Free Radicals: The Pros and Cons of Antioxidants Cancer Chemotherapy and Antioxidants

Does the administration of antioxidants during cancer chemotherapy affect antineoplastic efficacy or the development of side effects? Although the majority of preclinical studies involving the use of in vitro systems and animal models support the contention that certain antioxidants are of benefit, few clinical studies have been done (1,2). Factors to consider in the design of studies to answer the question posed above include the properties of the individual antioxidants, the mechanism of action of the antineoplastic agents, and the mechanism whereby antineoplastic agents cause their side effects. Additionally, the impact of chemotherapy-induced oxidative stress upon antineoplastic efficacy and the role that reactive oxygen species (ROS) may play in drug-induced apoptosis need to be elucidated. All antioxidants cannot be viewed as equal when evaluating their potential impact on cancer chemotherapy, and an individual antioxidant cannot be anticipated to have the same impact on the activity of all cancer chemotherapeutic agents. Small molecular weight antioxidant molecules are effective reducing agents but some, including glutathione (GSH), Nacetyl cysteine (NAC), and alpha-lipoic acid, also are strong nucleophiles because they possess a sulfhydryl group. While all antioxidants are capable of detoxifying free radicals, those that possess strong nucleophilic properties can bind and inactivate the electrophilic intermediates of antineoplastic agents that act via nucleophilic substitution reactions, i.e., platinum-coordination complexes and most alkylating agents. Competition between nucleophilic antioxidants and the nucleophilic cellular targets of these anticancer agents can reduce the efficacy of the therapy. Selenium also can be considered a nucleophilic antioxidant. Although inorganic selenium does not function as an antioxidant, it is incorporated into selenoproteins (as selenocysteine or selenomethionine) and other selenium compounds such as methylselenol. Because selenium possesses properties similar to sulfur, selenoproteins and organoselenols have nucleophilic properties. Additionally, selenium induces the synthesis of the cysteine-rich metallothioneins, which can bind to electrophilic intermediates of platinum-coordination complexes and alkylating agents, and elevated levels of methallothioneins are associated with resistance to these antineoplastic agents (3). If generation of ROS by a cancer chemotherapeutic agent or a free radical intermediate of the drug plays a role in its cytotoxicity, antioxidants may interfere with the drug’s antineoplastic activity. However, if the reactive species are responsible only for the drug’s adverse effects, antioxidants may actually reduce the severity of such effects without interfering with the drug’s antineoplastic activity. Thus, it is important to distinguish between a drug’s ability to induce oxidative stress in biological systems and the role, if any, that ROS or free radical intermediates play in the mechanism of action of the drug. The drugs of many classes of antineoplastic agents are known to generate a high level of oxidative stress in biological systems (1). These classes of drugs include the anthracyclines, most alkylating agents, platinum-coordination complexes, epipodophyllotoxins, and camptothecins. For these drugs, the hepatic microsomal monooxygenase system is a primary site where ROS are generated, although other enzymatic (e.g., xanthine oxidase) and nonenzymatic (Fenton and HaberWeiss reactions) mechanisms also play a role. The electron transport system of cardiac mitochondria is another site where significant levels of ROS are generated by anthracyclines (4). Although some classes of antineoplastic agents generate high levels of oxidative stress, others, including the taxanes, vinca alkaloids, antifolates, and nucleoside and nucleotide analogues, generate only low levels. Nevertheless, all drugs generate some free radicals as they induce apoptosis in cancer cells. One of the primary pathways of drug-induced apoptosis is the pathway that involves release of cytochrome c from mito1 Presented as part of the conference “Free Radicals: The Pros and Cons of Antioxidants,” held June 26–27 in Bethesda, MD. This conference was sponsored by the Division of Cancer Prevention (DCP) and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Department of Health and Human Services (DHHS); the National Center for Complementary and Alternative Medicine (NCCAM), NIH, DHHS; the Office of Dietary Supplements (ODS), NIH, DHHS; the American Society for Nutritional Science; and the American Institute for Cancer Research and supported by the DCP, NCCAM, and ODS. Guest editors for the supplement publication were Harold E. Seifried, National Cancer Institute, NIH; Barbara Sorkin, NCCAM, NIH; and Rebecca Costello, ODS, NIH. 2 To whom correspondence should be addressed. E-mail: [email protected]. 3 Abbreviations used: GGT, -glutamyl transpeptidase; GSH, glutathione; NAC, N-acetyl cysteine; ROS, reactive oxygen species.