free radicals into the body in order to kill the disease, compromising the quality of life in addition to inducing pain and discomfort to the patient (2, 3). In order to reduce the negative effects of chemotherapy, antioxidants have been introduced as natural supplements to help counteract the negative effects of conventional treatments and prevent the reoccurrence of the disease (2). The main antioxidants that are used as supplements by cancer patients are vitamin C, vitamin E, and selenium. These antioxidants are helpful when used correctly; however, they can have adverse effects on the body reacting as pro-oxidants as well. Cancer is caused by the development of the byproducts of aerobic metabolism called reactive oxygen species (ROS) (4). ROS are natural occurring in the mitochondria and are necessary for various defense mechanisms in cells (4). ROS can cause changes to the structural and functional processes of the cell when subject to oxidative stress (4, 5). Oxidative stress is identified as the principle factor in the development of critical illnesses (6). These changes caused by oxidative stress damage DNA and other cellular components resulting in the development of human diseases such as cancer (5). “Often,

French 2 uncontrolled cell proliferation and metastasis of cancer cells has been known to be associated with the loss of cell regulation of cell homeostasis due to the presence of cancer promoters or absence of tumor suppressor genes (1).” Nutritional factors are extremely important in the prevention of the development of cancerous malignancies as well as stopping the production of genes that stimulate tumor growth (1). People who consume fruits and vegetables regularly in their diet are less susceptible to the damages of free radicals and are less likely to develop diseases caused by oxidative stress (5). Antioxidants consumed through fruits and vegetables provide a complex assortment of micronutrients and macronutrients which encourage the body’s natural defense and prevention of disease (5, 7). The antioxidant vitamin C provides many benefits to the body, particularly when fighting cancer and other abnormalities within the cells. Vitamin C is essential for healing wounds and fractures as well as preventing scurvy and the absorption of nonheme iron within the body (5). It is a “potent and versatile antioxidant, effectively quenching free radicals and protecting cell membranes and intracellular proteins from oxidative damage (8).” As an antioxidant, Vitamin C also enhances the use of other nutrients while offering protection against the oxidative damage of lipids through the restoration of vitamin E (5). Increased antibody response, mitogenic response, and neutrophil function are also ways in which vitamin C assists in disease prevention (8). Vitamin C has the capacity to lessen the amount of oxidative stress and reduce the amount of neurophil damage that is associated with acute and chronic diseases such as cancer (8). Although there are many antioxidant features provided by vitamin C, it also has

French 3 the potential to act as a pro-oxidant when fighting cancer. Catalyzed by transition metals that enter the body through chemotherapy, vitamin C has an impending duplicitous action causing oxidative damage to cellular components including DNA (3, 5). “Oxidative damage caused by vitamin C in plasma may be a real danger to surrounding tissues (5).” When combine with methotrexate, a component of chemotherapy, vitamin C can cause methotrexate toxicity resulting in kidney damage (9). In addition to DNA damage and kidney damage, vitamin C can also harm the linings of arteries causing an increased risk of stroke (5). The confiscation of metal ions within the cells by proteins indicates that the role of vitamin C as pro-oxidant is less likely, however, there is still a slight chance that vitamin C can negatively effect the body (5). In addition to vitamin C, vitamin E is also an antioxidant that assists the body in fighting cancer. Vitamin E is the major fat soluble antioxidant found in lipid tissue which provides the main defense against the oxidation of fats in lipid peroxidation (5). This antioxidant is an essential component of tissues containing high amounts of polyunsaturated fats (5). It aids in the prevention of damage to the structure and function of cellular membranes caused by free radicals (5). Caused by inhibition of the protein kinase C, vitamin E conducts the modulation of cellular signaling and the modulation of the immune function to regulate gene transcription and induce apoptosis (4). Vitamin E works to protect against oxygen- free- radical reactions, cellular oxidative damage, and helps to prevent some side effects of chemotherapy such as numbing, tingling, burning, and peripheral pain (3, 5). Vitamin E acts as a pro-oxidant during extreme levels of toxicity. Doses at 1200 mg/day and higher of vitamin E are known to cause antiplatelet effects, upsets in

French 4 the gastrointestinal system, altered serum and lipoprotein levels, blurred vision and gonadal dysfunction (4). These pro-oxidant effects are inconsistent in testing and have occurred infrequently in patients with high levels of vitamin E (4). Some studies suggest that higher intakes of vitamin E may cause certain types of cancer, Alzheimer’s disease, and heart disease (5). Although these pro-oxidant effects of vitamin E are documented, they remain inconsistent and unproven (5). Selenium is another antioxidant that can help prevent damages caused by free radicals. Benefits of selenium when used to decrease the development of cancer include the inhibition of oxidative damage to DNA, modulation of apoptosis, adjustment of cellular gene expression, and the recharging of cellular proliferation (7). In addition to these internal advantages of selenium, the antioxidant has the ability to reduce nerve cell damage as well (9). Selenium slows the metabolism of carcinogens and the binding of carcinogens to DNA, thus decreasing the development of cancer and the progression DNA abnormalities within the body (4). Selenium is also a fundamental cofactor in the glutathione enzymic function and has positive effects on the cellular immune function (6). “Patients with a low plasma Se level are three times more likely to die compared with those with a higher plasma level (6).” Lower mortality rates can be observed through patients that have incorporated selenium supplements into their diets when compared to those without selenium supplementation (6). Studies show that high doses of selenium do not appear toxic, nor does selenium appear to act as a pro-oxidant when increase levels of the supplement are consumed (6). Some side effects that have pro- oxidant characteristics associated with selenium include vomiting, nail changes,

French 5 weight loss, and irritability (9). Selenium can be considered the most promising antioxidant assisting in the fight against cancer (9). Although their effects are primarily positive, the results of vitamin C, vitamin E, and selenium depends on their capability to prevent tissue damage caused by oxidative stress as well as effectively repairing damage where it has previously occurred (9). Oxidative stress is the result of normal metabolism; however when combine with chemotherapeutic agents such as radiotherapy, the oxidative stress is exploited leading to ROS damage resulting in the formation of carcinogens and cell abnormalities (9). It is proven that antioxidants are likely to lower deaths among patients with cancer (6). People consuming diets with a variety of fruits and vegetables are most likely getting the amount of antioxidants they need to assist in fighting the disease (6). Also, those favoring healthy diets are apt to participate in addition lifestyle activities that reduce their risk of developing cancer, most likely exercising, not smoking, and limiting their alcohol consumption (7). Adequate amounts of vitamin C, vitamin E, and selenium are extremely beneficial in reducing the harmful effects of chemotherapy and preventing growth of cancer cells. When combined with conventional therapies, antioxidants are becoming essential to a successfully destroying cancer within the body and creating better lives for the patients that suffer with the painful disease.

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French 7 8. Webb AL, Villamor E. Update: effect of antioxidant and non- antioxidant vitamin supplementation on immune function. Nutrition Reviews, 2007; 65: 181- 217. 9. Werneke U. Risk management of nutritional supplements in chronic illness: the implications for the care of cancer and depression. Proceedings of the Nutrition Society, 2007; 66: 483- 92.