Cancer Chemotherapy and Antioxidants

Abstract

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) 3 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.