Nutrition and Cancer, 64(2), 315–322 Copyright C  2012, Taylor & Francis Group, LLC ISSN: 0163-5581 print / 1532-7914 online DOI: 10.1080/01635581.2012.649100 The Antioxidants Vitamins A and E and Selenium Do Not Reduce the Incidence of Asbestos-Induced Disease in a Mouse Model of Mesothelioma Cleo Robinson, Samantha Woo, Amy Walsh, Anna K. Nowak, and Richard A. Lake Tumour Immunology Group, National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia Epidemiological evidence indicates that supplementation with some dietary factors is associated with a lower incidence of cancer. An effective cancer prevention strategy for the millions of people worldwide who have been exposed to asbestos could have enormous benefit. We tested whether dietary supplementation of the antioxi- dants vitamin A, E, and selenium could alter the pattern of disease in the MexTAg transgenic mouse model, in which mice uniformly develop mesothelioma after asbestos exposure. We focused on an- tioxidants because one of the most widely accepted hypotheses for the mechanism by which asbestos fibers cause cancer proposes the involvement of reactive oxygen and nitrogen species. We compared the survival of MexTAg mice that had been inoculated with asbestos fed on diets supplemented with 250,000 IU/kg vitamin A (retinoic acid), or 1,000 mg/kg vitamin E (α-tocopherol acetate) or 3 mg/kg selenium, or both vitamin E and selenium concurrently and, addi- tionally, diets deficient in each antioxidant. We found that neither the time to develop symptoms of disease nor overall survival times were altered by any of the diets. We conclude that the data do not support the notion that dietary antioxidants will moderate the rate of mesothelioma in asbestos-exposed populations. INTRODUCTION Malignant mesothelioma is an aggressive tumor arising from the mesothelial cells lining the pleura, peritoneum, or peri- cardium. Epidemiological data and clinical evidence have con- firmed that asbestos is the principal carcinogen associated with mesothelioma (1). Although asbestos use has declined consider- ably in the Western world, the contamination of our environment from historic use means that the rate of development of mesothe- lioma is predicted to continue to rise until at least 2020. Many Submitted 13 April 2011; accepted in final form 6 December 2011. Address correspondence to Cleo Robinson, Tumour Immunology Group, National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, 4th Floor, G Block, QEII Medical Centre, Verdun St., Nedlands, Perth, WA, 6009, Australia. Phone: 61 8 9346 1581. Fax: 61 8 9346 2816. E-mail: cleo.robinson@uwa.edu.au developing countries still mine and manufacture asbestos, fre- quently without protective clothing or masks, suggesting that the worldwide rate of development of the disease will rise for the foreseeable future. Consequently, there is a large population of people with known asbestos exposure for which a cancer prevention strategy could be beneficial. Epidemiological studies have consistently indicated that di- etary factors, including vitamins and minerals, are associated with a lower cancer incidence (2,3). In some cases, experimen- tal models and randomized trials corroborate these data (4–10). Carcinogens frequently cause redox changes or induce re- active oxygen or nitrogen species that promote DNA damage and potentially result in oncogene activation, genomic instabil- ity, aberrant intracellular signaling, resistance to apoptosis, and cell proliferation (11,12). Asbestos fibers are known to gen- erate reactive oxygen and nitrogen species and cause oxidation and/or nitrosylation of proteins and DNA (13–15). Antioxidants are predicted to prevent or reduce the rate of some cancers by neutralization of free radicals and upregulation of detoxify- ing and antioxidant enzymes, thus reducing the mutagenic load (11,16,17) and would therefore be a logical choice for preven- tion of asbestos-induced mesothelioma. It has been previously shown that antioxidants lycopene, vitamins A and E, and the trace element selenium can reduce cancer incidence by as much as 60% in prostate and colon cancer models (18–20). Selenium is required for glutathione peroxidase activity, and it also reg- ulates COX-2, a key enzyme of prostaglandin synthesis (21). This is relevant to this study because mesotheliomas overex- press COX-2, and high levels of COX-2 correlate with a poor prognosis (22,23). Vitamin A was tested in a large cohort chemoprevention study of asbestos exposed workers and residents in the asbestos mining community at Wittenoom in Western Australia. Although people with chronically low plasma retinol levels had a higher incidence of mesothelioma and lung cancer (24), final analysis did not suggest that vitamin A supplementation per se was beneficial (25). Vitamin E injections inhibited the growth of a human 315 Downloaded by [University of Western Australia] at 17:54 30 April 2012